Heterocyclic compounds for the treatment of neurodegenerative diseases

Abstract

Provided herein are compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, which are used for inhibition of SARM1 proteins, as well as compositions comprising these compounds and methods of treatment by their administration.

Description

HETEROCYCLIC COMPOUNDS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES CROSS-REFERENCE OF RELATED APPLICATIONS

[0001] This application claims the benefit of priority to United States Provisional Patent Application No. 63 / 705,378, filed on October 9, 2024, and United States Provisional Patent Application No. 63 / 881,021, filed on September 12, 2025, the contents of each of which are incorporated by reference herein in their entirety.FIELD OF THE DISCLOSURE

[0002] Provided herein are compounds of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, which are used for inhibition of SARM1 (selective androgen receptor modulator 1) proteins, as well as compositions comprising these compounds and methods of treatment by their administration.BACKGROUND

[0003] Axon degeneration, a key, early component of most neurodegenerative diseases, is an active process regulated by the NADase SARM1. SARM1 forms a homooctamer and acts as a metabolic sensor. In healthy neurons under metabolic steady-state conditions. SARM1 is autoinhibited by NAD binding to an allosteric site on the ARM domain. Under conditions of cellular stress, NAD levels drop and nicotinamide mononucleotide (NMN) displaces NAD at this site to cause conformational rearrangement of the octamer, dimerization of the catalytic TIR domains and formation of six active sites. Upon activation, rapid hydrolysis of NAD by SARM1 leads to mitochondrial dysfunction, shutdown of ATP synthesis. Calcium influx, dismantling of the cytoskeleton and subsequent release of NfL, a biomarker of axon degeneration. SARM1 loss or inhibition has been shown to protect axons and reduce plasma NfL levels after nerve injury. Due to its central role in regulating axon degeneration, SARM1 is an emerging target in small molecule drug discovery for treating a variety of neurodegenerative diseases. See, for example, Gerdts et al., SARM1 activation triggers axon degeneration locally via NAD(+) destruction. Science 3482016, pp.453-457 and Krauss et al., (2020) Trends Pharmacol. Sci.41, 281, each of which is hereby incorporated by reference in its entirety.

[0004] Neurodegenerative diseases and injuries are devastating to both patients and caregivers. Costs associated with these diseases currently exceed several hundred billion dollars annually in the Unites States alone. Since the incidence of many of these diseases and disorders increases with age, their incidence is rapidly increasing as demographics change. There is asignificant unmet medical need for effective therapeutics to treat neurodegenerative diseases. The present disclosure addresses these needs.BRIEF DESCRIPTION OF THE DISCLOSURE

[0005] In one aspect, provided herein are compounds of Formula (I):(R1)Por a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,wherein:L is selected from -CH2C(O)-, -CF2C(O)-, -S(O)2-; -S(O)-, and -CR3R4-; Ring A is phenyl. 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl. or C5-10 cycloalkyl;Ring B is a 5- to 6-membered heteroaryl;X1is C;X2and X3are independently selected from CR2, S, N, and NR2, wherein X2and X3are not both N;each R1is independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, =0, C3-6 cycloalkyl, -O(C 1.4 alkyl), COOH, CN, CONH2, -C(=O)NH(C1-4alkyl), -C(=O)N(C1-4alkyl)2, -C(=O)O(C1-4alkyl), -C(O)RC, -S(O)2Re, 5- to 10 membered heteroaryl, 5- to 10- membered heterocyclyl, and -NRaRb, wherein the C3-6 cycloalkyl, 5- to 10 membered heteroaryl, and 5- to 10-membered heterocyclyl are optionally substituted with one to four substituents, wherein each substituent is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, and cyano;each R2is independently selected from halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, -ORf, -NRaRb. 5- to 10-membered heteroaryl, and phenyl; wherein the C1-6 alkyl, 5- to 10-membered heteroaryl and phenyl are optionally substituted with 1 to 4 substituents independently selected from halo, oxo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -CH2-Ci-6alkoxy, cyano, and 5- to 6-membered heterocycloalkyl;Raand Rbare independently selected fromH, C1-6 alkyl, C1-6 haloalkyl and C3-6 cycloalkyl;or Raand Rb, taken together with the nitrogen atom to which they are attached, form a 3- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl, wherein the 3- to 6-membered heterocyclyl and the 5- to 6-membered heteroaryl are optionally substituted with one to four substituents, wherein each substituent is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl. C3-6 cycloalkyl, C1-6 alkoxy, and cyano;Rcis a 3- to 6-membered heterocyclyl;Reis a C1-6 alkyl or a C3-6 cycloalkyl;Rfis selected from H, Ci-6alkyl, C1-6 haloalkyl and C3-6 cycloalkyl, wherein the C1-6 alkyl and C1-6 haloalkyl are optionally substituted by a phenyl or 5 to 10 membered heteroaryl;R3and R4are each independently selected from hydrogen, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, and C3-6 cycloalkyl, wherein the C1-6 alkyl is optionally substituted with C1-6 alkoxy; and wherein the C3-6 cycloalkyl is optionally substituted with one to four substituents, wherein each substituent is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, and cyano; orR3and R4taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl or a 3- to 6-membered heterocyclyl, wherein the C3-6 cycloalkyl and the 3-to 6-membered heterocyclyl is optionally substituted with one to four substituents, wherein each substituent is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, and cyano;p is 0. 1, 2, 3, or 4;q is 0. 1, 2, 3. or 4; andis a single or double bond.

[0006] In another aspect, also provided herein are pharmaceutical compositions comprising a compound described herein (e.g., a compound of Formula (I)), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable excipient.

[0007] In another aspect, also provided herein are methods of treating or preventing axonal degeneration, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound of Formula (I)), or astereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising the compound.

[0008] In yet another aspect, also provided herein are methods of treating a neurodegenerative disease, the method comprising administering to an subject in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound of Formula (I)), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising the compound.

[0009] In yet another aspect, also provided herein are methods of inhibiting SARM1, comprising contacting a biological sample with an effective amount of a compound described herein (e.g., a compound of Formula (I)), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising the compound.DETAILED DESCRIPTION OF THE DISCLOSURE DEFINITIONS

[0010] The term ‘'halogen” or ‘'halo” refers to F, Cl, Br or I. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl.

[0011] The term "alkyl" refers to a saturated linear or branched-chain monovalent hydrocarbon radical. In one example, the alkyl radical is one to eighteen carbon atoms (C1-18). In other examples, the alkyl radical is C1-12, C1-10, C1-8, C1-6. C1-5. Ci-4, or C1-3. Examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CHs)2), I -butyl (n-Bu, n-butyl, - CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, –CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, –CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, –C(CH3)3), 1-pentyl (n-pentyl, –CH2CH2CH2CH2CH3), 2-pentyl (–CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (–CH(CH3)CH(CH3)2), 3-methyl-l-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (–CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (–C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CHs)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3.3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, 1-heptyl and 1-octyl.

[0012] The terms “cyano” or “nitrile” refers to -C=N or -CN.

[0013] The term “alkoxy” refers to -O-alkyl.

[0014] The term ‘‘haloalkoxy” refers to -O-haloalkyl.

[0015] The term “aryl” refers to a carbocyclic aromatic group, whether or not fused to one or more groups, having the number of carbon atoms designated, or if no number is designated, up to 14 carbon atoms. One example includes aryl groups having 6-14 carbon atoms. Another example includes aryl groups having 6-10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl. naphthacenyl, 1, 2,3,4-tetrahydronaphthalenyl, IH-indenyl, 2,3-dihydro-lH-indenyl, and the like (see. e.g.. Lang's Handbook of Chemistry (Dean, J. A., ed.) 13thed. Table 7-2

[1985] ). A particular aryl is phenyl.

[0016] The term “cycloalkyl” refers to a saturated hydrocarbon ring group. Cycloalkyl encompasses mono-, bi-, tricyclic, spiro and bridged, saturated ring systems. In one example, the cycloalkyl group is 3 to 12 carbon atoms (C3-12). In other examples, cycloalkyl is C3-7, C3-8, C3-10, or C5-10. In other examples, the cycloalkyl group, as a monocycle, is C3-8, C3-6, or C5-6. In another example, the cycloalkyl group, as a bicycle, is C7-C12. In another example, the cycloalkyl group, as a spiro system, is C5-12. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Exemplary arrangements of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems. Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. Examples of spirocycloalkyl include, spiro[2.2]pentane. spiro [2.3] hexane, spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane.

[0017] The term “heterocyclyl” or “heterocycloalkyl” refers to a cycloalkyl containing from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and in one embodiment, at least one heteroatom is nitrogen.

[0018] The term “heteroaryl” refers to any mono-, bi-, or tricyclic aromatic ring system containing from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and in an example embodiment, at least one heteroatom is nitrogen. See, for example, Lang’s Handbook of Chemistry (Dean, J. A., ed.) 13thed. Table 7-2

[1985] , Included in the definition are any bicyclic groups where any of the above heteroaryl rings are fused to an aryl ring, wherein the aryl ring or the heteroaryl ring is joined to the remainder of the molecule. Also included in the definition are any bicyclic groups where any of the above heteroaryl rings are fused to a cycloalkyl or heterocycloalkyl ring, wherein the cycloalkyl or heterocycloalkyl ring or the heteroaryl ring is joined to the remainder of the molecule. In one embodiment, heteroaryl includes 5-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen,sulfur or oxygen. Example heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl. thiadiazolyl. oxadiazolyl. tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[l,5-b]pyridazinyl, imidazol[l,2-a]pyrimidinyl and purinyl, as well as benzo-fused derivatives, for example benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl, indazolyl and indolyl.

[0019] In particular embodiments, a heteroaryl group is attached at a carbon atom of the heteroaryl group. By way of example, carbon bonded heterocyclyl groups include bonding arrangements at position 2, 3, 4, 5, or 6 of a pyridine ring, position 3, 4, 5, or 6 of a pyridazine ring, position 2, 4, 5, or 6 of a pyrimidine ring, position 2, 3, 5, or 6 of a pyrazine ring, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, position 2, 4, or 5 of an oxazole, imidazole or thiazole ring, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of an aziridine ring, position 2, 3, or 4 of an azetidine ring, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline ring or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline ring.

[0020] In certain embodiments, the heteroaryl group is N-attached. By way of example, nitrogen bonded heterocyclyl or heteroaryl groups include bonding arrangements at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3 -imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, IH-indazole, position 2 of an isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or |3-carboline.

[0021] " Fused" refers to any ring structure described herein that shares one or more atoms (e g., carbon or nitrogen atoms) with an existing ring structure in the compounds described herein.

[0022] The term “haloalkyl” refers to an alkyl chain in which one or more hydrogen has been replaced by a halogen. Examples of haloalkyls are trifluoromethyl, difluoromethyl, and fluoromethyl.

[0023] The compounds provided herein include compounds of Formula (I), or any other formula set forth herein, and the compounds listed in the Tables herein, including stereoisomers (including atropisomers), geometric isomers, tautomers, isotopes, and salts (e.g., pharmaceutically acceptable salts) thereof. In some embodiments, provided herein are pharmaceutically acceptable salts of the compounds according to Formula (I) or any other formula as described herein, or the compounds listed in the Tables herein. In a further particularembodiment, compounds provided herein are compounds of Formula (I) or any other formula as described herein, or the compounds listed in the Tables herein, as free bases or acids.

[0024] The term “optionally substituted” unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4, or 5 or more, or any range derivable therein) of the substituents listed for that group in which said substituents may be the same or different. In an embodiment, an optionally substituted group has 1 substituent. In another embodiment an optionally substituted group has 2 substituents. In another embodiment an optionally substituted group has 3 substituents. In another embodiment an optionally substituted group has 4 substituents. In another embodiment an optionally substituted group has 5 substituents.

[0025] As used herein, the term “unsubstituted” may mean that the specified group bears no substituents beyond the moiety recited (e.g., where valency is satisfied by hydrogen).

[0026] The term "substituent" denotes an atom or a group of atoms replacing a hydrogen atom on the parent molecule. The term "substituted" denotes that a specified group bears one or more substituents. Where any group may carry multiple substituents and a variety of possible substituents is provided, the substituents are independently selected and need not to be the same. The term "unsubstituted" means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents, independently chosen from the group of possible substituents. When indicating the number of substituents, the term "one or more" means from one substituent to the highest possible number of substitution, i.e., replacement of one hydrogen up to replacement of all hydrogens by substituents. For instance, “one or more” substituents includes 1, 2, 3, 4, or 5 substituents. Examples of substituents include, but are not limited to, hydroxy, alkyl, alkoxy, halo, haloalkyl, oxo, cyano, nitro, amino, monoalkylamino, dialkylamino, 3-10-membered cycloalkyl. 3-10-membered heterocycloalky 1, 5-10-membered ary l, and 5-10 membered heteroaryl.

[0027] In the description herein, if there is a discrepancy between a depicted structure and a name given to that structure, then the depicted structure controls.

[0028] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds, but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers, or mixtures thereof, and includes “enantiomers” and “diastereomers.” “Enantiomers” refers to two stereoisomers whose structures are non-superimposable mirror images of one another.“Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

[0029] Where enantiomeric and / or diastereomeric forms exist of a given structure, flat bonds indicate that all stereoisomeric forms of the depicted structure may be present. Where enantiomeric and / or diastereomeric forms exist of a given structure, wedged or hashed bonds indicate the composition is made up of at least 90%, by weight, of a single stereoisomer with known stereochemistry. Where enantiomeric and / or diastereomeric forms exist of a given structure, flat bonds and the presence of a symbol indicate that the composition is made up of at least 90%, by weight, of a single stereoisomer with unknown stereochemistry at thestereocenter indicated by “*”. For example, indicates that the

[0030] As used herein a wavy line “” that intersects a bond in a chemical structure indicate the point of attachment of the atom to which the wavy bond is connected in the chemical structure to the remainder of a molecule, or to the remainder of a fragment of a molecule.

[0031] As used herein, represents a single or double bond in a chemical structure.

[0032] In certain embodiments, divalent groups are described generically without specific bonding configurations. It is understood that the generic description is meant to include both bonding configurations, unless specified otherwise. For example, in the group R’-R2-R3, if the group R2is described as -CH2C(O)-, then it is understood that this group can be bonded both as R1-CH2C(O)-R3. and as R1-C(O)CH2-R3. unless specified otherwise.

[0033] The term “pharmaceutically acceptable” refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, such as, for example, a human, as appropriate.

[0034] Compounds described herein may be in the form of a salt, such as a pharmaceutically acceptable salt. “Pharmaceutically acceptable salts” include both acid and base addition salts. “Pharmaceutically acceptable acid addition salt” refers to those salts whichretain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

[0035] The term ‘"pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particular base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropyl amine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particular organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

[0036] In some embodiments, a salt is selected from a hydrochloride, hydrobromide, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate, p-toluenesulfonate, bisulfate, benzenesulfonate, ethanesulfonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, formate, glycolate, palmitate. L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate. stearate, furoate (e.g.. 2-furoate or 3-furoate), napadisylate (naphthalene-1,5-disulfonate or naphthalene- 1 -(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonate or ethane- 1 -(sulfonic acid)-2-sulfonate), isothionate (2 -hydroxyethylsulfonate), 2-mesitylenesulfonate, 2-naphthalenesulfonate, 2.5-dichlorobenzenesulfonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipate, esylate, malonate, mesitylate (2-mesitylenesulfonate), napsylate (2-naphthalenesulfonate), camsylate (camphor- 10-sulfonate,for example (lS)-(+)-10-camphorsulfonic acid salt), glutamate, glutarate, hippurate (2-(benzoylamino)acetate), orotate, xylate (p-xylene-2-sulfonate), and pamoic (2,2'-dihydroxy-1, 1 '-dinaphthylmethane-3,3'-dicarboxylate).

[0037] A “sterile” formulation is aseptic or free from all living microorganisms and their spores.

[0038] The term “stereoisomers” refer to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, conformers and the like.

[0039] The term “chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.

[0040] The term “diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

[0041] The term “enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0042] Stereochemical definitions and conventions used herein generally follow S. P. Parker. Ed.. McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L. or R and S. are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0043] 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. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0044] “Atropisomers” are stereoisomers arising because of hindered rotation around a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers.

[0045] The present disclosure also encompass isotopically-labeled compounds of the compounds described herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds described herein, and their uses. Exemplary isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,32P,33P,35S,18F,36Cl,123I, and125I. Certain isotopically-labeled compounds described herein (e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (3H) and carbon-14 (14C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i. e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as15O,13N,11C and18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds described herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, can generally be prepared by following procedures analogous to those disclosed in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0046] Compounds described herein may contain one or more asymmetric carbon atoms. Accordingly, the compounds may exist as diastereomers, enantiomers or mixtures thereof. The syntheses of the compounds may employ racemates, diastereomers or enantiomers as starting materials or as intermediates. Mixtures of particular diastereomeric compounds may be separated, or enriched in one or more particular diastereomers, bychromatographic or crystallization methods. Similarly, enantiomeric mixtures may be separated, or enantiomerically enriched, using the same techniques or others known in the art. Each of the asymmetric carbon or nitrogen atoms may be in the R or S configuration and both of these configurations are within the scope of the present disclosure.

[0047] In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds described herein. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined. Unless otherwise specified, if solid wedges or dashed lines are used, relative stereochemistry is intended.

[0048] A “subject,’7“individual,” or “patient” is a vertebrate. In certain embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, farm animals (such as cows), sport animals, pets (such as guinea pigs, cats, dogs, rabbits and horses), primates, mice and rats. In certain embodiments, a mammal is a human. In embodiments comprising administration of a compound of to a patient, the patient is typically in need thereof.

[0049] The terms “inhibiting” and “reducing.” or any variation of these terms, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%. 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%. or more, or any range derivable therein, reduction of activity compared to normal.

[0050] A “therapeutically effective amount" means an amount of a compound described herein, such as a compound of Formula (I), or any other Formula specified herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, sufficient to produce a desired therapeutic or prophylactic outcome of a disease, condition or disorder described herein, including, for example, treating or preventing the disease, condition or disorder; attenuating, ameliorating or eliminating one or more symptoms of the disease, condition, or disorder; and / or preventing or delaying the onset of one or more symptoms of the disease, condition or disorder. “Treatment” (and variations such as “treat” or “treating”) refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated. Desirable effects of treatment include alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, stabilized (i.e., not w orsening) state of disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, prolonging survival as compared to expected survival if not receiving treatment and remission or improved prognosis. In some embodiments, compoundsdescribed herein are used to delay development of a disease or disorder or to slow the progression of a disease or disorder. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder, (for example, through a genetic mutation).

[0051] A "therapeutic effect," as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0052] The terms "antagonist" and "inhibitor" are used interchangeably, and they refer to a compound having the ability to inhibit a biological function of a target protein, whether by inhibiting the activity or expression of the protein, such as SARM1. Accordingly,the terms "antagonist" and "inhibitors" are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition.

[0053] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds described herein, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as2H,3H,nC,13C,14C,13N,15N,150,170,18O,32P,33P,35S,18F,36Cl,123I, and125I, respectively. Isotopically-labeled compounds (e g., those labeled with3H and14C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in compounds described herein, one or more carbon atoms are replaced by13C- or14C-enriched carbon. Positron emitting isotopes such as15O,13N,11C, and18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0054] It is specifically contemplated that any limitation discussed with respect to one embodiment of the present disclosure may apply to any other embodiment. Furthermore, any compound or composition described herein may be used in any methods described herein, and any method described herein may be used to produce or to utilize any compound or composition described herein.

[0055] The use of the term “or” is used to mean “and / or” unless explicitly indicated to refer to alternatives only or the alternative are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and / or.”

[0056] Throughout this application, the term “about” is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value.

[0057] As used herein, “a” or “an” means one or more, unless clearly indicated otherwise. As used herein, “another” means at least a second or more.

[0058] Headings used herein are intended only for organizational purposes.SARM1 INHIBITORS

[0059] In one aspect, provided herein are compounds which are capable of selectively binding to and / or modulating a SARM1 protein.

[0060] In one aspect, provided herein are compounds of Formula (I):(R1)Por a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,wherein:L is selected from -CH2C(O)-, -CF2C(O)-. -S(O)2-; -S(O)-, and -CR3R4-;Ring A is phenyl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl, or C5-10 cycloalkyl;Ring B is a 5- to 6-membered heteroaryl;X1is C;X2and X3are independently selected from CR2. S, N, and NR2, wherein X2and X3are not both N;each R1is independently selected from halogen, Ci-6 alkyl, Ci-6 haloalkyl, =0, C3-6 cycloalkyl, -0(C 1-4 alkyl), COOH, CN, CONH2, -C(=0)NH(Ci-4alkyl), -C(=O)N(Ci-4alkyl)2, -C(=0)0(Ci-4alkyl), -C(O)RC, -S(0)2Re, 5- to 10 membered heteroaryl. 5- to 10-membered heterocyclyl. and -NRaRb, wherein the C3-6 cycloalkyl. 5- to 10 membered heteroaryl, and 5- to 10-membered heterocyclyl are optionally substituted with one to four substituents, wherein each substituent is independently selected from halo, C1-6 alky l, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, and cyano;each R2is independently selected from halogen, cyano, C1-6alkyl, C1-6haloalkyl, -ORf, -NRaRb, 5- to 10-membered heteroaryl, and phenyl; wherein the Ci-6alkyl, 5- to 10-membered heteroar l and phenyl are optionally substituted with 1 to 4 substituents independently selected from halo, oxo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -CH2-C1-6alkoxy. cyano, and 5- to 6-membered heteorcycloalkyl;Raand Rbare independently selected from H, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloal kyl;or Raand Rb, taken together with the nitrogen atom to which they are attached, form a 3- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl, wherein the 3- to 6-membered heterocyclyl and the 5- to 6-membered heteroaryl are optionally substituted with one to four substituents, wherein each substituent is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, and cyano;Rcis a 3- to 6-membered heterocyclyl;Reis a C1-6 alkyl or a C3-6 cycloalkyl;Rfis selected from H, C1-6 alkyl, C 1-6 haloalkyl and C3-6 cycloalkyl, wherein the C1-6 alkyl and C1-6 haloalkyl are optionally substituted by a phenyl or 5- to 10-membered heteroaryl:R3and R4are independently selected from hydrogen, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, and C3-6 cycloalkyl, wherein the C1-6 alkyl is optionally substituted with C1-6 alkoxy, and wherein the C3-6 cycloalkyl is optionally substituted with one to four substituents, wherein each substituent is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, and cyano; orR3and R4taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl or a 3- to 6-membered heterocyclyl, wherein the C3-6 cycloalkyl and the 3- to 6-membered heterocyclyl are optionally substituted with one to four substituents, wherein eachsubstituent is independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, and cyano;p is 0, 1, 2, 3, or 4;q is 0, 1, 2, 3, or 4; andis a single or double bond.

[0061] According to some embodiments of the compound of Formula (I), or a or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is selected from the group consisting of -CH2C(O)-, -CF2C(O)-, -S(O)2-, and -CR3R4-. According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is selected from the group consisting of -S(O)2- and -CR3R4-. According to some embodiments of the compound of Formula (1), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is -CR3R4-.

[0062] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is -CR3R4-. and R3and R4are independently selected from the group consisting of hydrogen, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, and C3-6 cycloalkyl, wherein the C1-6 alkyl is optionally substituted with C1-6 alkoxy, and wherein the C3-6 cycloalkyl is optionally substituted with one to four substituents, wherein each substituent is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, and cyano. In some embodiments, the cycloalkyl is substituted with 1 to 4 substituents independently selected from the group consisting of C1-4 alkyd, C1-4 haloalkyl, and halogen. In one such embodiment, the cycloalkyl is substituted with 1 to 4 substituents independently selected from the group consisting of F, methyl, CF3, CH2F, CHF2, and CH2CHF2. In some embodiments, the cycloalkyl is substituted with 1 to 4 halo substituents, such as F. In some embodiments, the alkyl is substituted with C1-3 alkoxy. In some embodiments, the alkyd is C1-3 alkyl substituted with -OCH3. According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, L is -CR3R4-. and R3and R4are independently selected from the group consisting of hydrogen, C1-3 alkyl, C1-3 alkyl substituted with C1-3 alkoxy, C1-3 haloalkyl, C1-3 hydroxyalkyl, and C3-6 cycloalkyl. According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R3and R4are independently selected from the group consisting of hydrogen, methyl, ethyl. -CH2OCH3, -CFs, CF2H, CFH2, -CH2OH, and cyclopropyl. According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R3and R4are independently selected from the group consisting of hydrogen and methyl. According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, one of R3and R4is H, and the other is selected from the group consisting of hydrogen, C1-3 alkyl. C1-3 alkyl substituted with C1-3 alkoxy, C1-3 haloalkyl. C1-3 hydroxyalkyl, and C3-6 cycloalkyl. According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, one of R3and R4is H, and the other is C1-6 alkyl. According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, one of R3and R4is H, and the other is selected from the group consisting of hydrogen, methyl, ethyl, -CH2OCH3, -CFs, CF2H, CFH2, -CH2OH, and cyclopropyl. According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, one of R3and R4is H, and the other is methyl. According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R3and R4are both methyl.

[0063] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R3and R4, taken together with the carbon atom to which they are attached, form a C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with one to four substituents, wherein each substituent is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl. C1-6 alkoxy, and cyano. In some embodiments, the cycloalkyl is substituted with 1 to 4 substituents independently selected from the group consisting of Ci-4 alkyl, Ci-4 haloalkyl, and halogen. In one such embodiment, the cycloalkyl is substituted with 1 to 4 substituents independently selected from the group consisting of F, methyl, CF3, CH2F, CHF2, and CH2CHF2. In some embodiments, the cycloalkyl is substituted with 1 to 4 halo substituents, such as F. In some embodiments, R3and R4, taken together with the carbon atom to which they are attached, form a cyclobutyl. In some embodiments, R3and R4, taken together with the carbon atom to which they are attached, form a cyclobutyl substituted with one or two F. In some embodiments, R3and R4, taken together with the carbon atom to which they are attached, form a 3- to 6-membered heterocyclyl. In some embodiments, R3and R4, taken together with the carbon atom to which they are attached, form a 4-membered heterocyclyl. In someembodiments, R3and R4, taken together with the carbon atom to which they are attached, form oxetanyl.

[0064] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:.0or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, Ring B, X1, X2, X3, R1, R2, p, and q are as defined for Formula (I).

[0065] According to some embodiments of the compound of Formula (I), the compound has Formula (I- 1):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, Ring B, X1, X2, X3, R1, R2, p, and q are as defined for Formula (I).

[0066] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, q is 1, 2, or 3.

[0067] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, q is 1, and R2is 5- to 10-membered heteroaryl or phenyl, wherein the 5- to 10-membered heteroaryl and phenyl are optionally substituted with 1 to 4 substituents independently selected from halo, oxo, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -CH2-C1-6alkoxy. cyano, and 5- to 6-membered heterocycloalkyl.

[0068] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, q is 2 or 3, and one R2is 5- to 10-membered heteroaryl or phenyl, wherein the 5- to 10-membered heteroaryl and phenyl are optionally substituted with 1 to 4 substituents independently selected from halo. C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl. C1-6 alkoxy, and cyano.

[0069] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, q is 2 or 3, one R2is 5- to 10-membered heteroaryl or phenyl, and at least one R2is halogen or methyl, wherein the 5- to 10-membered heteroaryl and phenyl are optionally substituted with 1 to 4 substituents independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, and cyano.

[0070] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R2is phenyl, wherein the phenyl is optionally substituted with I to 4 substituents independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, and cyano.

[0071] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R2is -NRaRb, and Raand Rbare independently selected from H, C1-6 alkyl, C1-6 haloalkyl and C3-6 cycloalkyl, or Raand Rb, taken together with the nitrogen atom to which they are attached, form a 3- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl, wherein the 3- to 6-membered heterocyclyl or the 5- to 6-membered heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently selected from halo. C1-6 alkyl. C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, and cyano. In some embodiments, the heterocyclyl or the heteroaryl is substituted with 1 to 4 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, and halogen. In one such embodiment, the heterocyclyl or the heteroaryl is substituted with 1 to 4 substituents independently selected from the groupconsisting of F, methyl, CF3, CH2F, CHF2, and CH2CHF2. In some embodiments, the heteroaryl, or heterocyclyl is substituted with 1 to 4 halo substituents, such as F.

[0072] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R2is ORf, wherein Rfis selected from H, C1-6 alkyl, C1-6 haloalkyl and C3-6 cycloalkyl, wherein the C1-6 alkyl and C1-6 haloalkyl are optionally substituted by a phenyl or 5- to 10-membered heteroaryl.

[0073] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,R2is (Rd)m, wherein m is 0, 1, 2, 3, or 4 and each Rdis independently selected from halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, and C1-6 alkoxy. According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, each Rdis independently selected from the group consisting of halogen, cyano, and C1-6 alkoxy.

[0074] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,

[0075] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R2is 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is optionallysubstituted with 1 to 4 substituents independently selected from halo, oxo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -CH2-C1-6alkoxy, cyano, and 5- to 6-membered heterocycloalkyl.

[0076] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,R2is selected from the group consisting of:wherein m is 0, 1, 2, 3, or 4; and each Rdis independently selected from halogen, cyano, C1-6 alkyl, C1-6 haloalkyl. C3-6 cycloalkyl, C1-6alkoxy, C1-6 haloalkoxy, -CH2-C1-6alkoxy, and 5- to 6-membered heterocycloalkyl. According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, each Rdis independently selected from halogen, cyano, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -CH2-C1-6alkoxy, and 5-membered heterocycloalkyl. According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, each Rdis independently selected from halogen, cyano, methyl, isopropyl, -CHF2, -CF3, cyclopropyl, methoxy, -OCHF2, -CH2-OCH3, and tetrahydrofuranyl.

[0077] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,, or

[0078] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, q is 1, 2, or 3, and Ring B and Retaken together, is selected from the group consisting of:

[0079] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0080] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,halogen, and each Rdis independently selected from halogen, cyano, Ci-6 alkyl, Ci-6 haloalkyl, Cs-6 cycloalkyl, and C1-6alkoxy.

[0081] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,m is 0, 1, 2, 3. or 4; R2is methyl, cyano, or halogen, and each Rdis independently selected from halogen, cyano, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, and C1-6 alkoxy.

[0082] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,

[0083] In some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,

[0084] In some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,

[0085] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,, wherein m is 0, 1, 2, 3, or 4 and each Rdis independently selected from halogen, cyano, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -CH2-C1-6alkoxy, and 5- to 6-membered heterocycloalkyl. According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, each Rdis independently selected from halogen, cyano, methyl, isopropyl, -CHF2, -CF3, cyclopropyl, methoxy, -OCHF2, -CH2OCH3. and tetrahydrofuranyl.

[0086] In some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, ring B isselected from the group consisting of:CN

[0087] In some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Ring B is, wherein m is 0, 1, 2, 3, or 4, and each Rdis independently selected from halogen, cyano, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, and C1-6alkoxy. According to some embodiments of the compound of Formula (I), or a stereoisomeror tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, m is 1 and Rdis halogen.

[0088] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,

[0089] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,

[0090] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,

[0091] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,selected from the group consisting of:to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Rdis methyl.

[0092] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,is selected from the group consisting of:

[0093] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, R1, R2, and p are as defined for Formula (I).

[0094] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, R1, R2, and p are as defined for Formula (I).

[0095] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, R1, R2, and p are as defined for Formula (I).

[0096] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, R1, R2, and p are as defined for Formula (I).

[0097] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, R1, R2, and p are as defined for Formula (I).

[0098] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, R1, R2, and p are as defined for Formula (I).

[0099] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:, ora stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, R1, R2, and p are as defined for Formula (I).

[0100] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:R2(R1)p(R1)por a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, R1, R2, and p are as defined for Formula (I).

[0101] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, R1, R2, and p are as defined for Formula (I).

[0102] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:R2a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, R1, R2, and p are as defined for Formula (I).

[0103] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, R1, R2, and p are as defined for Formula (I).

[0104] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, R1, R2, and p are as defined for Formula (I).

[0105] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, R1, R2, and p are as defined for Formula (I).

[0106] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A, R1, R2, and p are as defined for Formula (I).

[0107] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, p is 1, 2, or 3.

[0108] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, each R1is independently selected from Ci-6 alkyl. Ci-6 haloalkyl. C3-6 cycloalkyl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl, wherein the cycloalkyl, heteroaryl, or heterocyclyl is substituted with 1 to 4 substituents independently selected from the group consisting of halo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, and cyano. In some embodiments, the cycloalkyl, heteroaryl, or heterocyclyl is substituted with 1 to 4 substituents independently selected from the group consisting of Ci-4 alkyl, Ci-4 haloalkyl, and halogen. In one such embodiment, the cycloalkyl, heteroaryl, or heterocyclyl is substituted with 1 to 4 substituents independently selected from the group consisting of F, methyl, CF3, CH2F, CHF2,and CH2CHF2. In some embodiments, the cycloalkyl, heteroaryl, or heterocyclyl is substituted with 1 to 4 halo substituents, such as F.

[0109] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, each R1is independently selected from the group consisting of halogen, C1-6 alkyl, C(O)RC, and -S(O)2Re. According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, each R1is independently selected from the group consisting of halogen, C1-3 alkyl, C(O)RC, and -S(O)2Re. According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, each R1is independently selected from the group consisting of halogen and C1-3 alkyl. According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, each R1is independently selected from the group consisting of halogen and methyl. According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, each R1is independently selected from the group consisting of halogen and -S(O)2Re, wherein Reis a C1-6 alkyl. According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, each R1is independently selected from the group consisting of halogen and -S(O)2CH3.

[0110] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, R1is -NRaRb, and Raand Rbare independently selected from H, C1-6 alkyl, C1-6 haloalkyl and C3-6 cycloalkyl, or Raand Rb, taken together with the nitrogen atom to which they are attached, form a 3- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl, wherein the 3- to 6-membered heterocyclyl or the 5- to 6-membered heteroaryl is optionally substituted with one to four substituents, wherein each substituent is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, and cyano. In some embodiments, the heterocyclyl or the heteroaryl is substituted with 1 to 4 substituents independently selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, and halogen. In one such embodiment, the heterocyclyl or the heteroaryl is substituted with 1 to 4 substituents independently selected from the group consisting of F, methyl, CF3, CH2F, CHF2, and CH2CHF2. In some embodiments, the heteroaryl, or heterocyclyl is substituted with 1 to 4 halo substituents, such as F.

[0111] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Ring A is selected from the group consisting of phenyl and 5- to 10-membered heteroaryl. According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Ring A is phenyl. According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Ring A is 5-to 6-membered heteroaryl.

[0112] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Ring A and (R¹)p, taken together, is selected from the group consisting of:compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, each R1is independently selected from the group consisting of halogen and methyl.

[0113] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,Ring A and (R1)p, taken together,According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, each R1is independently selected from the group consisting of halogen and methyl.

[0114] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.Ring A and (R1)p, taken together,is According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, each R1is independently selected from the group consisting of halogen and methyl.

[0115] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Ring A and (R1)p, taken together, is selected from the group consisting of:embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, each R1is independently selected from the group consisting of halogen and methyl.

[0116] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,Ring A and (R1)p, taken together, isAccording to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, each R1is independently selected from the group consisting of halogen and methyl.

[0117] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, Ring A and (R’)p. taken together, is selected from the group consisting of:

[0118] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,Ring A and (R1)p, taken together, iss

[0119] According to some embodiments of the compound of Formula (1), the compound has Formula (II):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring B, X1, X2, X3, L, R1, R2, p. and q are as defined for Formula (I).

[0120] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:, andor a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L, R1, R2and p are as defined for Formula (I). In some such embodiments, L is -CR3R4-.

[0121] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1, R2, and p are as defined for Formula (I).

[0122] According to some embodiments of the compound of Formula (I), the compound has Formula (III):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring B, X1, X2, X3, L, R1, R2, and q are as defined for Formula (I).

[0123] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L, R1, and R2are as defined for Formula (I). In one such embodiment, L is -CR3R4-.

[0124] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:. andor a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1and R2are as defined for Formula (I).

[0125] According to some embodiments of the compound of Formula (I), the compound has Formula (IIIa-1):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1and R2are as defined for Formula (I).

[0126] According to some embodiments of the compound of Formula (I), the compound has Formula (IV):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring B, X1, X2, X3, L, R1, R2, and q are as defined for Formula (I).

[0127] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L, R1, and R2are as defined for Formula (I). In some such embodiments, L is -CR3R4-.

[0128] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1and R2are as defined for Formula (I).

[0129] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring B, X1, X2, X3, L. R1. R2, p. and q are as defined for Formula (I).

[0130] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L, R1, R2, and p are as defined for Formula (I).

[0131] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1, R2, and p are as defined for Formula (I).

[0132] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring B, X1, X2, X3, L, R1, R2, and q are as defined for Formula (I).

[0133] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L, R1, and R2are as defined for Formula (I).

[0134] According to some embodiments of the compound of Formula (I), the compound has a formula selected from the group consisting of:R1R1. R1E For a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1and R2are as defined for Formula (I).

[0135] According to some embodiments of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the compound is selected from the group consisting of the compounds in Table 1, shown below, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.Table 1. Exemplary compounds of the present disclosure. Salts of such compounds are also contemplated. See the Examples section for preparation of such compounds. Compounds thatdo not have preparation details explicitly described in the Examples may be prepared by modifying the preparation details for other compounds provided herein, using methods generally known in the art.Example / Compound Number Structure Name£2 ).3-chloro-N-(1-(3,5-dichlorophenyl)-1H-pyrazol-3-yl)-2-methylbenzenesulfonamide(S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-3-methyl-[2,2'-bipyridin]-6-amine(R)- or (S)- 2-(6-(((S)-1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)amino)pyridin-3-yl)propanenitrileCz o CN (7?)- or (5)- 2-(5-((GS’)-l-(4-chloro-l,5- ZI zdimethy 1- 177-py razol-3 - ( o o.4a / 4b yl)ethyl)amino)pyridin-2- — N 3^ JINyl)propanenitrilefz^* '^1 / XI(S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-5-methylpyridin-2-amine(S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-6-(1H-imidazol-1-yl)-5-methylpyridin-2-amine / N-N(S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-5-methyl-6-(1H-pyrazol-1-yl)pyridin-2-amine / N-N ^5 / C(S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-5-methyl-6-(3-methyl-1H-pyrazol-1-yl)pyridin-2-amine(S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-5-methyl-6-(4-methyl-1H-imidazol-1-yl)pyridin-2-amineamine(S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-5-methyl-6-(4-methyl-1H-pyrazol-1-yl)pyridin-2-amineCl(S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-1-(4-fluorophenyl)-1H-pyrazol-3-aminez\zz\ \ o o Q o....Cl(S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-amine\^^ f fzz(S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-1-(5-chloropyrimidin-2-yl)-1H-pyrazol-3-amine(R)- or (S)- 2-(6-(((S)-1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)amino)pyridin-3-yl)-2-cyclopropylacetonitrile / (S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine(S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-3-methyl-[2,3'-bipyridin]-6-amine(S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-3-methyl-[2,4'-bipyridin]-6-amine(S)-4-(3-((1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)amino)-1H-pyrazol-1-yl)benzonitrileON(S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-1-(pyrimidin-2-yl)-1H-pyrazol-3-amine(S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-5-methyl-6-(1-methyl-1H-imidazol-4-yl)pyridin-2-amine(S)-4-(6-((1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)amino)-3-methylpyridin-2-yl)-1-methyl-1H-pyrazole-5-carbonitrile(S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-5-methyl-6-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-amineCl(S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-1-(2,4-difluorophenyl)-1H-pyrazol-3-amine(S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-5-methyl-6-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-2-amine(S)-5-chloro-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)pyridin-2-amine(S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-5-(trifluoromethyl)pyridin-2-amine / (S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-5-methoxypyridin-2-amine / z^Xx <Z*(S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-5-methyl-6-(4-methyl-1H-1,2,3-triazol-1-yl)pyridin-2-amine(S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-5-methyl-6-(pyrazin-2-yl)pyridin-2-amine(S)-5-chloro-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)thiazol-2-amine(S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-6-methylpyridazin-3-amine / (S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-4-phenylthiazol-2-amine / (S)-1-(6-((1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)amino)-3-methylpyridin-2-yl)-1H-imidazole-5-carbonitrile(5)-5-chloro-JV-( 1 -(4-chloro- 1,5- dimethyl-1H-pyrazol-3-yl)ethyl)-3-fluoropyridin-2-amine(5)-5-chloro-JV-( 1 -(4-chloro- 1,5- dimethyl - 1 H-pyrazol -3 -yl)ethyl)-6-( 1 - A A methyl- l / / -pyrazol-4-yl)pyridin-2- IZ IZ amine(S)-N-( 1 -(4-chloro- 1,5 -dimethyl- 177- ci= / o oA __yN:=\ pyrazol-3-yl)ethyl)- 1-(5- — V N- INI H 00chloropyrimidin-2-yl)-4-fluoro-177- / 1 1 pyrazol-3-amineFZ\ ' (, S)-5-chloro-JV-( 1 -(4-chloro- 1,5- o dimethyl- l / / -pyrazol-3 -yl)ethyl)-6-(3 - methylisoxazol-5-yl)pyridin-2 -amine [Tl^ (S)-5 -chloro-N-( 1 -(4-chloro- 1,5- dimethyl-lH-pyrazol-3-yl)ethyl)-6-( 1 - methyl- lH-pyrazol-4-yl)pyridin-2- amine(, S')-A'-( 1 -(4-chloro- 1,5 -dimethyl- 1 / 7-Cl\ L x = U(” x G XT A pyrazol-3-yl)ethyl)-5-methyl-6-( 1,2,4- ' N-O - LN HL J triazin-6-yl)pyridin-2 -amine(S)-4-(6-(( 1 -(4-chloro- 1,5 -dimethyl- 1 H-pyrazol-3 -yl)ethyl)amino) -3 - — N'NX|FNmethylpyridin-2-yl)- 1 -methyl- 1H- PApyrazole-5-carbonitrile(5)-6-((l -(4-chloro- 1, 5-dimethyl-l H- pyrazol-3 -yl)cthyl)amino)-2-( 1 - methyl- 177-py razol -3 -yl)nicotinonitrile ^. N (5)-6-(( 1 -(4-chloro- l,5-dimethyl-177-CL1jfjL pyrazol-3 -yl)ethyl)amino)-2-( 1 - methyl- l / / -pyrazol-4-yl)nicotinonitrilc p N-FN rNr L=Nr / (. S')-6-((l -(4-chloro- 1, 5-dimcthyl-l / / -CIpyrazol-3-yl)ethyl)amino)-2-(3- L!jfl-_Z^>7zXXNX^’NX^N'hk _ methyl- 177-py razol - 1 -yl)nicotinonitrile 'N— E NHL-~ / / (S)- 1 -(5 -chloropyrimidin-2-yl)-N-( 1 - (2,3-difluorophenyl)ethyl)-lH- pyrazol-3-amine(S)-N-( 1 -(4-chloro- 1,5-dimethyl- 1H- Cl? L T!- TT- CLM'A N- / pyrazol-3-yl)ethyl)-l-(5-chloropyridin- — a n H 2-yl)-l / f-pyrazol-3-amine VN / r<\N=\ (S)-JV-(1 -(4-chloro- 1.5-dimethyl- 177- Cl 1 L, N-<\ / koNN-Y 1 pyrazol-3-yl)ethyl)-l-(furo[3,2- — c n H c / |pyrimidin-2-yl)- l / 7-pyrazol-3-amine N'N / IZr<\N=\ (S)-N-( 1 -(4-chloro- 1,5-dimethyl- 177- C! = f, N— A— OMeoN_7 pyrazol -3 -yl)ethy 1)- 1 -(5- - Il H Z Q z= methoxypyrimidin-2-yl)-177-pyrazol-3- N'N\ / amine / i<ss\N=\ (5')-. V-( 1 -(4-chloro- 1,5-dimethyl- 177- ci i JL, N-(\ X. pyrazol-3-yl)ethyl)-1-(5,7- — ( / ll H dihydrofuro[3,4-d]pyrimidin-2-yl)-1H- VN / o pyrazol-3-aminertf*\,N=\ (S)-. N'-( 1 -(4-chloro- 1,5-dimethyl- 177- Cl? JL N-(\ / )—5N- / pyrazol-3-yl)ethyl)-1-(5-methylpyrimidin-2-yl)-1H-pyrazol-3- N'Namine / 0ZI r^sAN=\ (, S')-. V-( 1 -(4-chloro- 1,5-dimethyl- 177- Cl 1 JL, N“(\N-f pyrazol-3-yl)ethyl)-1-(4,5- — (' 11 H \ dimethylpyrimidin-2-yl)-177-pyrazol-3- VNamine / (S)-. N'-( 1 -(4-chloro- 1,5-dimethyl- 177- Cl -: 1 N— 4 / N=\pyrazol-3-yl)ethyl)-1-(6,7-dihydro-5H- — f ll H cyclopenta[d]pyrimidin-2-yl)-1H- N'Npyrazol-3-amine / (< S)-5-chloro-7V-(l-(4-chloro-l,5- dimethyl-177-pyrazol-3-yl8)ethyl)-6-(5- methy li soxazol -3 -y l)py ri din-2-amine (< S)-5-chloro-JV-(l-(4-chloro-l,5-Cli JTY dimethyl-177-pyrazol-3-yl)ethyl)-6-(4- _ J^]<^‘Nx^N'z>r^N\ _ methyloxazol-2-yl)pyridin-2-amine \-NH0^7 / (< S)-5-chloro-JV-(l-(4-chloro-l,5- dimethyl-177-pyrazol-3-yl)ethyl)-6-(3- chloro- 177- 1,2,4-triazol- 1 -y l)py ridin-2- amine^^xCI (< S)-5-chloro-7V-(l-(4-chloro-l,5- dimethyl-177-pyrazol-3-yl)ethyl)-6-(3- _C> L^!N^ XNT<^N',VC|\-N W chloro-177-pyrazol-l-yl)pyridin-2- / amine(5)-5-chloro-JV-( 1 -(4-chloro- 1,5- Cl = fl 4 dimethyl-1H-pyrazol-3-yl)ethyl)-6-(3- 56 L A A A, N,FvKHQ (difluoromethyl)- 1 H-pvrazol - 1 - 1 A / 7 yl)pyridin-2-amineZ. (5)-5-chloro-JV-( 1 -(4-chloro- 1,5- dimethyl- l / 7-pyrazol-3 -yl)ethyl)-6-(2- 57 methyloxazol-4-yl)pyri din-2 -amine IZ IZ(5)-5-chloro-JV-( 1 -(4-chloro- 1,5- o o dimethyl- IH-pyrazol-3 -yl)ethyl)-6-(2- 58 A fzLi / methyloxazol-5 -yl)pyridin-2 -amineS / / "c •zQ(5)-5-chloro-JV-( 1 -(4-chloro- 1,5-CL JO dimethyl-l / 7-pyrazol-3-yl)ethyl)-6- 59 Jy^AO'N-NHO-V (oxazol-2-yl)pyridin-2-amine / (5)-5-chloro-JV-( 1 -(4-chloro- 1,5-Clv? JO dimethyl-1H-pyrazol-3-yl)ethyl)-6-(1- 60 / MN-N ^ Nx; Z=z / methyl- 1H- 1,2,4-triazol-3 -yl)pyridin- / z 2-amineGz(, S)-N-( 1 -(4-chloro- 1,5 -dimethyl- 177- pyrazol-3-yl)ethyl)- 1-(5- 62 ZIp (. fluoropyrimidin-2-yl) - 177-pyrazol-3 - amine(R)- or (S)- N-(1-(4-chloroisothiazol-5-yl)ethyl)-1-(5-chloropyrimidin-2- a / 63b yl)-177-pyrazol-3-amineN — S(S)- 1 -(5 -chloropyrimidin-2-yl)-N-( 1 - 64 (4-fluoro- 1,5 -dimethyl- lH-pyrazol-3 - yl)ethyl)- lH-pyrazol-3-amine i / r.=A (7?)- or (5)- l-(5-chloropyrimidin-2- N — / ,N=A \N. A.kN- AKzz-ci yl)-fV-( 1 -(4,5 -dichloro- 1 -methyl- 177- a / 65b ci-4 'T * N imidazol-2-yl)ethyl)-177-pyrazol-3- rNx amineCli r=Af N=A (7?)- or (S)- l-(5-chloropyrimidin-2- N — (. \yl) -N-( 1 -(4,5-dichlorothiazol-2- a / 66b a-< O yl)ethyl)- 177-pyrazol-3-aminey-sClCl, CI (5)-5-chloro-7V-( 1 -(4-chloro- 1,5- dimethyl- 177-pyrazol-3 -yl)ethyl)-4-( 1 - 67 O \ O if N-^ 2N<Z^ N"N-N HN\— / methyl- 177-pyrazol-3 -yl)thiazol-2- / ’ — 'amine(R)- or (S)- N-(1-(5-chloro-1,2-dimethyl-1H-imidazol-4-yl)ethyl)-1- a / 68bNN-^CIH(5-chloropyrimidin-2-yl)-lH-pyrazol- 3 -amineci 1 N=A (R)- or (S)- N-(l-(4-chloro-5- fluoropyridin-3 -yl)ethyl)- 1 -(5 - a / 69b N V ^j_y[1 J HN clchloropyrimidin-2-yl) - 1 H-pyrazol-3 - amine(R)- or (S)- N-(1-(4-chloro-5-fluoro-1- \ 1 N — Z \ methyl- 177-py razol -3 -yl)ethyl)- 1-(5- a / 70b N >CIchloropyrimidin-2-yl) - 177-py razol -3 - N-Nhamine / I Nsri (R)- or (S)- l-(5-chloropyrimidin-2- yl)-N-( l-(4,5-dimethylthiazol-2- a / 71b yl)ethyl)- lH-pyrazol-3-amine ysH1 r=X N=r\ (R)- or (S)- l-(5-chloropyrimidin-2-., 1 N— Z \ yl)-N-(l-(5-chlorothiazol-2-yl)ethyl)- a / 72b 4 H N-Z 1 H-pyrazol-3-amineClCl (R)- or (S)- 5-chloro-N-(l-(4-chloro- 1,5-dimethyl- lH-pyrazol-3-yl)ethyl)- ci i 1 -(pyrimidin-2-yl)- lH-pyrazol-3- a / 73b L 1 AN~<\ / ) amine—NN-yN - N / 5-chloro-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-4-(1-methyl-1H-pyrazol-4-yl)thiazol-2-amine \^NN-N / F(R)- or (S)- N-(1-(2,3-difluorophenyl)-2,2,2-trifluoroethyl)-1-(5-methylpyrimidin-2-yl)-1H-pyrazol-3-amine(7?)- or (S)- l-(5-chloropyrimidin-2- iN:r\ yl)-N-(l-(4-chlorothiazol-2-yl)ethyl)- a / 76b Cl S N A' ClC‘^\ v** O 4 H 1 H-pyrazol-3-amineF / S rs=\ F!~, N-( 1 -(2,3 -difluorophenyl)cyclobutyl)- 77F-xyA-N-«> 1 -(5 -methylpyrimidin-2-yl)- 1H- pyrazol-3-amine(R)- or (S)- N-(1-(4,5-dichlorothiazol-2-yl)ethyl)-1-(5-methoxypyrimidin-2- / / " Oa / 78b CI — q N -Z \ yl)-lH-pyrazol-3-aminey- sClci. P (5)-5-chloro-JV-( 1 -(4-chloro- 1,5- 79 dimethyl-l / / -pyrazol-3-yl)ethyl)-4- N-N HN” A (pyrimidin-2 -yl)thiazol-2 -amine / (R)- or (S)- 5-chloro-N-(l-(4,5- i A'01dichlorothiazol-2-yl)ethyl)-6-( 1 - a / 80b methyl-lH-l,2,4-triazol-3-yl)pyridin-HN=Z 2 -amineClCl i r=A (R)- or (5)- l-(5-chloropyrimidin-2- \ 1 R. N -Z \a / 81b yl)-N-(l-(3,4-dichloroisothiazol-5- Cl-z55^ • N N- / / Ciyl)ethyl)- lH-pyrazol-3-amine N -SH"0 _> N^ (R)- or (S)- 2-((l-(5-chloropyrimidin- 2-yl)-lH-pyrazol-3-yl)amino)-2-(4,5- / Z~CIa / 82b CI— d T ‘ N N dichlorothiazol-2-yl)ethan- 1 -ol ysHCll-(5-chloropyrimidin-2-yl)-N-(l-(4,5- Nrr, / N— Z \ dichlorothiazol-2-yl)propyl)-lH- ' Z / ~ CIa / 83b ci-z T * NNN_y pyrazol-3-aminey.sHCl>N(R)- or (S)- 6-((l-(4,5-dichlorothiazol- 2-yl)ethyl)amino)-2-( 1 -methyl- 1H- a / 84b 1,2,4-triazol-3-yl)nicotinonitrile ci __zS7fx*xN \ Trs-\__.HN X / ClN-(l -(4,5-dichloro-3- S^ J-.W-A*N'N~^ #~-O / (methylsulfonyl)thiophen-2-yl)ethyl)- 851 -(5 -methoxypyrimidin-2-yl)- 1H- Cl / pyrazol-3-amineF (R)- or (S)- N-(l-(4,5-dichlorothiazol- j r=^ N=X 2-yl)-2,2,2-trifluoroethyl)- 1 -(5- a / 86b methoxypyrimidin-2-yl)-lH-pyrazol- 3 -amineCl(R)- or (S)- l-(5-chloro-4- isopropylpyrimidin-2-yl)-N-(l-(5- 1 r=\ NcVchlorothiazol-2-yl)cthyl)-lH-pyrazol- a / 87b J-a3 -amine\\ ’ rl / SCli r=\ (R)- or (5)- 3-(3-((l-(5-chlorothiazol- a / 88b 2-yl)ethyl)amino)- IH-pyrazol- 1 -yl)- 1 - methylpyrazin-2( lH)-oneQ o N-((S)- 1 -(5 -chlorothiazol-2-yl)ethyl)- 1 -( 1 -((. S)-tctrahydrofuran-3-yl )- 1H- 1.2.4-triazol-3-yl)-lH-pyrazol-3- 1 I amine;N-((R)-1-(5-chlorothiazol-2-yl)ethyl)-1-(1-((S)-tetrahydrofuran-3-yl)-1H-1,2,4-triazol-3-yl)-1H-pyrazol-3-amine;N-((S)-1-(5-chlorothiazol-2-yl)ethyl)-1-(1-((R)-tetrahydrofuran-3-yl)-1H-1,2,4-triazol-3-yl)-1H-pyrazol-3-amine;, orN-((R)-1-(5-chlorothiazol-2-yl)ethyl)- ^r r O 1 -( 1 -(( / ?)-tctrahydrofuran-3 -yl)- 1H- 1,2,4-triazol-3-yl)-1H-pyrazol-3-aminezZ (R)- or (5)- l-(5-chloropyrimidin-2- Q yl)-N-( 1 -(4,5-dichlorothiazol-2-yl)-2- a / 90b ZT methoxy ethyl) - lH-pyrazol-3-amine ( ZI Qf. / * f. *.i zz*y co O- —j jn t- N-( 1 -(5-chlorothiazol-2-yl)ethyl)- 1 - 1 ° jQo o o (oxazolo [5,4-b] pyridin-2-yl)- 1 H- _ 1 _ 1 yX pyrazol-3-amine91. N-NVN "ClysN-( 1 -(5-chlorothiazol-2-yl)ethyl)- 1 -(5 - methylpyrazin-2-yl)- lH-pyrazol-3- 92amineN-( 1 -(5-chlorothiazol-2-yl)ethyl)- 1 -(5 - methoxypyrimidin-2-yl)-lH-pyrazol- 93 3 -amine(R)- or (5)- N-(l-(5-chloro-4- methylthiazol-2-yl)ethyl)-1-(5- a / 94b chloropyrimidin-2-yl) - 1 H-pyrazol-3 - amine1 -(benzo [d]oxazol-2-y l)-N-( 1 -(5 - chlorothiazol-2-yl)ethyl)-lH-pyrazol- 3 -amine95F N-( 1 -(5-chlorothiazol-2-yl)ethyl)- 1 -(5 - (difluoromethyl)pyrimidin-2-yl)-1H- 96CIVSv / pyrazol-3-amine2N-( 1 -(5-chlorothiazol-2-yl)ethyl)- 1 -(6- methylpyridazin-3-yl)-lH-pyrazol-3- 971 1 amine / \ N=n N-(l-(4,5-dichlorothiazol-2- \z X- N — (*• A~O yl)cyclobutyl)- 1 -(5- 98 methoxypyrimidin-2-yl)-lH-pyrazol-Ci-y(HVz3 -amineCli r=\ N-N 1 -(6-chloro- 1,2,4-triazin-3 -yl)-N-( 1 - (5-chlorothiazol-2-yl)ethyl)-lH- 99 N-^C!ylHpyrazol-3-amineCl(R)- or (S)- N-(l-(5-chlorothiazol-2- FN^A 1., A r==Xyl)ethyl)-l-(5- -N1_XN ==X >-FzAo (difluoromethoxy)pyrimidin-2 -yl)- 1 H- lOOa / lOObH pyrazol-3-amineClF (R)- or (S)- N-(l-(4,5-dichlorothiazol- 1 r=\ N~» ^__F2-yl)ethyl)-l-(5- lOla / lOlbCi_ zNA*N'V ° (difluoromethoxy)pyrimidin-2-yl)-lH- HNpyrazol-3-amineClN-(l-(4,5-dichlorothiazol-2- yl)cyclobutyl)- 1 -(5-,sA|A N-P \_F102C1~O H / “ (difluoromethoxy)pyrimidin-2-yl)-lH- pyrazol-3-amine ClN-(l-(4,5-dichlorothiazol-2-yl)-3,3- difluorocyclobutyl)- 1 -(5 - S^AfAk N-J / \_F103 (difluoromethoxy)pyrimidin-2-yl)-lH- Cl-O Hpyrazol-3-amineClF N-(3-(4,5-dichlorothiazol-2-yl)oxetan- A p==\ N=A >-F 3-yl)-l-(5- \z L,N-<\ A-o104 S-^A'NNN~y (difluoromethoxy)pyrimidin-2-yl)-lH-C1_<pr Hpyrazol-3-amineClN-(l-(4,5-dichlorothiazol-2-yl)-3- IFvA / N=\ A fluorocyclobutyl)- 1 -(5- \z L. T A Ao 105 (difluoromethoxy)pyrimidin-2-yl)-lH- CI — c n H VN pyrazol-3-amine Cl(R)- or (5)- 5-chloro-N-(l-(5- i jfirclchlorothiazol-2-yl)etliyl)-6-( 1 -methyl- a / 106b 1H- 1,2,4-triazol-3 -yl)pyridin-2 -amine 1 zN-(1-(5-chlorothiazol-2-yl)ethyl)-1-(4-methyloxazol-2-yl)-1H-pyrazol-3-amineCIYSWZ\ Q. £V- ^N HN-^j methyloxazol-2-yl)-lH-pyrazol-3- TZNamineCI'T'S\ / YV- f N-( 1 -(5 -chlorothiazol-2-yl)ethyl)- 1 -(4- 108 'N HN— 7 (difluoromethyl)oxazol-2-yl)-lH- ^ zz pyrazol-3-amineCk <. N-(1-(5-chlorothiazol-2-yl)ethyl)-1-(4- 109 2? A-Z o (trifluoromethyl)oxazol-2-yl)- 1H-NF pyrazol-3-amineCcL N-( 1 -(5 -chlorothiazol-2-yl)ethyl)- 1 -(5 - 11 vZ.S% TY,0 V-N NH^N \ o-A / / isopropyloxazol-2-yl)-lH-pyrazol-3- amineCl. <5 J N-( 1 -(5 -chlorothiazol-2-yl)ethyl)- 1 - 111NHN-^Y^ R3N - (4,5-dimethyloxazol-2-yl)-lH- pyrazol-3-aminCl N-( 1 -(5 -chlorothiazol-2-yl)ethyl)- 1 -(4- 112 VY HNN? XZ (methoxymethyl)oxazol-2-yl)- 1H- pyrazol-3-amineCL „ JV-(l-(5-chlorothiazol-2-yl)ethyl)-l-(4- 113 cyclopropyloxazol-2-yl)-lH-pyrazol- 3 -amineN-(1-(5-chlorothiazol-2-yl)ethyl)-1-(5- 114 cyclopropyloxazol-2-yl)-lH-pyrazol- o / 3 -amineCl., CI (5)-5-chloro-JV-( 1 -(4-chloro- 1,5- dimethyl- 17 / -py razol -3 -yl)ethyl)-4-( 1 - 115 2 ~CA methyl- 1H- 1,2,4-triazol-3 -yl)thiazol- / N-N HNZ^C N=— / 'N2 -amineci.,ci (5)-5-chloro-7V-( 1 -(4-chloro- 1,5- dimethyl- l / f-pyrazol-3 -yl)ethyl)-4-(2- 116 2N-N HN\_ ' methyl-2H-1,2,3-triazol-4-yl)thiazol- / '“N 2-aminensAN=\ (S)-N-( 1 -(4-chloro- 1,5 -dimethyl- 1 / 7- Cl: JL,N—y / '-O pyrazol-3 -yl)ethyl)- 1 -(furo[3,2- 117 K^N^N N-^ l— & H H <7]pyrimidin-2-yl)- 177-pyrazol-3-amine VN / (S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-2-(5-chloropyrimidin-2-yl)thiazol-4-amine(S)-N-( 1 -(4-chloro- 1,5-dimethyl- 1H- pyrazol-3-yl)ethyl)-2-(oxazol-2- yl)thiazol-4-amine(S)-N-( 1 -(4-chloro- 1,5-dimethyl- 1H- 1z pyrazol -3 -yl)ethyl)-2-( 1 -methyl- 177- l,2,4-triazol-3-yl)thiazol-4-amine \ Q IZ IZ -n.= IZ (S)-N-( 1 -(4-chloro- 1,5-dimethyl- 177- M - - JL N N-Z J'N-NH oXpyrazol -3 -yl)ethy 1)- 1 -(1 -methyl-177- l,2,4-triazol-3-yl)-177-pyrazol-3-amine / Cl o w wA ozA^-(l-(5-chloropyrimidin-2-yl)-4- fluoro-177-pyrazol-3-yl)-2,2-difluoro-2- (pyridin-3-yl)acetamideF 2V-(l-(5-chloropyrimidin-2-yl)-4- fluoro-177-pyrazol-3-yl)-2-(2,3- difluorophenyl)acetamideHX covzJN.zNo (S)-6-((l-(4-chloro-l,5-dimethyl-177-CL JU pyrazol-3- \ 'I HN-N ZI K yl)ethyl)amino)nicotinonitrile / o < ZI.7V-(1 -(2-fluorophenyl)ethyl)-5- z*^^s(trifluoromethyl)pyridin-2-amine 1A^-(2-(2-fluorophenyl)propan-2-yl)-5- (trifluoromethyl)pyridin-2-amine7V-(2,2,2-trifluoro-l-(2- F p j^Y0"3fluorophenyl)ethyl)-5- |i jH(trifluoromethyl)pyridin-2-amine N-(2 -fluoro- 1 -(2-fluorophenyl)ethyl)-5- (trifluoromethyl)pyridin-2-amine jV-(cyclopropyl(2-FY fluorophenyl)methyl)-5 - (J" H "N(trifluoromethyl)pyridin-2-amine A^-(l-(2-fluorophenyl)cyclobutyl)-5- (trifluoromethyl)pyridin-2-amineF. F N-(3,3 -difluoro- 1 -(2- fluorophenyl)cyclobutyl)-5- 131 F fVCFa(trifluoromethyl)pyridin-2-amine|l J HN-(3 -(2-fluorophenyl)oxetan-3-y l)-5 - 132 (trill uoromethyl)pyridin-2-amine7V-(l-(2-fluorophenyl)cyclopropyl)-5- 133 (trifluoromethyl)pyridin-2-amineci | r^\ N=\ 7V-(l-(4-chloroisothiazol-3-yl)ethyl)-l- 134 (5-chloropyrimidin-2-yl)- IW-pyrazol-3-Haminec<xl (2-( 1 -(( 1 -(5 -chloropy rimidin-2-y 1)- 177-Npyrazol-3-yl)amino)ethyl)-3,4- =\r i f135, N— o a— a difluorophenyl)(morpholino)methanone[1 1 HF1-(5-chloropyrimidin-2-yl)-N-(1-(4,5-difluoropyridin-3-yl)ethyl)-1H-pyrazol-3-amine7V-(l-(3-chloropyridin-2-yl)ethyl)-l-(5- 137 chloropyrimidin-2-yl)-177-pyrazol-3- aminel-(5-chloropyrimidin-2-yl)-7V-(l-(3- 138 fluoro-4-methylpyridin-2-yl)ethyl)-177- pyrazol-3-amineCN^ONazetidin- 1 -y l(2-( 1 -((1 -(5- chloropyrimidin-2-yl)-177-pyrazol-3- 139 I 1 L, N-(\r; N N N-^ ^“Clyl)amino)ethyl)-3,4- difluorophenyl)methanoneF

[0136] In another embodiment of the compound of Formula (I), the compound is a compound selected from the group consisting of Compound 37. Compound 66a, Compound 66b, Compound 78a, Compound 78b, Compound 80a, Compound 80b, Compound 86a, Compound 86b, Compound 101a, and Compound Compound 101b, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0137] The compounds described herein (e.g., compounds of Formula (I)) may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as ( / )-or (5*)- or, as (D)- or (L)- for amino acids. Embodiments thus include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0138] Embodiments provided herein include all manner of rotamers and conformationally restricted states of a compound provided herein. Atropisomers, which are stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers, are also included. As an example, certain compounds provided herein may exist as mixtures of atropisomers or purified or enriched for the presence of one atropisomer.

[0139] In some embodiments, the compound of Formula (I) is a mixture of atropisomers. In other embodiments, the compound of Formula (I) is a substantially purified atropisomer. In some embodiments, the compound of Formula (I) is a substantially purified (R)-atropisomer. In some other embodiments, the compound of Formula (I) is a substantially purified (R)-atropisomer.SYNTHESIS OF SARM1 INHIBITORS

[0140] Compounds of the present disclosure can be made by a variety of methods depicted in the illustrative synthetic reaction schemes shown and described below. The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis,' Wiley & Sons: New York, vol. 1-21; R. C. LaRock, Comprehensive Organic Transformations, 2nd edition Wiley-VCH. New York 1999;Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees (Eds.)Pergamon, Oxford 1984. vol. 1-9; Comprehensive Heterocyclic Chemistry II, A. R. Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley & Sons: New York, 1991, vol. 1-40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds described herein can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained herein.

[0141] For illustrative purposes, reaction Schemes below provide routes for synthesizing the compounds described herein as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used. Although some specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be substituted to provide a variety of derivatives or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0142] The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, cry stallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0143] Unless specified to the contrary, the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about -78 °C to about 150 °C, more preferably from about 0 °C to about 125 °C, and most preferably and conveniently at about room (or ambient) temperature, or, about 20 °C.

[0144] Some compounds in following schemes are depicted with generalized substituents; however, one skilled in the art will immediately appreciate that the nature of the substituents can varied to afford the various compounds described herein. Moreover, the reaction conditions are exemplar)’ and alternative conditions are well known. The reaction sequences in the following examples are not meant to limit the scope of the invention as set forth in the claims.

[0145] Persons skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare other compounds described herein. For example, the synthesis of non-exemplified compounds of compounds described herein (e.g.. compounds of Formula (1)) may be successfully performed by modifications apparent to those skilled in theart, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the present disclosure.METHODS OF TREATMENT WITH AND USES OF SARM1 INHIBITORS

[0146] The present disclosure provides a variety of uses and applications for compounds and / or compositions as described herein, for example in light of their activities and / or characteristics as described herein. In some embodiments, such uses may include therapeutic and / or diagnostic uses. Alternatively, in some embodiments such uses may include research, production, and / or other technological uses.

[0147] In one aspect, the present disclosure provides methods comprising administering one or more compounds of Formula (I) to an individual, e.g., to treat, prevent, or reduce the risk of developing one or more conditions characterized by axonal degeneration. In some such embodiments, the compound of Formula (I) is a SARM1 inhibitor.

[0148] For instance, in one aspect, the present disclosure provides a method of treating or preventing axonal degeneration comprising administering to an individual in need thereof a therapeutically effective amount of the compound of Formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising the compound of Formula (1) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing and a pharmaceutically acceptable excipient. In one aspect, the individual is a human. In one aspect, the individual has a condition characterized by axonal degeneration or is at risk of developing a condition characterized by axonal degeneration.

[0149] Another embodiment of the present disclosure relates to a method of inhibiting SARM1 activity in an individual in need thereof, comprising steps of administering to said individual a therapeutically effective amount of a compound of Formula (I) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of Formula (I) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing and a pharmaceutically acceptable excipient.

[0150] Inhibition of enzymes in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to biological assays, gene expression studies, and biological target identification.

[0151] In certain embodiments, the present disclosure relates to a method of treating axonal degeneration in a biological sample or inhibiting SARM1 in a biological sample comprising the step of contacting said biological sample with a compound of Formula (I) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of Formula (I) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing and a pharmaceutically acceptable excipient. In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein are useful, for example as a method of inhibiting the degradation of neurons derived from a subject. In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein, are useful for inhibiting the degeneration of a neuron, or portion thereof, cultured in vitro. In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein, are useful as stabilizing agents to promote in vitro neuronal survival.

[0152] In some embodiments, the compounds and / or pharmaceutical compositions of the present disclosure inhibit NADase activity of SARM1. Alternatively, or additionally, in some embodiments, the compounds or pharmaceutical compositions of the present disclosure alleviate one or more attributes of neurodegeneration. In some embodiments, the present disclosure provides methods of treating a neurodegenerative disease or disorder comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (I) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising a compound of Formula (I) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing and a pharmaceutically acceptable excipient. In one aspect, the neurodegenerative disease is associated with axonal degeneration.

[0153] In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein are useful, for example, in the practice of medicine. In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein are useful, for example, to treat, prevent, or ameliorate axonal degeneration (e.g., one or more features or characteristics thereof). In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein are useful, for example to inhibit axonal degeneration, including axonal degeneration that results from reduction or depletion of NAD+.

[0154] In certain embodiments, the present disclosure provides compounds that are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure. Compounds provided by this disclosure are alsouseful for the study of SARM1 activity in biological and pathological phenomena and the comparative evaluation of new SARM1 activity inhibitors in vitro or in vivo. In certain embodiments, the present disclosure provides assays for identifying and / or characterizing compounds and / or compositions provided herein. In some embodiments, provided assays utilize particular reagents and / or systems (e.g., certain vector constructs and / or polypeptides) useful in assaying SARM1 activity.

[0155] In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein are useful, for example as a method of inhibiting the degradation of neurons derived from a subject. In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein, are useful for inhibiting the degeneration of a neuron, or portion thereof, cultured in vitro. In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein, are useful as stabilizing agents to promote in vitro neuronal survival.

[0156] In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein are useful, for example in affecting biomarkers associated with neurodegeneration. In some embodiments, changes in biomarkers can be detected systemically or with a sample of CSF, plasma, serum, and / or tissue from a subject. In some embodiments, one or more compounds and / or compositions can be used to affect a change in the concentration ofNF-L and / or NF-H contained the CSF of a subject. In some embodiments, one or more compounds and / or pharmaceutical compositions as described herein can affect constitutive NAD and / or cADPR levels in neurons and / or axons.

[0157] In some embodiments, compounds and / or compositions as described herein may be administered to individuals suffering from one or more diseases, disorders, or conditions. In some embodiments, the one or more diseases, disorders, or conditions are mediated by SARM1.

[0158] In some embodiments, the present disclosure provides inhibitors of SARM1 activity for treatment of neurodegenerative or neurological diseases or disorders that involve axon degeneration or axonopathy. The present disclosure also provides methods of using inhibitors of SARM1 activity to treat, prevent or ameliorate axonal degeneration, axonopathies and neurodegenerative or neurological diseases or disorders that involve axonal degeneration.

[0159] In some embodiments, an individual to whom a compound or pharmaceutical composition is administered as described herein exhibits one or more signs or symptoms associated with axonal degeneration; in some embodiments, the subject does not exhibit any signs or symptoms of neurodegeneration.

[0160] In some embodiments, provided methods comprise administering a compound of Formula (I) to an individual in need thereof. In some such embodiments, the individual is at risk of developing a condition characterized by axonal degeneration. In some embodiments, the individual has a condition characterized by axonal degeneration. In some embodiments, the patient has been diagnosed with a condition characterized by axonal degeneration.PHARMACEUTICAL COMPOSITION

[0161] In another aspect, also provided herein are pharmaceutical compositions or medicaments containing a therapeutically effective amount of a compound described herein (e.g. compounds of Formula (I)), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing and at least one therapeutically inert excipient, as well as methods of using the compounds described herein to prepare such compositions and medicaments.

[0162] An embodiment, therefore, includes a pharmaceutical composition comprising a therapeutically effective amount of a compound described herein (e.g. compounds of Formula (I)) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. A further embodiment includes a pharmaceutical composition comprising a therapeutically effective amount of a compound described herein (e.g. compounds of Formula (I)), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, together with a pharmaceutically acceptable excipient.

[0163] In one example, a therapeutically effective amount of compounds described herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, with the desired degree of purity may be formulated by mixing with physiologically acceptable excipients, z.e., excipients that are non-toxic to recipients at the dosages and concentrations employed into a dosage form at ambient temperature and at the appropriate pH. In another embodiment, compounds described herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing is sterile. The compounds described herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

[0164] Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the severity of the disorder, the particular patient being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of theagent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The "‘therapeutically effective amount" of the compounds described herein (e.g., a compound of Formula (I)), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit SARM1 activity. Typically, such amount may be below the amount that is toxic to normal cells, or the patient as a whole.

[0165] 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 tamperproof assemblage to prevent indiscreet access to the contents of the package. In addition, the container may have deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.

[0166] A therapeutically effective amount of a compound described herein (e g. compounds of Formula (I)), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapul monary, intradermal, intrathecal, epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0167] A therapeutically effective amount of a compound described herein (e.g. compounds of Formula (I)), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.

[0168] A typical formulation is prepared by mixing a therapeutically effective amount of a compound described herein (e.g. compounds of Formula (I)), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing and an excipient. Suitableexcipients include carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulphate, polyoxysorbitan oleate), binders (for example poly vinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g., antioxidants, for example ascorbic acid), colorants (e.g., inorganic pigments, for example iron oxides) and taste and / or odour correctants, and are well known to those skilled in the art and are described in detail in, e.g., Ansel. H. C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, R. C., Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press. 2005. The formulations may also include one or more buffers, surfactants, lubricating agents, suspending agents, preservatives, opaquing agents, glidants, processing aids, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (z.e., a compound described herein (e.g. compounds of Formula (I)) or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0169] In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcry stalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0170] In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coating. In specific embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solutions, optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs and / or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and / orpigments are optionally utilized to characterize different combinations of active compound doses.

[0171] In certain embodiments, therapeutically effective amounts of at least one of the compounds described herein are formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, push-fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, soft capsules, contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

[0172] In other embodiments, therapeutically effective amounts of at least one of the compounds described herein are formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In still other embodiments, the compounds described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, formulations for injection are presented in unit dosage form (e.g.. in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations. In still other embodiments, the pharmaceutical compositions are formulated in a form suitable for parenteral injection as sterile suspensions, solutions or emulsions in oily or aqueous vehicles. Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and / or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In additional embodiments, suspensions of a compound described herein (e.g., a compound of Formula (I)), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highlyconcentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0173] In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques and excipients are optionally used as suitable. Pharmaceutical compositions comprising a therapeutically effective amount of a compound described herein (e.g., a compound of Formula (I)), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0174] Pharmaceutical compositions include at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound described herein (e.g., a compound of Formula (I)), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, as an active ingredient. The active ingredient is in free-acid or freebase form, or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, excipients, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0175] Methods for the preparation of compositions comprising a therapeutically effective amount of a compound described herein (e g., a compound of Formula (I)), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, include formulating the compound described herein, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, with one or more inert, pharmaceutically acceptable excipients to form a solid, semi-solid or liquid. Solidcompositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions and creams. The form of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.

[0176] In some embodiments, pharmaceutical composition comprising a therapeutically effective amount of a compound described herein (e.g. compounds of Formula (I)), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, illustratively takes the form of a liquid where the agents are present in solution, in suspension or both. Typically, when the composition is administered as a solution or suspension a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.

[0177] In certain embodiments, useful aqueous suspensions contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein comprise a mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate and dextran.

[0178] Useful pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of a compound described herein (e.g., a compound of Formula (I)), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. The term "solubilizing agent" generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80, are useful as solubilizing agents, as are ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

[0179] Furthermore, useful pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic,phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

[0180] Additionally, useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0181] Other useful pharmaceutical compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury -containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[0182] Still other useful compositions include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.

[0183] Still other useful compositions include one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0184] In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.ARTICLES OF MANUFACTURE

[0185] In yet another aspect, provided herein are articles of manufacture, or "kits", containing materials useful for the treatment of the diseases and disorders described above is provided. In one embodiment, the kit comprises a container comprising a compound described herein (e.g., a compound of Formula (I)), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. The kit may further comprise a label or package insert on or associated with the container. The term "package insert" is used to referto instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and / or warnings concerning the use of such therapeutic products. Suitable containers include, for example, bottles, vials, syringes, blister pack, etc. The container may be formed from a variety of materials such as glass or plastic. The container may hold a compound described herein (e.g., a compound of Formula (I)), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or a formulation thereof which is effective for treating the condition and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is a compound described herein (e.g. compounds of Formula (I)), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Alternatively, or additionally, the article of manufacture may further comprise a second container comprising a pharmaceutical diluent, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution or dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0186] In another embodiment, the kits are suitable for the delivery of solid oral forms of a compound described herein (e.g. compounds of Formula (I)), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, such as tablets or capsules. Such a kit can include a number of unit dosages. An example of such a kit is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms.EXAMPLES

[0187] The following examples illustrate the preparation and biological evaluation of compounds within the scope of the disclosure. These examples and preparations which follow are provided to enable those skilled in the art to more clearly understand and to practice the invention described herein. They should not be considered as limiting the scope of the invention described herein, but merely as being illustrative and representative thereof.Abbreviations

[0188] The following abbreviations are used in the Examples:CDI: 1,1-carbonyldiimidazoleDCE: dichloroethaneDCM: dichloromethaneDEA: diethylamineDIPEA: N, N-diisopropylethylamineDMAP: 4-dimethylaminopyridineDMDACH: (lS,2S)-(+)-N, N'-Dimethylcyclohexane-l,2-diamineDMEDA: 1,2-dimethylethylenediamineDMF: dimethylformamideDMSO: dimethylsulfoxideEE: EtOAc / EtOHEtOAc: ethyl acetateEtOH: ethanolHFIP: 1,1, 3, 3, -hexafl uoro-2-propanolHOAc: acetic acidHPLC: high performance liquid chromatographyi-PrOH: isopropanolLCMS: liquid chromatography-mass spectrometryMeOH: methanolMeCN: AcetonitrileMsCl: methanesulfonyl chlorideMTBE: methyl tert-butyl ethern-BuOH: n-butanolNMR: nuclear magnetic resonanceTBAF: tetra-n-butyl ammonium fluorideTBSCl: tert-butyldimethylsilyl chlorideTEA: triethylamineTFA: trifluoroacetic acidTHF: tetrahydrofuranTLC: thin layer chromatographyprep-TLC: preparative thin layer chromatographySEM-Cl: 2-(trimethylsilyl)ethoxymethyl chlorideSFC: supercritical fluid chromatographyLCMS Analytical Methods

[0189] Agilent 10-min: Experiments were performed on an Agilent 1290 UHPLC coupled with Agilent MSD (6140) mass spectrometer using ESI as ionization source. The LCseparation was using a Phenomenex XB-C18, 1.7mm, 50 × 2.1 mm column at a flow rate of 0.4 ml / minute. MPA (mobile phase A) was water with 0.1% FA and MPB (mobile phase B) was acetonitrile with 0.1% FA. The gradient started at 2% MPB and ended at 98% MPB over 7 min and held at 98%B for 1.5 min following equilibration for 1.5 min. LC column temperature was 40 °C. UV absorbance was collected by a DAD detector and mass spec full scan was applied to all experiments.

[0190] Agilent 30-min: Experiments were performed on an Agilent 1290 HPLC coupled with Agilent MSD (6140) mass spectrometer using ESI as ionization source. The LC separation was done on an Agilent Zorbax Eclipse XDB-C18, 3.5 um, 100 x 3.0 mm column at a flow rate of 0.7 ml / minute. MPA (mobile phase A) was water with 0.1% FA and MPB (mobile phase B) was acetonitrile with 0.1% FA. The gradient started at 2% MPB and ended at 98% MPB over 25.5 min and held at 98%B for 2.5 min following equilibration for 1.5 min. LC column temperature was 40 °C. UV absorbance was collected by a DAD detector and mass spec full scan was applied to all experiments.

[0191] Thermo qE 10-min: The samples were analyzed on a Dionex Ultimate 3000 coupled with Thermo Scientific Q Exactive HRMS using ESI as ionization source. The LC separation was done on a Phenomenex XB-C18, 1.7μm, 50 × 2.1 mm column at a flow rate of 0.4 ml / minute. MPA (mobile phase A) was water with 0.1% FA and MPB (mobile phase B) was acetonitrile with 0.1% FA. The gradient started at 2 % MPB and ended at 98% MPB over 7 min and held at 98% MPB for 1.5 min following an equilibration for 1.5 min. LC column temperature was 40 °C. UV absorbance was collected by a DAD detector and mass spec full scan was applied to all experiments.

[0192] Thermo qE 30-min: The samples were analyzed on a Dionex Ultimate 3000 coupled with Thermo Scientific Q Exactive HRMS using ESI as ionization source. The LC separation was done on an Agilent Zorbax Eclipse XDB-C18, 3.5 um, 100 x 3.0 mm column at a flow rate of 0.7 ml / minute. MPA (mobile phase A) was water with 0.1% FA and MPB (mobile phase B) was acetonitrile with 0.1% FA. The gradient started at 2% MPB and ended at 98% MPB over 25.5 min and held at 98%B for 2.5 min following equilibration for 1.5 min. LC column temperature was 40 °C. UV absorbance was collected by a DAD detector and mass spec full scan was applied to all experiments.Examples of Syntheses:Intermediate AStep 1: Synthesis of 5-chloro-2-(3-nitro-lH-pyrazol-l-yl)pyrimidine

[0193] To a solution of 3-nitro-177-pyrazole (25.0 g, 221 mmol, 1 equiv) in DMSO (500 mL) were added K2CO3 (36.6 g, 265 mmol, 1.2 equiv) and 2,5-dichloropyrimidine (36.2 g, 243 mmol, 1.1 equiv). The reaction was stirred at 25 °C for 16 h. Upon completion as determined by LCMS. water (1 L) and ethyl acetate (500 mL) was added. The mixture was stirred at 25 °C for 0.5 h, and then filtered. The filter cake was collected to yield 5-chloro-2-(3-nitro-1H-pyrazol-1-yl)pyrimidine (49 g, 98% yield) as a white solid. ¹H NMR (400 MHz, DMSO): δ 9.06 (s, 2H), 8.81 (d, J = 2.4 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H). LCMS: (ESI, m / z) [M+H]⁺ = 226.1Step 2: Synthesis of l-(5-chloropyrimidin-2-yl)-lH-pyrazol-3-amine

[0194] Solution 1: 5-chloro-2-(3-nitro-1H-pyrazol-1-yl)pyrimidine (10.0 g, 44.3 mmol) in THF (1000 mL) and MeOH (1000 mL). The fixed bed (named FLR1, volume 5 mL) was completely packed with granular catalyst 5% Pd / Al2O3(WXSC1050). The H2 back pressure regulator was adjusted to 1 MPa, and the flow rate of H2 was 30 mL / min. Then the solution SI was pumped by Pump 1 {SI, Pl, 2 mL / min] to fixed bed {FLR1, SS, fixed bed, 6.350(1 / 4’ ')mm, 5 mL, 45 °C}. Then the reaction mixture was collected from the reactor output. The reaction mixture was concentrated to give the crude product, which was triturated with ethyl acetate (100 mL) and hexane (300 mL). The mixture was filtered, and the filter cake was collected to yield 1-(5-chloropyrimidin-2-yl)-1H-pyrazol-3-amine (Intermediate A, 5.5 g, 63% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO): δ 8.78 (s, 2H), 8.26 (d, J = 2.8 Hz, 1H), 5.89 (d, J = 2.8 Hz, 1H), 5.43 (br s, 2H). LCMS: (ESI, m / z) [M+H]⁺ = 196.0.Intermediate B•z\ Step 1: Synthesis of 4-chloro-N-methoxy-N,1,5-trimethyl-1H-pyrazole-3-carboxamide

[0195] A solution of 4-chloro-1,5-dimethylpyrazole-3-carboxylic acid (238.4 g, 1365.6 mmol, 1 equiv) in thionyl chloride (2000 mL) was stirred at 70 °C for 2 hours. The resulting mixture was concentrated under reduced pressure to dryness, flushed with nitrogen, dissolved in DCM (2 L), and cooled to 0°C. The flask was charged with N, O-dimethylhydroxylamine hydrochloride (159.48 g, 1635.0 mmol, 1.2 equiv) followed by dropwise addition of DIEA (704.39 g, 5449.9 mmol, 4 equiv). The resulting mixture was stirred at 0 °C for 1 hour under a nitrogen atmosphere. The reaction was quenched with 2L of water and extracted with CH2C12 (3 x 1 L). The combined organic layers were washed with brine (3x1 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with DCM (2 L). The precipitated solids were collected by filtration and washed with hexane (2x200 mL) to yield 4-chloro-N-methoxy-N,l,5-trimethyl-lH-pyrazole-3-carboxamide (184 g, 62% yield) as a white solid. LCMS: (ES, m / z): 218 [M+H]+Step 2: Synthesis of l-(4-chloro-1.5-dimethyl-lH-pyrazol-3-yl)ethan-l-one

[0196] 4-chloro-N-methoxy-N,l,5-trimethylpyrazole-3-carboxamide (268 g, 1231.3 mmol, 1 equiv) was nitrogen flushed, dissolved in THF (2 L), and cooled to 0 °C. Methylmagnesium bromide (3 M solution in diethyl ether) (533.6 mL, 1600.7 mmol, 1.3 equiv) was added dropwise and stirred for 1 hour under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4C1 (aq.) (lOOmL) at 0°C. The resulting mixture was extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (2x300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with hexane (200 mL). The precipitated solids were collected by filtration and washed with hexane (2x100 mL) to yield 1-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethan-l-one (186 g, 88% yield) as a white solid. LCMS: (ES, m / z): 173 [M+H]+Step 3: Synthesis of (R)-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethylidene)-2-methylpropane-2-sulflnamide

[0197] A solution of l-(4-chloro-l,5-dimethylpyrazol-3-yl)ethanone (186 g, 1077.6 mmol, 1 equiv), (R)-tert-butanesulfinamide (195.90 g, 1616.361 mmol, 1.5 equiv), and titanium isopropoxide (612.53 g, 2155.1 mmol, 2 equiv) in THF (1.8 L) were stirred at 70 °C for overnight. The mixture was allowed to cool down to 0 °C and quenched with water at room temperature. The resulting mixture was filtered; the filter cake was washed with ethyl acetate (3x200 mL). The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (2x100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue w as purified by trituration with hexane (20 mL) to yield (S)-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethylidene)-2-methylpropane-2-sulfinamide (210 g, 71% yield) as a light yellow solid. LCMS: (ES, m / z): 276 [M+H]+Step 4: Synthesis of (R)-N-((S)-l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulflnamide

[0198] To a stirred solution of (R)-N-[(4-chloro-1,5-dimethylpyrazol-3-yl)ethylidene]-2-methylpropane-2-sulfinamide (160 g, 580.1 mmol, 1 equiv) was nitrogen flushed, dissolved in THF (1200 mL), and cooled to -78 °C. L-Selectride (2030.5 mL, 2030.5 mmol, 3.5 equiv) was added dropwise and the resulting mixture was stirred at -78 °C for 2 hours. The reaction was quenched by the addition of sat. NH4C1 (aq.) (100 mL) at -70 °C. The resulting mixture was filtered and the filter cake was washed with ethyl acetate (3x100 mL). The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (2x100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc in PE) to yield (R)-N-((S)-l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (87 g, 54% yield) as a white solid. LCMS: (ES, m / z): 278 [M+H]+Step 5: Synthesis of (lS)-l-(4-chloro-l,5-dimethylpyrazol-3-yl)ethanamine hydrochloride

[0199] A solution of HC1 in l,4-dioxane(4.0 M) (300 mL) was cooled 0 °C and (R)-N-[(lS)-l-(4-chloro-l,5-dimethylpyrazol-3-yl)ethyl]-2-methylpropane-2-sulfinamide (120 g, 431.9 mmol, 1 equiv) was added in portions. The solution was stirred for 1 hour and then directly concentrated under reduced pressure. The residue was dissolved in MeOH (200 mL) and concentrated under reduced pressure. The residue was purified by trituration with diethyl ether (500 mL). The precipitated solids were collected by filtration and washed with ethyl ether (2x200 mL) to yield (lS)-l-(4-chloro-l,5-dimethylpyrazol-3-yl)ethanamine hydrochloride (86.53 g, 95% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.60 (s, 3H), 4.44 – 4.27 (m, 1H), 3.78 (s, 3H), 2.25 (s, 3H), 1.50 (d, J = 6.9 Hz, 3H). LCMS: (ES, m / z): 174.10 [M+H]⁺Intermediate CStep 1: Synthesis of (E)-l-(5-chlorothiazol-2-yl)-N-(lH-pyrazol-3-yl)methanimine

[0200] To a mixture of 1H-pyrazol-3-amine (4.6 g, 55.7 mmol) and l-(5-chlorothiazol-2-yl)ethan-l-one (9 g, 55.7 mmol, 1 equiv) in toluene (220 mL) was added Ti( / PrO)4 (31.6 g, 111.4 mmol. 2 equiv). The reaction mixture was stirred at 110 °C for 2 hours. After completion, the mixture was concentrated under reduced pressure. The crude purified by purified by column chromatography (3% MeOH in DCM) to yield (E)-1-(5-chlorothiazol-2-yl)-N-(1H-pyrazol-3-yl)methanimine (10 g, 80% yield) as a white solid. LCMS (ESI, m / z) [M+H]+= 226.9.Step 2: Synthesis ofN-(l-(5-chlorothiazol-2-yl)ethyl)-lH-pyrazol-3-amine

[0201] To a solution of (E)-1-(5-chlorothiazol-2-yl)-N-(1H-pyrazol-3-yl)methanimine (9.5 g, 41.9 mmol, 1 equiv) in MeOH (200 mL) and THF (20 mL) was slowly added NaBH₄ (5.2 g, 137.1 mmol, 3 equiv) slowly at 0 °C under nitrogen. The reaction was stirred at room temperature for 16 hours. Upon completion as determined by TLC, the reaction mixture was quenched by aqueous NH4CI solution (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (5% MeOHin DCM) to yield N-(l-(5-chlorothiazol-2-yl)ethyl)-177-pyrazol-3-amine (Intermediate C, 7.5 g, 78% yield) as a white solid. ¹H NMR (400 MHz, DMSO): δ 11.60 (s, 1H), 7.66 (s, 1H), 7.38 (s, 1H), 6.03 (br s, 1H), 5.49 (s, 1H), 4.79 – 4.60 (m, 1H), 1.47 (d, J = 6.8 Hz, 3H). LCMS (ESI, m / z) [M+H]⁺ = 229.1.Intermediate DStep 1: Synthesis of 5-(difluoromethoxy)-2-(3-nitro-lH-pyrazol-l-yl)pyrimidine

[0202] To a solution of 3-nitro-l / 7-pyrazole (200 mg, 1.77 mmol, 1 equiv) in DMF (12 mL, 0.15 M) were added 2-chloro-5-(difluoromethoxy)pyrimidine (383 mg, 2.12 mmol, 1.2 equiv) and cesium carbonate (1.44 g, 4.42 mmol, 2.5 equiv). The reaction mixture was stirred at 120 °C for 3 hours. Upon completion as determined by LCMS, the reaction was diluted with water (40 mL) and extracted with EtOAc (40 mL x 3). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (13-30% EtOAc in n-hexane) to yield 5-(difluoromethoxy)-2-(3-nitro-1H-pyrazol-1-yl)pyrimidine (330 mg, 73% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO): δ 8.99 (s, 2H), 8.88 (d, J = 2.8 Hz, 1H), 7.47 (t, J = 72.4 Hz, 1H), 7.36 (d, J = 2.8 Hz, 1H). LCMS (ESI, m / z) [M+H]⁺ = 258.1.Step 2: Synthesis of l-(5-(difluoromethoxy)pyrimidin-2-yl)-lH-pyrazol-3-amine

[0203] To a solution of 5-(difluoromethoxy)-2-(3-nitropyrazol-l-yl)pyrimidine (330 mg, 1.28 mmol, 1 equiv) in MeOH ( 10 mL, 0.13 M) was added 10% palladium on carbon (136 mg, 0.13 mmol, 0.1 equiv) was stirred at 50 °C for 16 hours under H₂ (15 Psi). Upon completion as determined by LCMS, the reaction was filtered and the filtrate was concentrated under reduced pressure to afford 1-(5-(difluoromethoxy)pyrimidin-2-yl)-1H-pyrazol-3-amine (Intermediate D, 290 mg. 99% yield) as a white solid. ¹H NMR (400 MHz, DMSO): δ 8.67 (s, 2H), 8.25 (d, J = 2.4 Hz, 1H), 7.28 (t, J = 73.2 Hz, 1H), 5.88 (d, J = 2.8 Hz, 1H), 5.38 (s, 2H). LCMS (ESI, m / z) [M+H]⁺ = 228.1Example 1: 3-chloro- / V-(l-(3,5-dichlorophenyl)-l / / -pyrazol-3-yl)-2- methylbenzenesulfonamideStep 1: Synthesis of l-(3,5-dichlorophenyl)-lH-pyrazol-3-amine

[0204] To a round bottom flask equipped with a stir bar was added 3 -aminopyridine (200 mg, 2.3 mmol, 1 equiv), 3,5-dichloroiodobenzene (936 mg, 3.4 mmol, 1.5 equiv), cesium carbonate (745 mg, 2.3 mmol, 1 equiv), copper iodide (43.5 mg, 0.23 mmol, 0.1 equiv) and diluted with NMP (23 mL, 0.1 M). The reaction was purged with nitrogen and heated to 120°C overnight. Upon completion as determined by LCMS, the reaction was diluted with water and extracted with DCM (3x 10 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (0-100% EtOAc / DCM) to yield l-(3,5-dichlorophenyl)-lH-pyrazol-3-amine (501 mg, 95% yield) as a light brown solid. LCMS: (ESI, m / z) [M+H]+= 227.9.Step 2: Synthesis of 3-chloro-N-(l-(3,5-dichlorophenyl)-lH-pyrazol-3-yl)-2-methylbenzenesulfonamide

[0205] To a round bottom flask equipped with a stir bar was added l-(3,5-dichlorophenyl)-lH-pyrazol-3-amine (100 mg, 0.4 mmol, 1 equiv), 3-chloro-2-methylbenzyenesulfonyl chloride (148 mg, 0.66 mmol, 1.5 equiv), pyridine (100 uL, 1.3 mmol, 3 equiv), and DCM (2.2 mL, 0.2 M). The reaction was stirred under nitrogen overnight. After completion, the reaction was rotovapped to remove the pyridine and DCM and purified via prep HPLC (Triart Cl 8 column 50 x 30 mm, 5 pm) using 0.1% NaOH in water with a gradient of 5-85% MeCN at 60 mL / min) to afford Compound 1 (142.2 mg, 85% yield) as a white solid. 'H NMR (400 MHz, DMSO): 5 11.40 (s, 1H), 8.47 (s, 1H), 7.99 (dd, J = 8.1, 1.3 Hz, 1H), 7.75 (dd, J = 8.1, 1.3 Hz, 1H), 7.72 (d, J = 1.8 Hz, 2H), 7.48 (t, J = 1.8 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 6.22 (d. J = 2.7 Hz, 1H), 2.66 (s, 3H). LCMS (ESI, m / z) [M+H]+= 415.98.Example 2: (. S,)-A (l-(4-chloro-l,5-dimethyl-l / / -pyrazol-3-yl)ethyl)-3-methyl-[2,2’- bipyridin] -6- amineStep 2 CK N Br N N N NH11'Cl Step 1: Synthesis of 6-chloro-3-methyl-2-(2-pyridyl)pyridine

[0206] To a solution of 2-bromo-6-chloro-3-methylpyridine (175 mg, 0.85 mmol) and tetrakis(triphenylphosphine)palladium(0) (58.7 mg, 0.050 mmol) in toluene (2.4 mL) was added 2-(tributylstannyl)pyridine (343.2 mg, 0.93 mmol). The resulting mixture was stirred and heated to 110°C for 16 hours under nitrogen atmosphere. After cooling to room temperature, the reaction was diluted with ethyl acetate (20 mL) and filtered through celite. The crude material was purified by flash column chromatography (SiCh, 0-70% ethyl acetate in heptanes) to afford 6-chloro-3-methyl-2-(2-pyridyl)pyridine (139 mg. 80% yield) as a tan solid. LCMS: (ESI, m / z) [M+H]+= 205.0.Step 2: Synthesis ofN-[(lS)-l-(4-chloro-l,5-dimethyl-pyrazol-3-yl)ethyl]-5-methyl-6-(2-pyridyl)pyridin-2-amine (Example 2)

[0207] To a solution of 6-chloro-3-methyl-2-(2-pyridyl)pyridine (41 mg, 0.20 mmol), BrettPhos Pd G3 (18.5 mg, 0.020 mmol) and (1S)-1-(4-chloro-1,5-dimethyl-pyrazol-3-yl)ethanamine;hydrochloride (50.5 mg, 0.24 mmol) in 1,4-dioxane (2.0 mL) was added hexamethyldisilazane lithium salt (1 M in THF, 0.60 mL, 0.60 mmol). The resulting mixture was allowed to stir for 20 minutes at room temperature under nitrogen atmosphere and then quenched by the addition on saturated aqueous NH4CI (15 mL). The reaction mixture was extracted using ethyl acetate (2 x 15 mL). The combined organic layer was washed with bring (20 mL), dried over anhydrous MgSC>4, filtered, and concentrated under reduced pressure to isolate a crude mixture. The crude material was purified via prep HPLC (Triart Cl 8 column 50 x 30 mm, 5 pm) using 0.1% formic acid in water with a gradient of 5-50% MeCN at 60 mL / min) to afford Compound 2 (40.8 mg, 0.12 mmol, 59.6% yield). 'H NMR (400 MHz, DMSO) 6 8.64 - 8.59 (m, 2H), 7.54 - 7.49 (m, 2H), 7.31 (d, J= 8.4 Hz, 1H), 6.64 (d, J= 7.9 Hz. 1H), 6.54 (d, J= 8.4 Hz, 1H). 5.13 (q, J= 7.1 Hz, 1H), 3.70 (s, 3H), 2.18 (d, J= 1.9 Hz, 6H), 1.42 (d, J = 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+=342.10.Example 3a / 3b: (5)-2-(6-(((5)-l-(4-chloro-l,5-dimethyl-lH-pyrazol-3- yI)ethyl)amino)pyridin-3-yl)propanenitrile and ( / ?)-2-(6-(( (. )- l-(4-chloro- 1,5-dimethyl- lH-pyrazol-3-yl)ethyl)amino)pyridin-3-yl)propanenitrileStep 1: Synthesis of2-(6-(((S)-l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)amino)pyridin-3-yl)propanenitrile

[0208] To a solution of 2-(6-bromopyridin-3-yl)propanenitrile (400 mg, 1.9 mmol), (S)-l-(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)ethan-l-amine dihydrochloride (467 mg, 1.9 mmol) in THF (6 mL) was added NaOTMS (638 mg, 5.69 mmol) and Gphos Pd G6 (179 mg, 0.19mmol). The resulting mixture was stirred at 50 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiCh, 20% ethyl acetate in petroleum ether) to afford 2-(6-(((S)-1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)amino)pyridin-3-yl)propanenitrile (200 mg, 35% yield) as a yellow oil. LCMS: (ESI, m / z) [M+H]+= 304.1Step 2: Synthesis of (S)-2-(6-(((S)-l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)amino)pyridin-3-yl)propanenitrile and (R)-2-( 6-( < (S)-l-( 4-chloro-l, 5-dimethyl-lH-pyrazol-3-yl)ethyl)amino)pyridin-3-yl)propanenitrile

[0209] 2-(6-(((5)-l -(4-chloro-l, 5-dimethyl-127-pyrazol-3-yl)ethyl)amino)pyridin-3-yl)propanenitrile (200 mg, 0.66 mmol) was separated by chiral SFC (Dai cel Chiralpak IK (250 mm x 30 mm, 10 urn), Supercritical CO2 / EtOH + 0.1% NH4OH = 20 / 80; 80 mL / min) to afford Compound 3a (peak 1, Rt = 1.193 min, 74 mg. 37% yield) and Compound 3b (peak 2. Rt = 1.266 min, 29.6 mg, 15% yield) both as white solid.

[0210] Compound 3a (stereoisomer 1):1H NMR (DMSO-d6, 400 MHz): δ = 7.94 (d, J= 2.4 Hz, 1H), 7.38 (dd, J= 2.4, 8.8 Hz, 1H), 6.84 (d, J= 8.0 Hz, 1H), 6.55 (d, J= 8.8 Hz, 1H), 5.18 - 5.09 (m, 1H), 4.07 (q, J= 7.2 Hz, 1H), 3.69 (s, 3H), 2.18 (s, 3H), 1.47 (d, J= 7.2 Hz, 3H), 1.39 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 304.2.

[0211] Compound 3b (stereoisomer 2):1H NMR (DMSO-d6, 400 MHz): δ = 7.94 (d, J = 2.4 Hz, 1H), 7.39 (dd, J = 2.0, 8.8 Hz, 1H), 6.84 (d, J= 8.0 Hz, 1H), 6.56 (d, J= 8.4 Hz, 1H), 5.18 - 5.09 (m, 1H), 4.08 (q, J = 7.2 Hz, 1H), 3.69 (s, 3H), 2.18 (s, 3H), 1.47 (d, J= 7.2 Hz, 3H), 1.40 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 304.2.Example 4a / 4b: (5)-2-(5-(((5)-l-(4-chloro-l,5-dimethyl-lH-pyrazol-3- yI)ethyl)amino)pyridin-2-yl)propanenitrile and ( / ?)-2-(5-(((A’)-l-(4-chloro-l,5-dimethyl- lH-pyrazol-3-yl)ethyl)amino)pyridin-2-yl)propanenitrileStep 1 step 2Step 1: Synthesis of 2-(5-(((S)-l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)amino)pyridin-2-yl)propanenitrile

[0212] 2-(5-(((S)-l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)amino)pyridin-2-yl)propanenitrile was prepared using the general procedure described for the preparation of Example 3 in Step 1.Step 2: Synthesis of (S)-2-(5-(((S)-l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)amino)pyridin-2-yl)propanenitrile and (R)-2-(5-(((S)-l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)amino)pyridin-2-yl)propanenitrile

[0213] 2-(5-(((< S)-l-(4-chloro-l,5-dimethyl-17f-pyrazol-3-yl)ethyl)amino)pyridin-2-yl)propanenitrile (199 mg. 0.66 mmol) was separated by chiral SFC (Daicel Chiralpak AY (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 85 / 15; 150 mL / min) to afford Compound 4a (peak 1, Rt = 2.225 min, 64.7 mg, 32% yield) and Compound 4b (peak 2, Rt = 2.517 min, 61.2 mg, 31% yield) both as white solid.

[0214] Compound 4a (stereoisomer 1):1H NMR (DMSO-ds, 400 MHz): 5 = 7.93 (d, J = 2.4 Hz, 1H), 7.09 (d, J= 8.4 Hz, 1H), 6.91 (dd, J = 2.8, 8.4 Hz, 1H), 6.35 (d, J = 7.6 Hz, 1H), 4.58 - 4.50 (m, 1H), 4.13 (q, J= 7.2 Hz, 1H), 3.69 (s, 3H), 2.17 (s, 3H), 1.50 - 1.42 (m, 6H). LCMS: (ESI. m / z) [M+H]*= 304.1.

[0215] Compound 4b (stereoisomer 2):1H NMR (DMSO- e, 400 MHz): 5 = 7.92 (d,.7 = 2.8 Hz. 1H), 7.09 (d, J= 8.4 Hz, 1H). 6.91 (dd. J = 2.8, 8.4 Hz, 1H), 6.35 (d,.7= 7.6 Hz, 1H), 4.58 - 4.50 (m, 1H), 4.13 (q, J= 7.2 Hz, 1H), 3.69 (s, 3H), 2.17 (s, 3H), 1.50 - 1.42 (m, 6H). LCMS: (ESI, m / z) [M+H]’= 304.1.Example 5: (S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-5-methylpyridin-2-amineGphos Rd G6 (0.1 equiv)NaOTMS (3 equiv)THF, 50 “C, 1 h

[0216] To a solution of 2-bromo-5-methylpyridine (140 mg, 0.81 mmol) and (5)-l-(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)ethan-l -amine dihydrochloride (200 mg, 0.81 mmol) in THF (5 mL) was added GPhos Pd G6 (77 mg, 0.08 mmol) and NaOTMS (274 mg, 2.44 mmol). The resulting mixture was stirred at 50 °C for 1 hour under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered. The filtrate was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 40-70% / 0.05% NH4OH + 10 mM NH4HCO3 in water) to afford Compound 5 (34 mg. 16% yield) as a clear oil. 'H NMR (DMSO- s, 400 MHz): δ 7.76 (s, 1 H), 7.17 (dd, J= 8.4, 2.0 Hz, 1 H), 6.45 (d, J = 8.4 Hz, 1 H), 6.36 (d, J= 8.0 Hz, 1 H), 5.13 - 5.04 (m, 1 H), 3.68 (s, 3 H), 2.17 (s, 3 H), 2.06 (s, 3 H), 1.37 (d, J= 6.8 Hz, 3 H). LCMS: (ESI, m / z) [M+H]+= 265.1.Example 6: (S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-6-(1H-imidazol-1-yl)-5-methylpyridin-2-amineStep 1Step 1: Synthesis of 6-bromo-2-imidazol-l-yl-3-methyl-pyridine

[0217] To a solution of imidazole (93 mg, 1.37 mmol) in DMF (8 mL) was added NaH (55 mg, 1.37 mmol). After stirring at 0 °C for 30 min, 6-bromo-2-fluoro-3-methyl-pyridine (260 mg, 1.37 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. Then the reaction was quenched with saturated NH4CI solution (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiCh, 50% ethyl acetate in petroleum ether) to afford 6-bromo-2-imidazol-l-yl-3-methyl-pyridine (220 mg, 67% yield) as colorless oil.Step 2: Synthesis of (S)-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-6-(lH-imidazol-l-yl)-5-methylpyridin-2-amine

[0218] To a solution of 6-bromo-2-imidazol-l-yl-3-methyl-pyridine (50 mg. 0.21 mmol) and (5)-l-(4-chloro-L5-dimethyl-lE7-pyrazol-3-yl) ethan-l-amine dihydrochloride (52 mg, 0.21 mmol) in THF (1 mL) was added NaOTMS (71 mg, 0.63 mmol) and GPhos Pd G6 (20 mg, 0.02 mmol). The resulting mixture was stirred at 50 °C for 2 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was fdtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile 20-45% / 0.225% formic acid in water) to afford Compound 6 (28 mg, 40 % yield) as a white solid. 'H NMR (DMSO-tie, 400 MHz): S 7.97 (s, 1H), 7.50 (s, 1H), 7.40 (d, J= 8.4 Hz, 1H), 7.03 (s, 1H). 6.93 (J= 8.0 Hz, 1H), 6.54 (d, J= 8.4 Hz, 1H), 5.12 - 5.01 (m, J = 6.8 Hz, 1H), 3.70 (s, 3H), 2.18 (s, 3H), 2.11 (s, 3H), 1.42 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 331.2Example 7: (S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-5-methyl-6-(1H-pyrazol-1-yl)pyridin-2-aminestep 1 step 2Step 1: Synthesis of 6-bromo-3-methyl-2-pyrazol-l-yl-pyridine

[0219] To a solution of pyrazole (90 mg, 1.32 mmol) in DMF (5 mL) was added NaH (53 mg, 1.32 mmol) under nitrogen atmosphere at 0 °C. After stirring at 0 °C for 30 min, to the reaction was added 6-bromo-2-fluoro-3-methylpyridine (250 mg. 1.32 mmol). The resulting mixture was stirred at room temperature for 2 hours. Then the reaction was quenched with saturated NH4CI solution (10 mL) and extracted with EtOAc (50 mL x 2). The combinedorganic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography (SiC>2, 5% ethyl acetate in petroleum ether) to afford 6-bromo-3-methyl-2-pyrazol-l-yl-pyridine (280 mg, 89% yield) as a white solid.1H NMR (CDC13, 400 MHz): 5 = 8.29 (d, J = 2.4 Hz, 1H), 7.74 (m, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 6.45 (t, J = 2.0 Hz. 1H), 2.57 (s, 3H).Step 2: Synthesis of (S)-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-5-methyl-6-(lH-pyrazol-l-yl)pyridin-2-amine

[0220] To a solution of 6-bromo-3-methyl-2-(1H-pyrazol-1-yl)pyridine (200 mg, 0.84 mmol) and (S)-1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-amine dihydrochloride (146 mg, 0.59 mmol) in THF (4 mL) was added Gphos Pd G6 (80 mg, 0.084 mmol), NaOTMS (283 mg, 2.52 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 1 hour. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase chromatograph (acetonitrile: 0-25% / 0.225% formic acid in water) to afford Compound 7 (104 mg, 37% yield) as a white solid. 'H NMR (DMSO-rfc, 400 MHz): d = 8.28 (s, 1H), 7.69 (s, 1H), 7.35 (d, J= 8.4 Hz, 1H), 6.89 (d, J= 7.2 Hz, 1H), 6.56 - 6.40 (m, 2H), 5.17 - 5.02 (m, 1H), 3.79 (s. 3H), 2.27 (s, 3H). 2.17 (s, 3H),1.43 (d, J = 6.8 Hz, 3H). LCMS: (ESI. m / z) [M+H]+= 331.1.Example 8: (S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-5-methyl-6-(3-methyl-1H-pyrazol-1-yl)pyridin-2-amine

[0221] (S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-5-methyl-6-(3-methyl-1H-pyrazol-1-yl)pyridin-2-amine was prepared using the general procedure described for the preparation of Example 6 by replacing imidazole with 3-methyl-1H-pyrazole in Step 1.

[0222] Compound 8: 'H NMR (DMSO-Js, 400 MHz): d = 8.17 (d. J= 2.4 Hz. 1H), 7.32 (d, J= 8.4 Hz, 1H), 6.84 (d, J= 7.6 Hz, 1H), 6.44 (d, J= 8.4 Hz, 1H), 6.23 (d, J= 2.4 Hz,1H), 5.12 - 5.00 (m, 1H), 3.68 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H), 2.16 (s, 3H), 1.42 (d, J= 7.2 Hz. 3H). LCMS: (ESI, m / z) [M+H]+= 345.2.Example 9: (S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-5-methyl-6-(4-methyl-1H-imidazol-1-yl)pyridin-2-amineStep 1 Step 2

[0223] (S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-5-methyl-6-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine was prepared using the general procedure described for the preparation of Example 6 by replacing imidazole with 4-methyl-1H-imidazole in Step 1.

[0224] Compound 9: 'H NMR (DMSO- >, 400 MHz): d 7.83 (d, J= 1.2 Hz. 1H), 7.36 (d, J= 8.4 Hz, 1H). 7.20 (s. 1H), 6.90 (d. J= 8.0 Hz. 1H), 6.50 (d, J= 8.4 Hz, 1H), 5.09 -5.02 (m, 1H), 3.70 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H), 2.11 (s, 3H), 1.41 (d,.7= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 345.2Example 10: (5)-7V-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-5-methyl-6-(4- methyl- IH-pyrazol- l-yl)pyridin-2-amine

[0225] (S)-jV-(l-(4-chl oro-1, 5-dimethyl- 177-pyrazol-3-y l)ethyl)-5-methyl-6-(4-methyl-177-pyrazol-l-yl)pyridin-2-amine was prepared using the general procedure described for the preparation of Example 6 by replacing imidazole with 4-melhyl-IH-pyrazole in Step 1.

[0226] Compound 10: 'H NMR (DMSO-rfc, 400 MHz): 88.06 (s, 1H), 7.50 (s, 1H), 7.32 (d, J= 8.4 Hz. 1H), 6.85 (d..7= 7.2 Hz. 1H), 6.44 (d, J = 8.4 Hz, 1H), 5.10 - 5.01 (m, 1H), 3.69 (s, 3H), 2.27 (s, 3H), 2.17 (s, 3H), 2.09 (s, 3H), 1.43 (d,.7= 6.8 Hz, 3 H). LCMS: (ESI, m / z) [M+H]+= 345.1.Example 11: (S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-1-(4-fluorophenyl)-1H-pyrazol-3-amineStep 1 Step 2Step 1: Synthesis of l-(4-fluorophenyl)-3-iodo-pyr azole

[0227] To a solution of 3-iodo-17f-pyrazole (2.1 g, 10.72 mmol) and (4- fluorophenyl)boronic acid (1.0 g, 7.15 mmol), in DCM (15 mL) was added Cu(OAc)2 (3.9 g, 21.44 mmol) and pyridine (1.7 mL, 21.4 mmol). The resulting mixture was stirred at room temperature for 16 h under oxygen atmosphere. Then the mixture was filtered and the filtrated was diluted with water (20 mL). The organic phase was separated and the aqueous phase was extracted with DCM (10 mL x 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiCh, 5% ethyl acetate in petroleum ether) to afford l-(4-fluorophenyl)-3-iodo-pyrazole (1.4 g. 68% yield) as a white solid. 'H NMR (CDCh, 400 MHz): 8 = 7.68 (d, J= 2.4 Hz, 1H), 7.67 - 7.60 (m, 2H), 7.15 (t, J = 8.8 Hz, 2H), 6.63 (d, J= 2.4 Hz, 1H). LCMS: (ESI, m / z) [M+H]-= 289.0.Step 2: Synthesis of (S)-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-l-(4-fl uorophenyl) -lH-pyrazol-3-amine

[0228] To a mixture of l-(4-fluorophenyl)-3-iodo-pyrazole (200 mg, 0.7 mmol), (5)- l-(4-chloro-l,5-dimethyl-17f-pyrazol-3-yl)ethan-l-amine dihydrochloride (205 mg, 0.8 mmol) / BuBrettPhos (34 mg, 0.07 mmol) and / BuBrettPhos Pd G3 (59 mg, 0.07 mmol) in THF (3mL) was added LHMDS (2.8 mL. 2.8 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. Then the reaction mixture was quenched with saturated NH4CI solution (5 mL) and extracted with DCM (10 mL x 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 45-75% / 0.225% FA in water) to afford Compound 11 (34.7 mg, 15% yield) as a white solid. 'H NMR (DMSO- >, 400 MHz): S = 8.09 (d, J = 2.8 Hz, 1H), 7.68 - 7.63 (m, 2H), 7.26 - 7.20 (m, 2H), 5.77 - 5.74 (m, 2H), 4.77 - 4.69 (m, 1H). 3.69 (s, 3H), 2.18 (s.3H), 1.43 (d. J = 6.8 Hz. 3H). LCMS: (ESI, m / z) [M+H]+= 334.1.Example 12: (S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-amine

[0229] (S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-amine was prepared using the general procedure described for the preparation of Example 11 by replacing (4-fluorophenyl)boronic acid with (4-methoxyphenyl)boronic acid in Step 1.

[0230] Compound 12:1H NMR (DMSO-d6, 400 MHz): δ= 8.00 (d, J= 2.4 Hz, 1H), 7.56 (d, J= 8.8 Hz, 2H), 6.95 (d, J= 8.8 Hz, 2H), 5.72 (d, J= 2.4 Hz, 1H), 5.63 (d, J= 8.0 Hz,1H), 4.75 - 4.68 (m, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 2.18 (s, 3H), 1.42 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 346.1.Example 13: (S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-1-(5-chloropyrimidin-2-yl)-1H-pyrazol-3-amineStep 1: Synthesis of (S)-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-lH-pyrazol-3-amine

[0231] To a mixture of 3-iodo-IT / -pyrazole (200 mg, 1.0 mmol), (S)-l-(4-chloro-l,5-dimethyl-l / 7-pyrazol-3-yl)ethan-l -amine dihydrochloride (280 mg, 1.15 mmol), / BuBrettPhos Pd G3 (86 mg, 0.1 mmol) and / BuBrettPhos (50 mg, 0.1 mmol) was added LiHMDS (IM in THF, 4.1 mL, 4.1 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 16 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was quenched with saturated NH4CI solution (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiCh, 10% EE (ethyl acetate: ethanol =3:1) in petroleum ether) to afford (5’)-A-(l-(4-chloro-l,5-dimethyl-l / 7-pyrazol-3-yl)ethyl)-177-pyrazol-3-amine (200 mg, 81% yield) as a yellow solid. ’H NMR (DMSO-fifc, 400 MHz): 0 = 11.43 (s, 1H), 7.28 (s, 1H), 5.43 (s, 1H), 5.10 - 4.90 (m, 1H), 4.59 - 4.48 (m, 1H), 3.68 (s, 3H), 2.17 (s, 3H), 1.37 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 240.1.Step 2: Synthesis of (S)-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-lH-pyrazol-3-amme

[0232] To a solution of (S)-A-(l-(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)ethyl)-lE7-pyrazol-3-amine (200 mg, 0.5 mmol) in DMF (3 mL) was added t-BuOK (62 mg, 0.6 mmol) at 0 °C. After stirring at 0 °C for 5 min, 2.5-dichloropyrimidine (75 mg, 0.5 mmol) was added in one portion. The mixture was stirred at room temperature for 3 hours. After quenching with saturated NH4CI solution (1 mL), the mixture was purified by reverse phase chromatography (acetonitrile: 34-64% / 0.225% formic acid in water) to afford Compound 13 (40.3 mg, 23% yield) as a white solid. 'H NMR (DMSO-d6, 400 MHz): <5 = 8.79 (s, 2H), 8.28 (d, J= 2.8 Hz, 1H), 6.18 (d, J= 8.4 Hz, 1H), 5.97 (d, J= 2.8 Hz, 1H), 4.92 - 4.77 (m, 1H), 3.71 (s, 3H), 2.19 (s, 3H), 1.43 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 352.1.Example 14a / 14b: (5)-2-(6-(((5)-l-(4-chloro-l,5-dimethyl-lH-pyrazol-3- yl)ethyl)amino)pyridin-3-yl)-2-cyclopropylacetonitrile and (7?)-2-(6-(((5)-l-(4-chloro- l,5-dimethyl-lH-pyrazoI-3-yl)ethyl)amino)pyridin-3-yl)-2-cyclopropyIacetonitrileStep 1: Synthesis of 2-(6-(((S)-l-(4-chloro-l,5 -dimethyl- IH-pyr azol- 3-yl)ethyl)amino)pyridin-3-yl)-2-cyclopropylacetonitrile

[0233] 2-(6-(((S)-l-(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)ethyl)amino)pyridin-3-yl)-2-cyclopropylacetonitrile was prepared using the general procedure described for the preparation of Example 3 by replacing 2-(6-bromopyridin-3-yl)propanenitrile with 2-(6-bromopyridin-3-yl)-2-cyclopropylacetonitrile in Step 1.Step 2: Synthesis of (S)-2-(6-(((S)-l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)amino)pyridin-3-yl)-2-cyclopropylacetonitrile and (R)-2-( 6-(((S)-l-( 4-chloro-l, 5-dimethyl-lH-pyrazol-3-yl)ethyl)amino)pyridin-3-yl)-2-cyclopropylacetonitrile

[0234] 2-(6-(((S)-l-(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)ethyl)amino)pyridin-3-yl)-2-cyclopropylacetonitrile (100 mg, 0.31 mmol) was separated by chiral SFC (Daicel Chiralpak AD (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH4OH = 65 / 35; 80 mL / min) to afford Compound 14a (peak 1, Rt = 1.327 min. 23.4 mg. 23% yield) and Compound 14b (peak 2, Rt = 1.413 min, 24.2 mg, 23% yield) both as white solid.

[0235] Compound 14a (stereoisomer 1):1H NMR (DMSO-rie, 400 MHz): ri = 7.93 (d, J= 2.0 Hz, 1 H), 7.40 (dd, J= 8.8, 2.4 Hz. 1 H). 6.84 (d, J= 8.0 Hz, 1 H), 6.56 (d, J= 8.8 Hz. 1 H). 5.17 - 5.10 (m. 1 H). 3.69 (s, 3 H), 3.61 (d, J= 8.8 Hz, 1 H), 2.18 (s, 3 H), 1.40 (d. J = 6.8 Hz, 3 H), 1.33 - 1.21 (m, 1 H), 0.70 - 0.59 (m, 1 H), 0.58 - 0.48 (m, 1 H), 0.47 - 0.41 (m, 1 H), 0.39 - 0.31 (m, 1 H). LCMS: (ESI, m / z) [M+H]+= 330.1.

[0236] Compound 14b (stereoisomer 2):1H NMR (DMSO-d6, 400 MHz): <5 = 7.93 (d, J= 2.4 Hz, 1 H), 7.40 (dd, J= 8.8. 2.4 Hz. 1 H). 6.84 (d, J= 8.0 Hz, 1 H), 6.56 (d, J = 8.8 Hz, 1 H), 5.19 - 5.09 (m, 1 H), 3.69 (s, 3 H), 3.61 (d, J= 8.8 Hz, 1 H), 2.18 (s, 3 H), 1.40 (d, J = 6.8 Hz, 3 H), 1.33 - 1.21 (m, 1 H), 0.70 - 0.59 (m, 1 H), 0.58 - 0.48 (m, 1 H), 0.47 - 0.41 (m, 1 H), 0.39 - 0.31 (m, 1 H). LCMS: (ESI, m / z) [M+H]+= 330.1.Example 15: (5)-A-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-5-methyl-6-(l- methyl- 1 H-pyrazoI-4-yl)pyridin-2-amineStep 1: Synthesis of (S)-6-bromo-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-5-methylpyridin-2-amine

[0237] To a solution of 2-bromo-6-fluoro-3-methyl-pyridine (1.0 g, 5.26 mmol) in DMSO (10 mL) was added (S)-l-(4-chloro-1.5-dimethyl-17 / -pyrazol-3-yl)ethanamine dihydrochloride (1.95 g, 7.89 mmol) and K2CO3 (3.64 g, 26.31 mmol). The resulting mixture was stirred at 140 °C for 16 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was diluted with water (10 mL). Then the mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated underreduced pressure. The crude was purified by flash column chromatography (Si Ch. 50% ethyl acetate in petroleum ether) to give (. S')-6-bromo-Af-(l-(4-chloro-l.5-dimethyl-l / / -pyrazol-3-yl)ethyl)-5-methylpyridin-2-amine (990 mg, 55% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+= 343.0.Step 2: Synthesis of (S)-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-5-methyl-6-(l-methyl-lH-pyrazol-4-yl)pyridin-2-amine

[0238] To a solution of (S)-6-bromo-A-(l-(4-chloro-l,5-dimethyl-l / 7-pyrazol-3-yl)ethyl)-5-methylpyridin-2-amine (150 mg, 0.44 mmol) and l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-177-pyrazole (109 mg, 0.52 mmol) in 1,4-dioxane (1.5 mL) and water (0.3 mL) was added Pd(dppf)C12 (32 mg, 0.04 mmol) and K2CO3 (181 mg, 1.31 mmol). The resulting mixture was heated at 100 °C for 1 h under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography (SiCh, 50% ethyl acetate in petroleum ether) to give the crude product, which was re-purified by reverse phase chromatography (acetonitrile: 10-40% / 0.225% formic acid in water) to afford Compound 15 (101 mg, 67% yield) as a white solid. *HNMR (DMSO-rfc, 400 MHz): <5 = 8.01(s, 1H), 7.85 (s, 1H), 7.17 (d, J= 8.4 Hz, 1H), 6.37 (d, J= 8.0 Hz, 1H), 6.32 (d, J= 8.0 Hz, 1H), 5.22 - 5.10 (m, 1H), 3.87 (s, 3H), 3.68 (s, 3H), 2.21 (s, 3H). 2.17 (s, 3H). 1.42 (d, J= 6.8 Hz, 3H). LCMS: (ESI. m / z) [M+H]+= 345.2.Example 16; (A)- / V-(l-(4-chloro-l,5-dimethyl-l H-pyrazol-3-yl)ethyl)-3-methyl-[2,3'- bipyridin]-6-amine

[0239] (< S)-A-(l-(4-chloro-l,5-dimethyl-l / 7-pyrazol-3-yl)ethyl)-3-methyl-[2,3'-bipyridin]-6-amine was prepared using the general procedure described for the preparation of Example 15 by replacing l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-17f-pyrazole with py ri din-3 -ylboronic acid in Step 2.

[0240] Compound 16: ’H NMR (DMSO-tfc, 400 MHz): 8 = 8.72 (s, 1H), 8.54 (d, J = 4.0 Hz. 1H), 7.91 (d. J= 7.6 Hz. 1H), 7.45 - 7.42 (m, 1H), 7.30 (d, J= 8.4 Hz, 1H), 6.60 (d,= 8.0 Hz, 1H), 6.52 (d, J= 8.8 Hz, 1H), 5.22 - 5.09 (m, 1H), 3.70 (s, 3H), 2.20 - 2.11 (m, 6H), 1.42 (d, J= 6.8 Hz. 3H). LCMS: (ESI. m / z) |M-H| = 342.2.Example 17: (A)- / V-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-3-methyl-[2,4'- bipyridin] -6- amineK2CO3 (3 equiv) Pd(dppf)CI2(0.1 equiv) dioxane / H2O, 100 °C, 2 h

[0241] (< S)-A-(l-(4-chloro-l,5-dimethyl-l / f-pyrazol-3-yl)ethyl)-3-methyl-[2,4'-bipyridin]-6-amine was prepared using the general procedure described for the preparation of Example 15 by replacing l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-177-pyrazole with 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine in Step 2.

[0242] Compound 17: ' H NMR (DMSO-tfc, 400 MHz): 8 = 8.61 (d, J= 6.0 Hz, 2H), 7.52 - 7.50 (m. 2H), 7.31 (d, J= 8.4 Hz, 1H), 6.59 (d, J= 8.0 Hz, 1H).6.54 (d, J= 8.4Hz, 1H), 5.19 - 5.09 (m, 1H), 3.70 (s, 3H), 2.20 - 2.15 (m, 6H), 1.42 (d, J = 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 342.2.Example 18: (5)-4-(3-((l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)amino)-lH- pyrazol- l-yl)benzonitrileStep 1: Synthesis of 4-(3-bromopyrazol-l-yl)benzonitrile

[0243] To a solution of 3-iodo-17 / -pyrazole (1.0 g, 5.16 mmol) in DMF (4 mL) was added 4-fluorobenzonitrile (749 mg, 6.19 mmol) and K2CO3 (1.07 g, 7.73 mmol). The mixture was heated to 100 °C for 6 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was diluted with water (50 mL). The mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography (S1O2. 20% ethyl acetate in petroleum ether) to give4-(3-bromopyrazol-l-yl)benzonitrile (0.9 g, 70% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+= 296.0.Step 2: Synthesis of (S)-4-(3-((l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)amino)-lH-pyrazol-l-yl)benzonitrile

[0244] To a solution of 4-(3-iodopyrazol-l-yl)benzonitrile (200 mg, 0.68 mmol), (l< S)-l-(4-chloro-1.5-dimethyl-pyrazol-3-yl)ethanamine dihydrochloride (200 mg, 0.81 mmol). / BuBrettPhos Pd G3 (58 mg, 0.07 mmol) and / BuBrettPhos (33 mg, 0.07 mmol) in THF (3 mL) was added LHMDS (IM in THF, 2.71 mL, 2.71 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. Then the reaction was quenched with saturated NH4CI (10 mL) solution and extracted with EtOAc (50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography (acetonitrile: 20-45% / 0.05% NH4OH + 10 mM NH4HCO3 in water) to afford Compound 18 (31 mg, 13% yield) as a white solid. 'H NMR (DMSO-J6, 400 MHz): d = 8.29 (d. J= 2.8 Hz. 1H), 7.88 - 7.75 (m, 4H), 6.13 (d,,7= 8.0 Hz, 1H), 5.89 (d, J= 2.4 Hz, 1H), 4.84 - 4.73 (m, 1H), 3.69 (s, 3H), 2.18 (s, 3H), 1.44 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 341.1.Example 19: (A)-A-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-l-(pyrimidin-2-yl)- lH-pyrazol-3-amine

[0245] To a mixture of (S)-JV-(l-(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)ethyl)-177-pyrazol-3-amine (200 mg, 0.5 mmol) in DMF (3 mL) was added Z-BuOK (62 mg, 0.6 mmol) at 0 °C. After stirring at 0 °C for 5 min, 2,5-dichloropyrimidine (57 mg, 0.5 mmol) was added in one portion. The mixture was stirred at room temperature for 3 hours. After quenching with saturated NH4CI solution (1 mL), the mixture was purified by reverse phase chromatography (acetonitrile: 26-56% / 0.225% formic acid in water) to afford Compound 19 (11.3 mg, 7% yield) as a white solid. 'H NMR (DMSO-ds, 400 MHz): <5 = 8.70 (d, J= 4.8 Hz, 2H), 8.31 (d, J= 2.8 Hz, 1H), 7.22 (t, J= 4.8 Hz, 1H), 6.04 (d, J= 8.4 Hz, 1H), 5.94 (d, J= 2.4 Hz, 1H), 4.90 - 4.76 (m, 1H), 3.71 (s, 3H), 2.19 (s, 3H), 1.44 (d, J = 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 318.1.Example 20: (5)-A-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-5-methyl-6-(l- methyl-lH-imidazol-4-yl)pyridin-2-amineStep 1: Synthesis of 6-chloro-3-methyl-2-(l-methylimidazol-4-yl)pyridine

[0246] To a solution of 2-bromo-6-chloro-3-methylpyridine (450 mg, 2.18 mmol) and l-methyl-4-(tributylstannyl)-lE7-imidazole (971 mg, 2.62 mmol) in DMF (lOrnL) was added Pd(PPh3)4 (252 mg, 0.22 mmol). The resulting mixture was stirred at 130 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure. The crude was punfied by flash column chromatography (SiCh, 20% ethyl acetate in petroleum ether) to give 6-chloro-3-methyl-2-(l-methylimidazol-4-yl)pyridine (130 mg, 29% yield) as a white oil. LCMS: (ESI, m / z) [M+H]+= 208.1.Step 2: Synthesis of (S)-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-5-methyl-6-(l-methyl-lH-imidazol-4-yl)pyridin-2-amine

[0247] To a solution of 6-chloro-3-methyl-2-(l-methylimidazol-4-yl)pyridine (130 mg, 0.63 mmol) and GS')-l-(4-chloro-l.5-dimethyl-l / / -pyrazol-3-yl)ethan-l-amine dihydrochloride (154 mg, 0.63 mmol) in THF (2 mL) was Gphos Pd G6 (59mg, 0.06 mmol) and NaOTMS (211 mg, 1.88 mmol). The resulting mixture was stirred at 50 °C for 2 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiCh, 50% ethyl acetate in petroleum ether) to give the crude product, which was further purified by reverse phase chromatography (acetonitrile: 9-39% / 0.225% formic acid in water) to afford Compound 20 (56 mg, 26% yield) as a white solid.JH NMR (DMSO-ri6, 400 MHz): <5 = 7.58 (s, 1H), 7.50 (s, 1H). 7.13 (d, J = 8.4 Hz, 1H), 6.32 (d, J= 8.4Hz, 1H), 6.23 (d, J = 8.4 Hz, 1H), 5.18 - 5.09 (m, 1H). 3.72 - 3.68 (m, 6H). 2.43 (s, 3H). 2.18 (s. 3H).1.42 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 345.2.Example 21: (5)-4-(6-((l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)amino)-3- methylpyridin-2-yl)-l-methyl-lH-pyrazole-5-carbonitrile

[0248] (S)-4-(6-((l-(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)ethyl)amino)-3-methylpyridin-2-yl)-l-methyl-l / / -pyrazole-5-carbonitrile was prepared using the general procedure described for the preparation of Example 15 by replacing 1 -methyl-4-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l / / -pyrazole with l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lE / -pyrazole-5-carbonitrile in Step 2.

[0249] Compound 21: 'H NMR (DMSO-cZe, 400 MHz): 3 - 7.99 (s, 1H), 7.28 (d, J = 8.4 Hz, 1H), 6.53 - 6.46 (m, 2H), 5.46 -5.37 (m, 1H), 4.05 (s, 3H), 3.71 (s, 3H). 2.26 (s, 3H), 2.18 (s.3H), 1.41 (d. J = 6.8 Hz. 3H). LCMS: (ESI, m / z) [M+H]+= 370.1.Example 22: (5)-Az-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-5-methyl-6-(2-methyl-2H-l,2,3-triazol-4-yl)pyridin-2-amine

[0250] (< S)- / V-(l-(4-chloro-l,5-dimethyl-17 / -pyrazol-3-yl)ethyl)-5-methyl-6-(2-methyl-27 / -l,2,3-triazol-4-yl)pyridin-2-amine was prepared using the general procedure described for the preparation of Example 15 by replacing l-methyl-4-(4,4,5,5-tetramethyl- l.3.2-dioxaborolan-2-yl)-l / 7-pyrazole with (2-methyl-27 / -l,2,3-triazol-4-yl)boronic acid in Step 2.

[0251] Compound 22: 'H NMR (DMSO-cfc, 400 MHz): <5 = 8.05 (s. 1H), 7.27 (d. J = 8.4 Hz, 1H), 6.61 (d, J= 8.0 Hz, 1H), 6.47 (d, J= 8.4 Hz, 1H), 5.20 - 5.11 (m, 1H), 4.19 (s, 3H), 3.68 (s, 3H), 2.37 (s, 3H), 2.16 (s, 3H), 1.42 (d, J = 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 346.1.Example 23; (5)-7V-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-l-(2,4- difluorophenyl)- IH-py razol-3- amine

[0252] (S)-JV-(l-(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)ethyl)-l-(2,4-difluorophenyl)-l / 7-pyrazol-3-amine was prepared using the general procedure described for the preparation of Example 11 by replacing (4-fluorophenyl)boronic acid with (2,4-difluorophenyl)boronic acid in Step 1.

[0253] Compound 23: ' H NMR (DMSO-i*. 400 MHz): d = 7.85 - 7.70 (m, 2H), 7.50 - 7.39 (m, 1H), 7.18 (t, J = 8.0 Hz, 1H), 5.86 (d, J= 8.4 Hz, 1H), 5.81 (d, J= 2.0 Hz, 1H), 4.76 - 4.68 (m, 1H), 3.69 (s, 3H), 2.18 (s, 3H), 1.43 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 352.2.Example 24: (5)-7V-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-5-methyl-6-(3- methyl- 1H- 1,2, 4- triazol- l-yl)pyridin-2-amineStep 1 Step 2

[0254] (5)-7V-(l-(4-chloro-l,5-dimethyl-lE7-pyrazol-3-yl)ethyl)-5-methyl-6-(3-methyl-l / / -l,2,4-triazol-l-yl)pyridin-2-amine was prepared using the general procedure described for the preparation of Example 6 by replacing imidazole with 3 -methyl- VH- 1.2,4-triazole in Step 1.

[0255] Compound 24: 'H NMR (DMSO-cZe, 400 MHz): 3 = 8.76 (s, 1H), 7.39 (d, J = 8.4 Hz. 1H), 6.98 (d. J = 7.2 Hz, 1H), 6.56 (d, J= 8.4 Hz, 1H), 5.08 - 4.99 (m, 1H), 3.69 (s, 3H), 2.34 (s. 3H), 2.21 (s, 3H). 2.17 (s, 3H), 1.43 (d, J = 6.8 Hz, 3H). LCMS: (ESI. m / z) [M+H]+= 346.2.Example 25: (S)-5-chloro-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)pyridin-2- amineK2CO3(4 equiv)DMSO, 140 °C, 16 h

[0256] To a mixture of 5-chloro-2-fluoropyridine (100 mg, 0.76 mmol) in DMSO (4 mL) was added (5)-l-(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)ethan-l-amine dihydrochloride (225 mg, 0.91 mmol) and K2CO3 (420 mg, 3.04 mmol). The reaction mixture was stirred at 140 °C for 16 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and purified by reverse phase chromatography (acetonitrile: 30-60% / 0.225% FA in water) to afford Compound 25 (28 mg, 13% yield) as a yellow solid.1H NMR (DMSO-tafc, 400 MHz): 8 - 7.93 (d, J= 2.8 Hz, 1H), 7.39 (dd, J= 8.8, 2.4 Hz, 1H), 6.96 (d, J= 8.0 Hz, 1H), 6.56 (d, J = 8.4 Hz. 1H), 5.14 - 5.06 (m, 1H), 3.69 (s, 3H), 2.18 (s, 3H), 1.39 (d, J= 7.2 Hz. 3H). LCMS: (ESI, m / z) [M+H]+= 285.1.Example 26: (A)- -(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-5- (trifluoromethyl)pyridin-2-amine

[0257] (S)-A-(l-(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)ethyl)-5-(trifluoromethyl)pyridin-2-amine was prepared using the general procedure described for the preparation of Example 25 by replacing 5-chloro-2-fluoropyridine with 2-fluoro-5-(trifluoromethyl)pyridine.

[0258] Compound 26: *HNMR (DMSO-<*, 400 MHz): <5 = 8.28 (s, 1H), 7.54 - 7.63 (m, 2H), 6.64 (d, J= 8.8 Hz, 1H), 5.31 - 5.17 (m, 1H), 3.70 (s, 3H), 2.19 (s, 3H), 1.42 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 319.0.Example 27: (A)-7V-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-5-methoxypyridin- 2-amineNH22HCI (1 equiv)Gphos Pd G6 (0.1 equiv)NaOTMS (3 equiv)THF, 50 °C, 1 h

[0259] (S)-N-(f -(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)ethyl)-5-methoxypyridin-2-amine was prepared using the general procedure described for the preparation of Example 5 by replacing 2-bromo-5 -methylpyridine with 2-bromo-5-methoxypyridine.

[0260] Compound 27: 'HNMR (DMSO-rfc. 400 MHz): 3 = 7.69 (d, J= 3.2 Hz. 1H).7.09 (dd, J= 8.8, 2.8 Hz, 1H), 6.51 (d, J= 9.2 Hz, 1H), 6.18 (d, J = 8.8 Hz, 1H), 5.09 - 4.99 (m, 1H), 3.68 (s, 3H), 3.67 (s, 3H), 2.18 (s, 3H), 1.37 (d, J= 6.4 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 281.1.Example 28: (5)-7V-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-5-methyl-6-(4- methyl- 1H- 1,2, 3- triazol- l-yl)pyridin-2-amineStep 1: Synthesis of 6-bromo-3-methyl-2-(4-methyl-lH-l,2,3-triazol-l-yl)pyridine

[0261] To a mixture of 6-bromo-2-fluoro-3-methylpyridine (1.3 g, 6.84 mmol) and 4-methyl-177-l,2,3-triazole (568 mg, 6.84 mmol) in DMSO (7 mL) was added K2CO3 (3.1 g, 13.68 mmol). The resulting mixture was stirred at 80 °C for 16 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was diluted with water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiCh, 0-10% ethyl acetate in petroleum ether) to give 6-bromo-3-methyl-2-(4-methyl-IT / -l.2.3-triazol-l-yl)pyridine (600 mg, 31% yield) as a white solid.XH NMR (CDCh. 400 MHz): 8 = 8.09 (s, 1H), 7.61 (d,.7= 8.0 Hz, 1H), 7.51 (d,.7= 8.0 Hz, 1H), 7.46 (d,.7= 7.6 Hz, 1H), 2.60 (s, 3H), 2.45 (s, 3H).Step 2: Synthesis of (S)-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-5-methyl-6-(4-methyl-lH-1, 2, 3-triazol-l -yl)pyridin-2-amine

[0262] To a mixture of 6-bromo-3-methyl-2-(4-methyl-17 / -l,2,3-triazol-l-yl)pyri dine (100 mg, 0.4 mmol) and (S)-l-(4-chloro-1.5-dimethyl-177-pyrazol-3-yl)ethanamine dihydrochloride (97 mg, 0.4 mmol) in THF (2 mL) was added NaOTMS (140 mg, 1.19 mmol) and GPhos Pd G6 (37 mg, 0.04 mmol). The reaction mixture was stirred at 50 °C for 1 hour under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was diluted with water (5 mL). Then the organic phase was separated and the aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Then the residue was purified by reverse phase chromatography (acetonitrile: 36-66% / 0.05% NTLOH + 10 mM NH4HCO3 in water) to afford the crude product, which was separated using chiral SFC (Daicel Chiralcel OJ (250 mm x 30 mm, 10 urn); Supercritical CO2 / MeOH+NFL’FLO = 80 / 20; 80 mL / min) to afford Compound 28 (28.6 mg, 20% yield) as a white solid.1H NMR (DMSO-<7e, 400 MHz): 3 = 8.16 (s, 1H), 7.45 (d. J= 8.4 Hz. 1H), 7.06 (d, J= 7.6 Hz, 1H), 6.61 (d, J= 8.4 Hz, 1H), 5.08 -5.00 (m, 1H), 3.70 (s, 3H), 2.33 (s, 3H). 2.17 (s, 6H). 1.42 (d, J= 6.8 Hz, 3H). LCMS: (ESI. m / z) [M+H]+= 346.1.Example 29; (A)-A-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-5-methyl-6- (pyrazin-2-yl)pyridin-2- amine

[0263] (S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-5-methyl-6-(pyrazin-2-yl)pyridin-2-amine was prepared using the general procedure described for thepreparation of Example 20 by replacing 1-methyl-4-(tributylstannyl)-1H-imidazole with 2-(tributylstannyl)pyrazine in Step 1.

[0264] Compound 29: *HNMR (DMSO-rfc, 400 MHz): 8 = 9.11 (d, J= 1.6 Hz, 1H), 8.64 (d, J= 2.8 Hz, 1H), 8.57 (d, J= 2.4 Hz, 1H), 7.33 (d, J= 8.4 Hz, 1H), 6.75 (d, J= 8.0 Hz, 1H), 6.60 (d, J= 8.0 Hz, 1H), 5.22 - 5.12 (m, 1H), 3.69 (s, 3H), 2.34 (s, 3H), 2.17 (s, 3H), 1.44 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 343.2.Example 30; (5)-5-chIoro-7V-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyI)thiazoI-2- am inStep 1: Synthesis of (S)-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)thiazol-2-amine

[0265] To a solution of 2-chlorothiazole (150 mg, 1.25 mmol) and (S)-l-(4-chloro- 1.5-dimethyl- 17 / -pyrazol-3-yl)ethan- 1 -amine dihydrochloride (340 mg, 1.38 mmol) in dioxane (6 mL) were added / -BuOK (560 mg, 5.02 mmol) and Pd-PEPPSI-IPent (99 mg. 0.13 mmol). The resulting reaction mixture was stirred at 100 °C for 16 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (SiCh. 60% ethyl acetate in petroleum ether) to give the crude product, which was further purified by reverse phase chromatography (acetonitrile: 28-58% / 0.05% NH4OH + 10 mM NH4HCO3 in water) to give (S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)thiazol-2-amine (40 mg. 12% yield) as a white solid.1H NMR (DMSO-cA. 400 MHz): 87.82 (d, J= 8.0 Hz, 1H). 6.97 (d, J= 3.6 Hz, 1H), 6.55 (d, J= 3.6 Hz. 1H), 4.95 - 4.85 (m, 1H), 3.70 (s, 3H), 2.18 (s, 3H), 1.42 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 257.0.Step 2: Synthesis of (S)-5-chloro-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)thiazol- 2-aminClNCS (1.1 equiv) MeCN, rt, 1 h

[0266] To a solution of (5')- / V-(l-(4-chloro-l,5-dimethyl-l / 7-pyrazol-3-yl)ethyl)thiazol-2-amine (40 mg, 0.16 mmol) in MeCN (2 mL) was added NCS (22 mg, 0.17mmol). The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (50% ethyl acetate in petroleum ether) to give the crude product, which was further purified by reverse phase chromatography (acetonitrile: 39-69% / 0.05% NH4OH + 10 mM NH4HCO3 in water) to afford Compound 30 (9.2 mg, 20% yield) as a white solid. ’H NMR (DMSO- e, 400 MHz): <5 = 8.09 (d, J= 7.6 Hz, 1H). 6.95 (s, 1H), 4.93 - 4.83 (m, 1H), 3.69 (s, 3H), 2.18 (s, 3H), 1.41 (d, J= 7.2 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 290.9.Example 31: (5)-A-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-6-methylpyridazin- 3-aminetBuBrettPhos Pd G3 (0.1 equiv)tBuBrettPhos (0.1 equiv)LiHMDS (4 equiv)THF, rt, 1 h

[0267] To a mixture of 3-bromo-6-methylpyridazine (150 mg, 0.87 mmol) and (5)-l-(4-chloro-l,5-dimethyl-l / 7-pyrazol-3-yl) ethan-l-amine dihydrochloride (235 mg, 0.95 mmol) in THF (3 mL) was added (BuBrettPhos Pd G3 (74 mg, 0.09 mmol) and tBuBrettPhos (42 mg, 0.09 mmol) under nitrogen atmosphere. Then to the resulting mixture was added LHMDS (1 M, 3.47 mL, 3.47 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour. Then it was quenched with saturated NH4CI (15 mL) solution and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 7-37% / 0.225% FA in water) to afford Compound 31 (29 mg, 13% yield) as a yellow oil.1H NMR (DMSO-d₆, 400 MHz): δ = 7.09 (d, J= 9.2 Hz, 1H), 6.82 - 6.75 (m, 2H), 5.26 - 5.18 (m, 1H), 3.69 (s, 3H), 2.34 (s, 3H), 2.18 (s, 3H), 1.42 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 266.1.Example 32: (5)-7V-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-4-phenylthiazol-2- amineGPhos PdG6 TESNaOTMS THF, 50 °C

[0268] To a mixture of 2-bromo-4-phenylthiazole (20 mg. 0.079 mmol, 1 equiv.), (l< S)-l-(4-chloro-l,5-dimethyl-pyrazol-3-yl)ethanamine;hydrochloride (18 mg, 0.087 mmol, 1.1 equiv.), (SP-4-2)-bromo[dicyclohexyl[3-(l,l-dimethylethoxy)-6-methoxy-2',6'-bis(l-methylethyl) [1,1 '-biphenyl] -2-yl-KC1'] phosphine-K ] [4 - [ [2 - (trimethylsilyl)ethoxy] carbonyl] phenyl] palladium (GPhos Pd G6 TES. 7.9 mg, 0.0079 mmol, 0.10 equiv.) and sodium trimethylsilanolate (19 mg. 0.16 mmol. 2.0 equiv.) was added tetrahydrofuran (790 pL. 0.1 M). Resulting solution was heated to 50 °C and stirred for 2 hour. The mixture was cooled to room temperature, added saturated aqueous ammonium chloride (5 mL) and was extracted with isopropyl acetate (5 mL) for 3 times. Organic layers were combined and dried with MgSO4. filtered and concentrated under reduced pressure. The residue was purified by prep HPLC (Triart C 18, 50 x 30 mm, 5 pm; 0.1 % ammonium hydroxide in water / acetonitrile using gradient of 40-80% acetonitrile; 60 rnL / min, 25 °C) to afford Compound 32 (17 mg, 65%) as a yellow solid.1H NMR (DMSO-d₆, 400 MHz) δ 7.98 (d. J = 7.6 Hz, 1H), 7.84 - 7.79 (m, 2H), 7.36 (t,.7= 7.6 Hz, 2H), 7.28 - 7.21 (m, 1H), 7.01 (s, 1H), 5.00 (p, J= 7.0 Hz, 1H), 3.71 (s, 3H), 2.19 (s, 3H), 1.48 (d, J= 6.9 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 333.09.Example 33: (5)-l-(6-((l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)amino)-3- methylpyridin-2-yl)-lH-imidazole-5-carbonitrileStep 2 Step 3Step 1: Synthesis of ethyl (E)-2-((6-bromo-3-methylpyridm-2-yl)imino)acetate

[0269] To a mixture of 6-bromo-3-methylpyridin-2-amine (2.0 g, 10.69 mmol) and ethyl 2-oxoacetate (50% purity in toluene, 2.18 g, 10.69 mmol) in EtOH (20 mL). The reaction mixture was stirred at 50 °C for 3 hours. The crude product was used for next step directly without further purification.Step 2: Synthesis of ethyl l-(6-bromo-3-methylpyridin-2-yl)-lH-imidazole-5-carboxylate

[0270] To the resulting mixture was added K2CO3 (4.2 g, 26.7 mmol), and then 2-tosylacetonitrile (2.0 g, 10.14 mmol) was slowly added. The reaction mixture was stirred at 80 °C for 3 hours After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved in water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography (SiCh, 0-40% ethyl acetate in petroleum ether) to give ethyl l-(6-bromo-3-methylpyridin-2-yl)-177-imidazole-5 -carboxylate (1 g, 30% yield) as a yellow solid.1H NMR (CDCl₃, 400 MHz): δ 7.85 (s, J = 0.8 Hz, 1H), 7.72 (d, J = 0.8 Hz, 1H), 7.60 -7.5 (m, 2H), 4.20 (q, J= 7.2 Hz, 2H), 2.07 (s, 3H), 1.24 (t, J= 7.2 Hz, 3H).Step 3: Synthesis of l-(6-bromo-3-methylpyridin-2-yl)-lH-imidazole-5-carboxamide

[0271] To a solution of ammonia (7 M in MeOH, 8.3 mL, 58.04 mmol) was added ethyl l-(6-bromo-3-methylpyridin-2-yl)-177-imidazole-5-carboxylate (600 mg, 1.93 mmol). The resulting mixture was stirred at 70 °C for 48 hours. After cooling to room temperature, the mixture was filtered and the cake was dried to give l-(6-bromo-3-methylpyridin-2-yl)-177-imidazole-5-carboxamide (280 mg, 51% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+= 281.1.Step 4: Synthesis of l-(6-bromo-3-methylpyridin-2-yl)-lH-imidazole-5-carbonitrile

[0272] To a solution of l-(6-bromo-3-methylpyridin-2-yl)-177-imidazole-5-carboxamide (280 mg, 1 mmol) in pyridine (3 mL) was added 2,2,2-trifluoroacetic anhydride (0.42 mL, 3 mmol). The resulting mixture was stirred at 80 °C for 16 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in water (15 mL) and then was extracted with ethyl acetate (15 mL x 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.The crude was purified by prep-TLC (100% dichloromethane, Rf= 0.4) to give l-(6-bromo-3-methylpyridin-2-yl)-17 / -imidazole-5-carbonitrile (210 mg, 80% yield) as a white solid.1H NMR (DMSO-d₆, 400 MHz): δ 8.50 (s, 1H), 8.11 (s, 1H), 8.00 (d, J= 8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 2.24 (s, 3H).Step 5: Synthesis of (S)- l-(6-((l-(4-chloro- 1,5-dimethyl- lH-pyrazol-3-yl)ethyl)amino)-3-methylpyridin-2-yl)-lH-imidazole-5-carbonitrile

[0273] To a mixture of 1-(6-bromo-3-methylpyridin-2-yl)-1H-imidazole-5-carbonitrile (100 mg, 0.38 mmol) and (S)-1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-amine (94 mg, 0.38 mmol) in THF (2 mL) was added NaOTMS (128 mg, 1.14 mmol), GPhos Pd G6 (36 mg, 0.04 mmol). The reaction mixture was stirred at 50 °C for 1 hour under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and diluted with water (5 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4. filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: 36–66% / 0.05% NH₄OH + 10 mM NH₄HCO₃ in water) to afford Compound 33 (35 mg, 26% yield) as a white solid.1H NMR (DMSO-d₆, 400 MHz): δ = 8.33 (s, 1H), 8.01 (s, 1H), 7.49 (d, J= 8.4 Hz, 1H), 7.11 (d, J = 7.6 Hz. 1H), 6.68 (d. J= 8.4 Hz, 1H), 5.11 - 5.04 (m, 1H), 3.39 (s, 3H), 2.17 (s. 3H), 2.01 (s, 3H), 1.41 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]’ = 356.1.Example 34: (S)-5-chloro-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-3-fluoropyridin-2-amine

[0274] (S)-5-chloro-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-3-fluoropyridin-2-amine was prepared using the general procedure described for the preparation of Example 25 by replacing 5-chloro-2-fluoropyridine with 5-chloro-2,3-difluoropyridine.

[0275] Compound 34:1H NMR (DMSO-d₆, 400 MHz): δ = 7.86 (d, J= 2.0 Hz, 1H), 7.62 (dd, J= 11.2, 2.0 Hz, 1H), 6.81 (d, J= 7.6 Hz, 1H). 5.28 - 5.20 (m, 1H), 3.68 (s, 3H), 2.17 (s, 3H), 1.45 (d, J= 7.2 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 303.0.Example 35; (5)-5-chloro-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-6-(l- methyl-lH-pyrazol-3-yl)pyridin-2-amineStep 1 Step 2Step 3Step 1: Synthesis of2-bromo-3-chloro-6-fluoropyridine

[0276] To a solution of 6-bromo-5-chloropyridin-2-amine (12.0 g, 57.85 mmol) in HF-pyridine (87.6 mL. 972.25 mmol) at 0 °C was added NaNCh (4.8 g, 69.41 mmol) portionwise. After addition, the resulting mixture was stirred at 0 °C for 15 min. and then stirred at room temperature for 30 minutes. Then the reaction mixture was poured onto ice- water, partially neutralized with saturated aqueous Na2COs solution. The mixture was extracted with ethyl acetate (150 mL x 2). The combined organic layers were washed with brine (150 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue w as purified by flash column chromatography (SiCh, solvent gradient: 100% petroleum ether) to give 2-bromo-3-chloro-6-fluoropyridine (10.3 g, 85% yield) as a yellow oil.JH NMR (CDCh, 400 MHz): 87.82 (dd, J= 6.8, 8.4 Hz, 1H), 6.91 (dd, J= 3.6, 8.4 Hz, 1H).Step 2: Synthesis of(S)-6-bromo-5-chloro-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)pyridin-2-amine

[0277] To a solution of 2-bromo-3-chloro-6-fluoropyridine (1.55 g, 7.37 mmol) and (< S’)-l-(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)ethan-l-amine dihydrochloride (2.0 g, 8.1 mmol) was added K2CO3 (4.58 g, 33.15 mmol) in DMSO (40 mL). The resulting mixture was stirred at 140 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiCh, 0-20% EtOAc in petroleum ether) to give (5)-6-bromo-5-chloro-A-(l-(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)ethyl)pyridin-2-amine (1.2 g, 45% yield) as a yellowsolid.1H NMR (DMSO-ofc, 400 MHz): 67.50 (d, J= 8.8 Hz, 1H), 7.44 (d, J= 8.0 Hz, 1H), 6.53 (d, J= 8.8 Hz, 1H), 5.12 - 4.92 (m, 1H), 3.70 (s, 3H), 2.19 (s, 3H). 1.40 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H+2]+= 365.0.Step 3: Synthesis of (S)-5-chloro-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-6-(l-methyl-lH-pyrazol-3-yl)pyridin-2-amine

[0278] To a solution of (S)-6-bromo-5-chloro-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)pyridin-2-amine (100 mg, 0.27 mmol), l-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-17 / -pyrazole (68.6 mg, 0.33 mmol) in 1,4-dioxane (1.5 mL) and water (0.3 mL) was added Pd(dppf)Ch (20 mg, 0.03 mmol) and K2CO3 (114 mg. 0.82 mmol). The resulting mixture was stirred at 100 °C for 1 hour under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography (acetonitrile: 25-55% / 0.225% formic acid in water) to afford Compound 35 (45.4 mg, 44% yield) as a yellow solid.1H NMR (DMSO-d₆, 400 MHz): δ 7.70 (d, J= 1.6 Hz, 1H), 7.42 (d, J= 8.8 Hz, 1H), 6.94 (d, J= 8.0 Hz, 1H), 6.67 (d, J= 2.0 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 5.22 - 5.10 (m, 1H), 3.89 (s, 3H), 3.69 (s, 3H), 2.17 (s, 3H). 1.42 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 365.1.Example 36: (S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-1-(5-chloropyrimidin-2-yl)-4-fluoro-1H-pyrazol-3-amineStep 1: Synthesis of 4-fluoro-3-iodo-lH-pyr azole

[0279] To a solution of 4-fluoro-lL7-pyrazole (500 mg, 5.81 mmol, 1 equiv) in acetonitrile (10 mL, 0.6 M) was added NIS (1.18 g.5.23 mmol, 0.9 equiv). The reaction mixture w as stirred at 75 °C for 16 hours under nitrogen protection. Upon completion as determined by LCMS, the reaction mixture was filtered and concentrated. The material was purified bycolumn chromatography (0-50% ethyl acetate / petroleum ether) to yield 4-fluoro-3-iodo-l / / -pyrazole (530 mg, 43% yield) as a yellow oil. LCMS: (ESI, m / z) [M+H]+= 213.0.Step 2: Synthesis of (S)-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-4-fluoro-lH-pyrazol-3-amine

[0280] To a mixture of 4-fluoro-3-iodo-l / 7-pyrazole (240 mg, 1.13 mmol, 1 equiv), (< S’)-l-(4-chloro-l,5-dimethyl-l / / -pyrazol-3-yl)ethanamine hydrochloride (363 mg, 1.73 mmol.1.5 equiv), / -BuBrettPhos (55 mg, 0.11 mmol, 0.1 equiv) and / -BuBrettPhos Pd G3 (97 mg, 0.11 mmol, 0.1 equiv) in THF (3 mL) was added LiHMDS (1.0 M in THF, 7.93 mL, 7.93 mmol, 7 equiv) dropwise at 0 °C under nitrogen protection. Then the reaction was stirred at room temperature for 2 hours. Upon completion as determined by LCMS, the reaction was quenched with saturated NH4CI solution (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organics were washed with brine, dried over sodium sulfate, fdtered and concentrated. The material was purified by column chromatography (0-50% ethyl acetate / petroleum ether) to yield (S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-4-fluoro-1H-pyrazol-3-amine (250 mg, 86% yield) as a light brown solid. LCMS: (ESI. m / z) [M+H]+= 258.1.Step 3: Synthesis of (S)-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-4-fluoro-lH-pyrazol-3-amine

[0281] To a solution of (S)-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)-4-fluoro-1H-pyrazol-3-amine (145 mg, 0.34 mmol, 1 equiv) and 1-BuOK (42 mg, 0.37 mmol, 1.1 equiv) in DMF (2 mL, 0.2 M) was added 2,5-dichloropyrimidine (50 mg, 0.34 mmol, 1 equiv)) at 0 °C. Then the reaction was stirred at room temperature for 3 hours. Upon completion as determined by LCMS, the reaction mixture was filtered and the filtrate was concentrated. The material was purified via prep HPLC (WePure Biotech XP tC18 column 150 x 30 mm, 7 pm) using 0.225% FA in water with a gradient of 41-71% MeCN at 25 mL / min) to afford Compound 36 (74 mg, 36% yield) as a white solid.1H NMR (400 MHz, DMSO): δ 8.78 (s, 2H), 8.42 (s, 1H), 6.26 (d, J = 7.6 Hz, 1H). 4.98 - 4.83 (m. 1H), 3.70 (s, 3H), 2.19 (s, 3H), 1.47 (d, J = 7.6 Hz, 3H). LCMS (ESI, m / z) [M+H]+= 370.1.Example 37: (5)-5-chloro-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-6-(3- methylisoxazol-5-yl)pyridin-2-aminePd(dppf)Cb (0.1 equiv) K2CO3(3 equiv) dioxane / H2O (0.2 M)

[0282] To a solution of (5)-6-bromo-5-chloro-7V-(l-(4-chloro-l,5-dimethyl-17f-pyrazol-3-yl)ethyl)pyridin-2-amine (100 mg, 0.27 mmol, 1 equiv) and 3-methyl-5-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoxazole (86 mg, 0.41 mmol, 1.5 equiv) in 1,4-dioxane (1 mL) and H2O (0.3 mL) were added Pd(dppf)Cl₂ (20 mg, 0.03 mmol, 0.1 equiv) and K2CO3 (114 mg, 0.82 mmol, 3 equiv). Then the reaction was stirred at 100 °C for 1 hour under nitrogen protection. After completion, the reaction mixture was filtrated and the filtrate was concentrated. The material was purified via prep HPLC (WePure Biotech XP tC 18 column 150 x 30 mm, 7 pm) using 0.225% FA in water with a gradient of 48-78% MeCN at 25 mL / min) to afford Compound 37 (25.9 mg. 26% yield) as a white solid.1H NMR (400 MHz, DMSO): δ 7.55 (d, J= 8.8 Hz, 1H), 7.30 (d, J= 7.6 Hz, 1H), 6.89 (s, 1H), 6.67 (d, J= 9.2 Hz, 1H), 5.24 - 5.10 (m, 1H), 3.71 (s, 3H), 2.31 (s, 3H), 2.18 (s, 3H), 1.44 (d, J= 6.8 Hz, 3H). LCMS (ESI, m / z) [M+H]+= 366.1.Example 38: (5)-5-chloro-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-6-(l- methyl-lH-pyrazol-4-yl)pyridin-2-amine / / Step 1: Synthesis of (S)-6-bromo-5-chloro-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)pyridin-2-amine

[0283] To a solution of 2-bromo-3-chloro-6-fluoro-pyridine (1.5 g, 7.13 mmol, 1 equiv) and (S)-l-(4-chloro-l,5-dimethyl-17 / -pyrazol-3-yl)ethan-l-amine hydrochloride (1.76 g, 8.38 mmol, 1.2 equiv) in DMSO (25 mL) was added K2CO3 (4.43 g, 32.08 mmol). Then the reaction was stirred at 140 °C for 16 hours. Upon completion as determined by LCMS, the reaction was diluted with water (25 mL) and extracted with ethyl acetate (50 x 3 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified by column chromatography (20% ethyl acetate in petroleum ether) to yield (S)-6-bromo-5-chloro-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)pyridin-2-amine (1.6 g, 62% yield) as a yellow solid. 'HNMR (400 MHz, DMSO): δ 7.50 (d, J= 8.8 Hz. 1H), 7.42 (d. J= 8.0 Hz, 1H), 6.53 (d, J= 8.8 Hz, 1H), 5.10 - 4.90 (m, 1H), 3.70 (s, 3H), 2.19 (s, 3H), 1.41 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 363.1.Step 2: Synthesis of (S)-5-chloro-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-6-(l-methyl-lH-pyrazol-4-yl)pyridin-2-amine

[0284] To a solution of (< )-6-bromo-5-chloro-A-(l-(4-chloro-l,5-dimethyl-l / f-pyrazol-3-yl)ethyl)pyridin-2-amine (100 mg, 0.27 mmol, 1 equiv) and 1 -methyl-4-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-177-pyrazole (69 mg, 0.33 mmol, 1.2 equiv) in 1,4-dioxane (1 mL) and water (0.3 mL) were added Pd(dppf)Cl₂ (20 mg, 0.03 mmol, 0.1 equiv) and K2CO3 (114 mg, 0.82 mmol, 3 equiv). Then the reaction was stirred at 100 °C for 1 hour under nitrogen. Upon completion as determined by LCMS, the reaction mixture was filtered and the filtrate was concentrated. The material was purified by via prep HPLC (WePure Biotech XP t C18 column 150 x 30 mm, 7 pm) using 0.225% FA in water with a gradient of 43-73% MeCN at 25 mL / min) to afford Compound 38 (63 mg, 63% yield) as a white solid. 'H NMR (400 MHz, DMSO): δ 8.28 (s, 1H), 8.02 (s, 1H), 7.38 (d, J= 8.4 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.41 (d, J= 8.8 Hz, 1H), 5.18 - 5.15 (m, 1H), 3.88 (s, 3H), 3.69 (s, 3H), 2.17 (s, 3H), 1.43 (d, J= 6.8 Hz, 3H). LCMS (ESI, m / z) [M+H]+= 365.1.Example 39: (X)-A-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-5-methyl-6-(l,2,4- triazin-6-yl)pyridin-2-amineStep 3 Step 4Step 1: Synthesis of 6-chloro-3-methyl-2-(tributylstannyl)pyridine

[0285] To a solution of 2-bromo-6-chloro-3-methylpyridine (2.0 g, 9.69 mmol, 1 equiv) in THF (40 mL, 0.2 M) was added n-BuLi (2.5 M, 4.26 mL, 10.66 mmol, 1.1 equiv) slowly at -30°C under nitrogen atmosphere. After stirring at -30 °C for 30 min, tributylchlorostannane (4.1g, 12.59 mmol, 1.3 equiv) was added slowly. Then the reaction waswarmed to room temperature and stirred for 2 h. After completion, the reaction mixture was quenched with aqueous NH4Cl solution (20 mL) and then extracted with EtOAc (20 mL x 3). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified by column chromatography (0-20% ethyl acetate in hexane) to yield 6-chloro-3-methyl-2-(tributylstannyl)pyridine (2 g, 50% yield) as a yellow oil.Step 2: Synthesis of 6-(6-chloro-3-methylpyridin-2-yl)-l,2,4-triazin-3-amine

[0286] To a solution of 6-chloro-3-methyl-2-(tributylstannyl)pyridine (1.5 g, 3.60 mmol, 1 equiv) and 6-bromo-l,2,4-triazin-3-amine (756 mg, 4.32 mmol, 1.2 equiv) in dioxane (25 mL) were added Pd(PPh3)2Cb (263 mg, 0.18 mmol, 0.05 equiv), Cui (68 mg, 0.36 mmol, 0.1 equiv) and CsF (1.09 g, 7.2 mmol, 2 equiv). The mixture was heated at 100 °C for 16 h under nitrogen atmosphere. After completion, the reaction was diluted with water and extracted with EtOAc (10 mL x 3). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified by prep HPLC (Welch Xtimate C18 column 150 x 30 mm. 5 pm) using 10 mM NH4HCO3 in water with a gradient of 30-60% MeCN at 25 mL / min) to yield 6-(6-chloro-3-methylpyridin-2-yl)-l,2,4-triazin-3-amine (500 mg, 63% yield) as a white solid. 'H NMR (400 MHz, CDCls): δ 8.94 (s, 1H), 7.62 (d, J= 8.0 Hz, 1H), 7.28 (d, J= 8.0 Hz, 1H), 5.44 (s, 2H), 2.65 (s, 3H).Step 3: Synthesis of 6-(6-chloro-3-methylpyridin-2-yl)-l,2,4-triazine

[0287] To a solution of 6-(6-chloro-3-methylpyridin-2-yl)-l,2,4-triazin-3-amine (300 mg, 1.35 mmol) in THF (5 mL) was added isopentyl nitrite (0.55 mL, 4.06 mmol, 3 equiv). Then the reaction was stirred at 60 °C for 16 h. After completion, the reaction was diluted with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified by column chromatography (0-20% ethyl acetate in / ?-hexane) to yield 6-(6-chloro-3-methylpyridin-2-yl)-l,2,4-triazine (100 mg, 36% yield) as a white solid. T1 NMR (400 MHz, CDCh): <59.70 (s, 1H), 9.37 (s, 1H). 7.70 (d, J= 8.0 Hz, 1H), 7.39 (d. J= 8.0 Hz. 1H), 2.72 (s, 3H).Step 4: Synthesis of (S)-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-5-methyl-6-(1,2, 4-triazm-6-yl)pyridin-2-amine

[0288] To a mixture of6-(6-chloro-3-methylpyridin-2-yl)-l,2,4-triazine (70 mg, 0.34 mmol, 1 equiv), (5 -l-(4-chloro-l,5-dimethyl-l / 7-pyrazol-3-yl)ethan-l-amine hydrochloride (109 mg, 0.52 mmol, 1.5 equiv), / -BuBrettPhos (16 mg, 0.03 mmol) and / -BuBrettPhos Pd G3 (29 mg, 0.03 mmol) in THF (3 ml) was added LiHMDS (1.0 M in THF, 1.69 mL, 1.69 mmol, 5 equiv) dropwise under nitrogen atmosphere. Then the reaction was stirred at room temperature for 2 h. After completion, the reaction was diluted with water (10 mL) and then extracted with EtOAc (20 mL x 3). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified by prep HPLC (Welch Xtimate C 18 column 150 x 30 mm, 5 pm) using 10 mM NH4HCO3 in water with a gradient of 45-75% MeCN at 25 mL / min) to afford Compound 39 (2.1 mg, 1.6% yield) as a white solid. 'H NMR (400 MHz, DMSO): δ 9.72 (s, 1H), 9.22 (s, 1H), 7.41 (d, J= 8.8 Hz, 1H), 6.96 (d, J = 7.2 Hz, 1H), 6.67 (d, J= 8.0 Hz, 1H), 5.20 - 5.11 (m, 1H), 3.69 (s, 3H), 2.40 (s. 3H), 2.16 (s, 3H), 1.45 (d. J= 6.8 Hz. 3H). LCMS (ESI, m / z) [M+H]+= 344.1.Example 40: (> S)-4-(6-((l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)amino)-3- methylpyridin-2-yl)-l-methyl-lH-pyrazole-5-carbonitrileStep 1: Synthesis of (S)-6-bromo-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-5-methylpyridin-2-amine

[0289] To a solution of 2-bromo-6-fluoro-3-methyl-pyridine (1.0 g, 5.26 mmol, 1 equiv) in DMSO (10 mL, 0.5 M) were added fS')-l-(4-chloro-l.5-dimethyl-l / / -pyrazol-3-yl)ethanamine hydrochloride (1.95 g, 9.28 mmol, 1.8 equiv) and K2CO3 (3.64 g, 26.31 mmol, 5 equiv). The resulting mixture was stirred at 140 °C for 16 h under nitrogen atmosphere. Upon completion as determined by LCMS, the reaction mixture was filtered and the filtrate was diluted with water (10 mL). Then the mixture was extracted with ethyl acetate (10 mL x 2). The combined organic phases were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The material was purified by column chromatography (0-50% ethyl acetate / petroleum ether) to yield GS)-6-bromo-Ar-(l-(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)ethyl)-5-methylpyridin-2-amine (990 mg, 55% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+= 343.0.Step 2: Synthesis of (S)-4-(6-((l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)amino)-3-methylpyridin-2-yl) -1 -methyl- lH-pyrazole-5 -carbonitrile

[0290] To a solution of (, S')-6-bromo-Af-( I -(4-chloro-l.5-dimethyl- l / / -p razol-3-yl)ethyl)-5-methylpyridin-2-amine (100 mg, 0.29 mmol, 1 equiv) and l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-17f-pyrazole-5-carbonitrile (81 mg, 0.35 mmol, 1.2 equiv) in 1,4-dioxane (1 mL) and water (0.2 mL) were added Pd(dppf)Ch (21 mg, 0.03 mmol, 0.1 equiv) and K2CO3 (120.65 mg, 0.87 mmol). The reaction mixture was stirred at 100 °C for 1 hour under nitrogen atmosphere. Upon completion as detennined by LCMS. the reaction mixture was filtered and diluted with water (5 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified via prep HPLC (WePure Biotech XP tC18 column 150 x 30 mm, 7 pm) using 0.225% FA in water with a gradient of 36-66% MeCN at 25 mL / min) to afford Compound 40 (59 mg, 54% yield) as a brown solid.!H NMR (400 MHz, DMSO): 8 7.99 (s, 1H), 7.28 (d, J= 8.4 Hz, 1H), 6.46 - 6.53 (m, 2H), 5.46 - 5.37 (m, 1H), 4.05 (s, 3H), 3.71 (s, 3H), 2.26 (s, 3H), 2.18 (s, 3H), 1.41 (d, J= 6.8 Hz, 3H). LCMS (ESI, m / z) [M+H]+= 370.1.Example 41: (5)-4-(6-((l-(4-chloro-l,5-dimethyI-lH-pyrazol-3-yl)ethyl)amino)-3- methylpyridin-2-yl)-l-methyl-lH-pyrazole-5-carbonitrileStep 1: Synthesis of (S)-2-bromo-6-( (l-( 4-chloro-l, 5-dimethyl- lH-pyrazol-3-yl)ethyl)amino)nicotinonitrile

[0291] To a solution of 2-bromo-6-fluoro-pyridine-3-carbonitrile (1 g, 4.98 mmol, 1 equiv) in DMSO (30 mL, 0.2 M) were added (S)-l -(4-chloro-l, 5-dimelhyl-l / / -pyrazol-3-yl)ethanamine (1.04 g, 5.99 mmol, 1.2 eq) and K2CO3 (2.06 g, 14.93 mmol, 3 equiv). The resulting mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. Upon completion as determined by LCMS, the reaction mixture was filtered and the filtrate was diluted with water (100 mL). Then the mixture was extracted with ethyl acetate (100 mL x 3). The combinedorganic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified by column chromatography (0-40% ethyl acetate / petroleum ether) to yield (S)-2-bromo-6-((l-(4-chloro-l,5-dimethyl-17 / -pyrazol-3-yl)ethyl)amino)nicotinonitrile (1.4 g, 79% yield) as a yellow solid. 'H NMR (400 MHz, DMSO): δ 8.35 (d, J = 5.2 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 6.59 (d, J = 4.8 Hz, 1H), 5.25 -5.16 (m, 1H), 3.71 (s, 3H). 2.19 (s, 3H), 1.43 (d. J = 6.8 Hz. 3H). LCMS (ESI, m / z) [M+H]+= 354.0.Step 2: Synthesis of (S)-4-(6-((l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)amino)-3-methylpyridin-2-yl)-l-methyl-lH-pyrazole-5-carbonitrile

[0292] To a solution of (S)-2-bromo-6-((l-(4-chloro-l,5-dimethyl-l / / -pyrazol-3-yl)ethyl)amino)nicotinonitrile (100 mg, 0.28 mmol, 1.0 equiv) and 1 -methyl-3-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-17 / -pyrazole (88 mg, 0.42 mmol, 1.5 equiv) in 1,4-dioxane (2 mL) and water (0.2 mL) were added Pd(dppf)C12 (21 mg, 0.03 mmol, 0.1 equiv) and K2CO3 (117 mg, 0.85 mmol, 3 equiv). The reaction mixture was heated at 100 °C for 16 hours under nitrogen atmosphere. Upon completion as determined by LCMS, the reaction mixture was filtered and the filtrate was concentrated. The material was purified by column chromatography (0-50% ethyl acetate / petroleum ether) to give the crude product, which was further purified via prep HPLC (WePure Biotech XP t C18 column 150 x 30 mm, 7 pm) using 0.225% formic acid in water with a gradient of 35-65% MeCN at 25 mL / min) to afford Compound 41 (44.8 mg, 45% yield) as a white solid.JH NMR (400 MHz, DMSO): 57.85 (d, J= 7.6 Hz, 1H), 7.77 (d, J= 2.0 Hz, 1H), 7.65 (d, J= 8.4 Hz, 1H), 6.77 (d, J= 2.4 Hz, 1H), 6.53 (d, J= 8.0 Hz, 1H). 5.35 - 5.25 (m, 1H), 3.91 (s. 3H), 3.70 (s, 3H), 2.18 (s, 3H), 1.45 (d, J= 6.8 Hz. 3H). LCMS (ESI, m / z) [M+H]+= 356.3.Example 42: (X)-6-((l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)amino)-2-(l-methyl- 1H- pyrazol-4-yl)nicotinonitrilePdfdppfiCb (0 1 equiv) K2CO3(3 equiv) dioxane / HzO (0 1 M)

[0293] To a solution of (S)-2-bromo-6-((l-(4-chloro-l,5-dimethyl-17 / -pyrazol-3-yl)ethyl)amino)nicotinonitrile (50 mg, 0.14 mmol, 1 equiv) and 1 -methyl-4-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l / 7-pyrazole (44 mg, 0.21 mmol, 1.5 equiv) in 1,4-dioxane (1 mL) and water (0.1 mL) were added Pd(dppf)Cl2 (10 mg, 0.01 mmol, 0.1 equiv) and K2CO3 (58 mg, 0.42 mmol. 3 equiv). The reaction mixture was heated at 100 °C for 16 hours under nitrogen atmosphere. Upon completion as determined by LCMS, the reaction mixture was filtered and the filtrate was concentrated. The material was purified by column chromatography (0-50% ethyl acetate / petroleum ether) to give the crude product, which was further purified via prep HPLC (WePure Biotech XP t C18 column 150 x 30 mm, 7 pm) using 0.225% formic acid in water with a gradient of 40-70% MeCN at 25 mL / min) to afford Compound 42 (25.5 mg, 51% yield) as a white solid.1H NMR (400 MHz, DMSO): δ 8.30 (s, 1H), 8.07 (s, 1H), 7.85 (d, J= 7.6 Hz, 1H), 7.62 (d, J= 8.8 Hz, 1H), 6.45 (d, J= 8.8 Hz, 1H), 5.38 - 5.25 (m. 1H), 3.91 (s. 3H), 3.70 (s, 3H), 2.18 (s, 3H), 1.46 (d. J= 6.8 Hz, 3H). LCMS (ESI, m / z) [M+H]+= 356.1.Example 43: (X)-6-((l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)amino)-2-(3-methyl- 1H- pyrazol- l-yl)nicotinonitrileDMIOACH (04 equiv) Cui (0.4 equiv) Cl K2CO3(3 eq) Cl dioxane (0.14 M)

[0294] To a solution of (S)-2-bromo-6-((l-(4-chloro-l,5-dimethyl-lL7-pyrazol-3-yl)ethyl)amino)nicotinonitrile (100 mg. 0.28 mmol, 1 equiv) and 3-methyl-lL7-pyrazole (26 mg, 0.31 mmol, 1.1 equiv) in 1,4-di oxane (2 rnL, 0.14 M) were added Cui (21 mg, 0.11 mmol, 0.4 equiv), DMDACH (16 mg, 0.11 mmol, 0.4 equiv) and K2CO3 (117 mg, 0.85 mmol, 3 equiv). The reaction mixture was heated at 100 °C for 16 hours under nitrogen atmosphere. Upon completion as determined by LCMS, the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (5 rnL x 3). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified via prep HPLC (WePure Biotech XP t C18 column 150 x 30 mm, 7 pm) using 0.225% formic acid in water with a gradient of 50-80% MeCN at 25 mL / min) to afford Compound 43 (25.5 mg, 51% yield) as a white solid. 'H NMR (400 MHz, DMSO): δ 8.39 (d, J= 2.4 Hz, 1H), 8.29 - 8.16 (m, 1H), 7.71 (d, J= 9.2Hz, 1H), 6.51 (d, J= 8.4 Hz, 1H), 6.39 (d, J= 2.4 Hz, 1H), 5.30 - 5.15 (m, 1H), 3.69 (s, 3H), 2.26 (s, 3H), 2.17 (s, 3H), 1.47 (d, J= 6.8 Hz, 3H). LCMS (ESI, m / z) [M+H]+= 356.1.Example 44: (5)-l-(5-chloropyrimidin-2-yl)-N-(l-(2,3-difluorophenyl)ethyl)-lH-pyrazol- 3-amineStep 1: Synthesis of (S)-N-(l-(2,3-difluorophenyl)ethyl)-lH-pyrazol-3-amine

[0295] To a solution of 3-iodo-17 / -pyrazole (200 mg, 1.03 mmol, 1 equiv) and (5)-l-(2,3-difluorophenyl)ethan-l -amine hydrochloride (220 mg. 1.13 mmol, 1.1 equiv) in THF (4 mL) were added / -BuBrettPhos Pd G3 (92 mg, 0.1 mmol, 0.1 equiv), / -BuBrettPhos (55 mg, 0.1 mmol, 0.1 equiv) and LiHMDS (1.0 M in THF, 4.12 mL, 4.12 mmol, 4 equiv) at 0 °C under N2. Then the reaction was stirred at room temperature for 3 hours. Upon completion as determined by LCMS, the reaction was quenched with saturated NH4CI solution (5 mL) and extracted with EtOAc (10 mL x 3). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified by column chromatography (0-2% MeOH / DCM) to yield (< S)-Ar-(l-(2,3-difluorophenyl)ethyl)-17F-pyrazol-3-amine (180 mg, 78% yield) as a yellow oil. 'H NMR (400 MHz, DMSO): <5 11.41 (s, 1H), 7.29 - 7.16 (m, 3H). 7.14 - 7.06 (m. 1H), 5.82 (d. J= 7.2 Hz. 1H), 5.38 (s, 1H), 4.86 -4.73 (m, 1H), 1.38 (d, J= 12 Hz, 3H). LCMS (ESI, m / z) [M+H]+= 224.2.Step 2: Synthesis of (S)-l-(5-chloropyrimidin-2-yl)-N-(l-(2,3-difluorophenyl)ethyl)-lH-pyrazol-3-amine

[0296] To a mixture of ( )- / V-(l-(2,3-difluorophenyl)ethyl)-l / 7-pyrazol-3-amine (100 mg, 0.45 mmol, 1 equiv) and t-BuOK (126 mg, 1.12 mmol, 2.5 equiv) in DMF (3 mL, 0.15 M) was added 2, 5-di chloropyrimidine (67 mg, 0.45 mmol, 1 equiv) at 0 °C. After completion, the reaction was filtered and the filtrate was purified via prep HPLC (Phenomenex Gemini-NX C18 column 150 x 40 mm, 5 pm) using 0.05% HC1 in water with a gradient of 50-80% MeCN at 25 mL / min) to afford Compound 44 (31.9 mg, 21% yield) as a yellow solid.1H NMR (400 MHz, DMSO): ri 8.77 (s, 2H), 8.29 (d, J= 2.8 Hz, 1H), 7.34 - 7.21 (m, 2H), 7.19 - 7.12 (m, 1H), 5.95 (d, J= 2.8 Hz, 1H), 5.05 (q, J= 6.8 Hz, 1H), 1.44 (d, J= 6.8 Hz. 3H). LCMS (ESI, m / z) [M+H] ' = 336.1.Example 45: (N)-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-l-(5-chloropyridin- 2-yl)-lH-pyrazol-3- amine

[0297] To a mixture of (S)-JV-(l-(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)ethyl)-17f-pyrazol-3-amine (100 mg, 0.42 mmol, 1 equiv) and Z-BuOK (117 mg, 1.04 mmol, 2.5 equiv) in DMF (2 mL) was added 5-chloro-2-fluoropyridine (60 mg, 0.46 mmol. 1.1 equiv). The mixture was stirred at room temperature for 2 h. After completion, the reaction was filtered and the filtrate was purified via prep HPLC (Phenomenex Gemini-NX C18 column 150 x 30 mm, 5 pm) using 0.225% formic acid in water with a gradient of 55-85% MeCN at 25 mL / min) to afford Compound 45 (25.7 mg, 18% yield) as a white solid. 'H NMR (400 MHz, DMSO): 8 8.35 (d, J= 2.4 Hz, 1H). 8.20 (d, J= 2.8 Hz, 1H), 7.96 (dd, J= 2.4, 8.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 6.11 (d, J= 8.4 Hz, 1H), 5.87 (d, J= 2.4 Hz, 1H), 4.82 - 4.72 (m, 1H), 3.69 (s, 3H), 2.18 (s, 3H), 1.44 (d, J= 6.8 Hz, 3H). LCMS (ESI, m / z) [M+H]+= 351.1.Example 46: (5)-A-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-l-(6,7- dihydrofuro[3,2-d]pyrimidin-2-yl)-lH-pyrazol-3-amineStep 3Step 1: Synthesis of 2-chlorofuro[3,2-d]pyrimidine

[0298] To a solution of 2,4-dichlorofuro[3,2-<7] pyrimidine (1.3 g, 6.9 mmol, 1 equiv) and acetic acid (2.4 mL, 41.3 mmol, 6 equiv) in MeOH (13 mL, 0.5 M) was added zinc dust (1.80 g, 27.5 mmol, 4 equiv). Then the reaction was heated at 70 °C for 4 h under nitrogen atmosphere. After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified (0-18% petroleum ether / ethyl acetate) to yield 2-chlorofuro[3,2-<7]pyrimidine (460 mg, 43% yield) as a white solid. ' H NMR (400 MHz, DMSO): d 9.16 (s, 1H), 8.68 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H).Step 2: Synthesis of 2-chloro-6, 7-dihydrofuro[3,2-d]pyrimidine

[0299] To a solution of 2-chlorofuro[3,2-or] pyrimidine (280 mg, 1.8 mmol, 1 equiv) in EtOH (20 mL) was added Rh / C (10% wt., 0.932 mg, 0.9 mmol, 0.5 equiv). Then the reaction was stirred at room temperature for 32 h under hydrogen atmosphere (45 psi). After completion, the reaction was filtered and the filtrate was concentrated to yield 2-chloro-6,7-dihydrofuro[3,2-<7]pyrimidine (240 mg crude) as a white solid. 'H NMR (400 MHz, DMSO): δ 7.95 (s, 1H), 4.68 (t, J= 8.8 Hz, 2H), 3.29 (t, J= 8.8 Hz, 2H).Step 3: Synthesis of (S)-N-(l-(4-chloro- 1,5-dimethyl-lH-pyrazol-3-yl)ethyl)- 1-(6, 7-dihydrofuro[3,2-d]pyrimidin-2-yl)-lH-pyrazol-3-amine

[0300] To a solution of 2-chloro-6,7-dihydrofuro[3,2-<7]pyrimidine (50 mg, 0.3 mmol, 1 equiv) in 1,4-dioxane (2 mL, 0.15 M) were added ( )-jV-(l-(4-chloro-l,5-dimethyl-H / -pyrazol-3-yl)ethyl)-177-pyrazol-3-amine (77.5 mg, 0.3 mmol), t-BuXPhos Pd G3 (26 mg, 0.03 mmol, 0.1 equiv) and K3PO4 (193 mg, 0.9 mmol. 3 equiv). The mixture was stirred at 100 °C for 16 hours under nitrogen atmosphere. After completion, the reaction was diluted with water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organics w ere washed with brine, dried over sodium sulfate, filtered and concentrated. The material w as purified via prep HPLC (Phenomenex Gemini -NX C18 column 150 x 30 mm, 3 pm) using 0.05% NH.vFLO + 10 mM NH4HCO3 in water with a gradient of 33-63% MeCN at 25 mL / min) to afford Compound 46 (17.3 mg, 28%) as awhite solid. ‘H NMR (400 MHz, DMSO): δ 8.19 (d, J = 2.8 Hz, 1H), 8.14 (s, 1H), 5.86 - 5.83 (m, 2H), 4.87- 4.86 (m, 1H), 4.69 (t, J= 8.8 Hz, 2H), 3.71 (s, 3H), 3.35 (t, J= 8.8 Hz, 2H), 2.20 (s, 3H), 1.44 (d, J= 6.8 Hz, 3H). LCMS (ESI. m / z) [M+H]+= 360.1.Example 47: (X)-A (l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-l-(5- methoxypyrimidin-2-yl)-lH-pyrazol-3-aminef-BuOK (2.5 equiv) DMF (0.2M)

[0301] To a mixture of (S)-A-(l-(4-chloro-l,5-dimethyl-lL7-pyrazol-3-yl)ethyl)-17f-pyrazol-3-amine (100 mg, 0.42 mmol, 1 equiv) and t-BuOK (117 mg, 1.04 mmol, 2.5 equiv) in DMF (2 mL) at 0 °C was added 2-chloro-5-methoxypyrimidine (120 mg. 0.83 mmol, 2 equiv). The mixture was stirred at room temperature for 16 h. After completion, the reactionwas filtered and the filtrate was purified via prep HPLC (Phenomenex Gemini NX C18 column 150 x 30 mm, 5 pm) using 0.225% FA in water with a gradient of 35-65% MeCN at 25 mL / min) afford Compound 47 (16.9 mg, 11% yield) as a yellow solid. 'H NMR (400 MHz, DMSO): δ 8.47 (s, 2H), 8.20 (d, J= 2.8 Hz, 1H), 5.93 - 5.83 (m, 2H), 4.86 - 4.73 (m, 1H), 3.90 (s, 3H), 3.70 (s, 3H), 2.19 (s, 3H), 1.43 (d, J= 6.8 Hz, 3H). LCMS (ESI, m / z) [M+H]+= 348.1.Example 48: (5)-7V-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-l-(5,7- dihydrofuro [3,4-d] pyrimidin-2-yI)-lH-pyrazoI-3-aminet-BuOK (2.5 equiv) - 1 DMF (0.2 M)

[0302] To a mixture of (5)- N- 1 -(4-chloro-l, 5-di methyl- 17 / -py razol-3-yl)ethyl)-l / 7-pyrazol-3-amine (100 mg, 0.42 mmol, 1 equiv) and i-BuOK (117 mg, 1.04 mmol, 2.5 equiv) in DMF (2 mL) at 0 °C was added 2-chloro-5,7-dihydrofuro[3,4-< / ]pyrimidine (72 mg, 0.46 mmol, 1.1 equiv). The mixture was stirred at room temperature for 16 h. After completion, the reaction was filtered and the filtrate was purified via prep HPLC (WePure Biotech XP tC18 column 150 x 30 mm. 7 pm) using 0.225% formic acid in water with a gradient of 28-58% MeCN at 25 mL / min) to afford Compound 48 (13.9 mg, 9% yield) as a yellow solid. 'H NMR (400 MHz, DMSO): δ 8.63 (s, 1H), 8.31 (d, J= 2.8 Hz, 1H), 6.07 (d, J= 8.4 Hz, 1H), 5.93 (d, J= 2.8 Hz, 1H), 5.08 (s, 2H), 4.95 (s, 2H), 4.87 - 4.79 (m, 1H), 3.71 (s, 3H), 2.19 (s, 3H), 1.43 (d, J= 6.8 Hz, 3H). LCMS (ESI, m / z) [M+H]+= 360.1.Example 49: (A')- / V-(l -(4-chIoro-l,5-dimethyI-l H-pyrazol-3-yl)ethyl)-l -(5- methylpyrimidin-2-yl)-lH-pyrazol-3-amine

[0303] To a mixture of (S)- / V-(l-(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)ethyl)-17f-pyrazol-3-amine (100 mg, 0.42 mmol, 1 equiv) and i-BuOK (117 mg, 1.04 mmol, 2.5 equiv) in DMF (2 mL) was added 2-chloro-5-methylpyrimidine (59 mg, 0.46 mmol, 1.1 equiv) at 0 °C. Then the reaction was stirred at 50 °C for 16 hours. After completion, the reaction was filtered and the filtrate was purified via prep HPLC (Welch Xtimate, C18 column 150 x 30 mm, 5 pm) using 0.225% formic acid in water with a gradient of 25-55% MeCN at 25 mL / min) to yield the crude product, which was further separated by chiral SFC (Daicel Chiralcel OD(250 mmx 30 mm, lO um), Supercritical CO2 / EtOH + 0.1% NH₄OH = 40 / 60; 80 mL / min) to afford Compound 49 (12.2 mg. 9% yield) as a yellow solid. 'H NMR (400 MHz. DMSO): 8 8.54 (s, 2H), 8.28 (d, J= 2.8 Hz, 1H), 5.97 (d, J= 8.8 Hz, 1H), 5.90 (d, J= 2.4 Hz, 1H), 4.85 - 4.72 (m, 1H), 3.71 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.43 (d, J= 6.8 Hz, 3H). LCMS (ESI, m / z) [M+H]+= 332.1.Example 50: (X)-A-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-l-(4,5- dimethylpyrimidin-2-yl)-lH-pyrazol-3- amine

[0304] To a mixture of ( / >')-;¥-( l-(4-chloro-1.5-di methyl- 17 / -pyrazol-3-yl)cthyl)- 1 / / -pyrazol-3-amine (100 mg, 0.42 mmol, 1 equiv) and 1-BuOK (117 mg, 1.04 mmol, 2.5 equiv) in DMF (2 mL) was added 2-chloro-4,5-dimethyl-pyrimidine (65 mg, 0.46 mmol. 1.1 equiv). The mixture was stirred at room temperature for 16 h. Then additional 2-chl oro-4, 5-dimethyl-pyrimidine (30 mg, 0.21 mmol, 0.5 equiv) was added and the reaction mixture stirred at 50 °C for 2 h. After completion, the reaction was filtered and the filtrate was purified via prep HPLC (Phenomenex Gemini-NX C18 column 150 x 30 mm, 5 pm) using 0.225% formic acid in water with a gradient of 30-60% MeCN at 25 mL / min) to afford Compound 50 (35.9 mg, 24% yield) as a yellow solid. 'H NMR (400 MHz, DMSO): <58.36 (s, 1H), 8.27 (d, J= 2.8 Hz, 1H), 5.95 (d, J= 8.4 Hz, 1H), 5.88 (d, J= 2.8 Hz, 1H), 4.87 - 4.73 (m, 1H), 3.70 (s, 3H), 2.42 (s, 3H), 2.19 (s, 6H), 1.43 (d. J= 6.8 Hz. 3H). LCMS (ESI, m / z) [M+H]+= 346.1.Example 51: (A)-'V-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-1-(6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)-lH-pyrazol-3-amine1-BuXPhos Pd G3 (0.1 equiv) K3PO4 (3 equiv) dioxane (0.2 M)

[0305] To a solution of 2-chloro-6.7-dihydro-5 / / -cyclopeiila|c / |pyrimidine(322 mg, 2.09 mmol, 1 equiv) and (< S)-A-(l-(4-chloro-1.5-dimethyl-l / 7-pyrazol-3-yl)ethyl)-l / 7-pyrazol-3-amine (500 mg, 2.09 mmol, 1 equiv) in 1,4-dioxane (10 mL, 0.2 M) were added K3PO4 (1.33 g, 6.26 mmol, 3 equiv) and / -BuXPhos Pd G3 (166 mg, 0.21 mmol, 0.1 equiv). Then the reaction was heated at 100 °C under nitrogen for 1 hour. After completion, the reaction was filtered and the filtrate was concentrated. The material was purified via prep HPLC (WelchXtimate C18 column 150 x 30 mm, 5 pm) using 0.225% FA in water with a gradient of 45-75% MeCN at 25 mL / min) to yield the crude product, which was further separated by chiral SFC (Daicel Chiralcel OD (250 mm x 30 mm, 10 um), Supercritical CO2 I EtOH + 0.1% NH4OH = 40 / 60; 80 mL / min) to afford Compound 51 (64.5 mg, 9% yield) as yellow oil.1H NMR (400 MHz, DMSO): δ 8.46 (s, 1H), 8.28 (d, J= 2.8 Hz, 1H), 5.96 (d, J= 8.4 Hz, 1H), 5.89 (d, J= 2.8 Hz, 1H), 4.89 - 4.75 (m, 1H). 3.72 (s, 3H), 2.96 - 2.84 (m, 4H), 2.20 (s. 3H), 2.13 - 2.00 (m, 2H), 1.44 (d. J= 6.8 Hz. 3H). LCMS (ESI, m / z) [M+H]+= 358.1.Example 52: (5)-5-chloro-A-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-6-(5- methylisoxazol-3-yl)pyridin-2-amineStep 4Step 1: Synthesis of 3-chloro-6-fluoropicolinaldehyde

[0306] To a solution of 2-bromo-3-chloro-6-fluoro-pyridine (4.75 g, 22.57 mmol, 1 equiv) in THF (80 mL, 0.3 M) at 0 °C was added z-PrMgCl LiCl (1.3 M, 38.2 mL, 49.66 m mol, 2.2 equiv) dropwise under nitrogen atmosphere. After addition, the reaction was stirred at 0 °C for 0.5 h. Then DMF (7.2 mL, 22.57 mmol, 1 equiv) was added dropwise and the reaction mixture was stirred at 0 °C for 0.5 h. After completion, the reaction mixture was diluted with saturated NH4CI solution (20 mL) and extracted with EtOAc (50 mL x 3). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified (0-50% ethyl acetate / petr oleum ether) to yield 3-chloro-6-fluoro-pyridine-2-carbaldehyde (1.05 g, 29% yield) as a yellow oil. 'H NMR (400 MHz, DMSO): 6 10.18 (s, 1H), 7.99 (dd. J= 8.8, 6.4 Hz, 1H), 7.17 (dd, J= 8.8, 3.6 Hz, 1H).Step 2: Synthesis of (E)-3-chloro-6-fluoropicolinaldehyde oxime

[0307] To a solution of solution of 3-chloro-6-fluoro-pyridine-2-carbaldehyde (1 g, 6.27 mmol, 1 equiv) in MeOH (20 mL) and water (10 mL) were added hydroxylamine hydrochloride (473 mg, 6.81 mmol, 1.1 equiv) and Na2COs (481 mg, 4.54 mmol, 0.7 equiv). Then the reaction was stirred at room temperature for 2 h. After completion, the reactionmixture extracted with EtOAc (20 mL x 3). The combined organics were washed with brine, dried over sodium sulfate, fdtered and concentrated. The material was purified (0–50% petroleum ether / ethyl acetate) to yield (E)-3-chloro-6-fluoropicolinaldehyde oxime (1.1 g crude) as a yellow oil, which was used directly in the next step without further purification.1H NMR (400 MHz, DMSO): d 12.19 (s. 1H), 8.33 (s. 1H), 8.17 (dd, J = 8.4, 7.2 Hz, 1H), 7.28 (dd, J = 8.4, 3.6 Hz, 1H).Step 3: Synthesis of (Z)-3-chloro-6-fluoro-N-hydroxypicolinimidoyl chloride

[0308] To a solution of (E)-3-chloro-6-fluoropicolinaldehyde oxime (1.1 g, 6.3 mmol, 1 equiv) in DMF (20 mL, 0.3 M) was added NCS (842 mg, 6.3 mmol, 1 equiv) portionwise. Then the reaction was stirred at room temperature for 2 h. After completion, the reaction was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to yield (Z)-3-chloro-6-fluoro-A-hydroxypicolinimidoyl chloride (1.3 g crude), which was used directly in the next step without further purification. LCMS: (ESI, m / z) [M+H]+= 208.9.Step 4: Synthesis of 3-(3-chloro-6-fluoropyridin-2-yl)-5-methylisoxazole

[0309] To a solution of (Z)-3-chloro-6-fluoro-A-hydroxypicolinimidoyl chloride (1.3 g crude, 6.22 mmol, 1 equiv) and 1-propyne (1.0 M, 6.22 mL. 6.22 mmol, 1 equiv) in DMF (20 mL, 0.3 M) was added TEA (0.86 mL, 6.22 mmol, 1 equiv) dropwise. Then the reaction was stirred at room temperature for 16 h. Upon completion as determined by LCMS, the reaction was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified by column chromatography (0-20% ethyl acetate / petroleum ether) to yield 3-(3-chloro-6-fluoropyridin-2-yl)-5-methylisoxazole (350 mg, 26% yield) as a yellow solid. 'HNMR (400 MHz, CDCls): 5 7.92 (dd, J= 8.4, 7.2 Hz, 1H), 6.98 (dd, J= 8.4, 3.6 Hz, 1H), 6.58 (s, 1H), 2.52 (s, 3H). LCMS: (ESI, m / z) [M+H]+= 213.1.Step 5: Synthesis of (S)-5-chloro-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-6-(5-methylisoxazol-3-yl)pyridin-2-amine

[0310] To a mixture of 3-(3-chloro-6-fluoro-2-pyridyl)-5-methyl-isoxazole (50 mg, 0.24 mmol, 1 equiv) and K2CO3 (163 mg, 1.18 mmol, 5 equiv) in DMSO (1 mL) was added (S)-1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-amine hydrochloride (87 mg, 0.41mmol, 1.8 equiv). Then the reaction was heated at 120 °C for 16 h under nitrogen atmosphere. Upon completion as determined by LCMS, the reaction was filtered and the filtrate was purified by prep-HPLC (WePure Biotech XP t C18 column 150 x 30 mm, 7 pm) using 0.225% FA in water with a gradient of 52-82% MeCN at 25 mL / min) to afford Compound 52 (36.7 mg, 42% yield) as a white solid. 'H NMR (400 MHz, DMSO): 6 8.53 (d, J= 8.8 Hz, 1H), 7.24 (d, J = 7.6 Hz. 1H), 6.65 (d. J = 8.8 Hz, 1H), 6.55 (s, 1H), 5.17 - 5.05 (m, 1H), 3.70 (s, 3H), 2.47 (s, 3H), 2.18 (s. 3H), 1.43 (d, J= 6.8 Hz, 3H). LCMS (ESI, m / z) [M+H]+= 366.0.Example 53: (5)-5-chloro-A-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-6-(4- methyloxazol-2-yl)pyridin-2-amineStep 1Step 1: Synthesis of 4-methyl-2-(tributylstannyl)oxazole

[0311] To a solution of 4-methyloxazole (700 mg, 8.42 mmol, 1 equiv) in THF (30 mL, 0.3 M) was added n-BuLi (2.5 M in hexane, 3.37 rnL, 8.42 mmol, 1 equiv) dropwise at -78 °C under nitrogen protection. After stirring at -78 °C for 0.5 h, tributylchlorostannane (2.31 rnL, 8.51 mmol) was added dropwise to the reaction. Then the reaction was stirred at -78 °C for an additional 2 h. After completion, the reaction was quenched with saturated NH4CI (10 mL) solution, and extracted with EtOAc (20 mL x 3). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to yield 4-methyl-2-(tributylstannyl)oxazole (2.2 g crude) as a yellow oil, which was used directly in the next step without further purification.Step 2: Synthesis of (S)-5-chloro-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-6-(4-methyloxazol-2-yl)pyridin-2-amine

[0312] To a solution of (< S)-6-bromo-5-chloro-X-(l-(4-chloro-l,5-dimethyl-l / 7-pyrazol-3-yl)ethyl)pyridin-2-amine (150 mg. 0.41 mmol, 1 equiv) and 4-methyl-2-(tributylstannyl)oxazole (1.53 g crude) in 1,4-dioxane (5 rnL, 0.1 M) were added Pd(PPh₃)₄ (48 mg, 0.04 mmol, 0.1 equiv) and Cui (8 mg, 0.04 mmol, 0.1 equiv). Then the reaction was stirred at 100 °C for 16 hours under nitrogen protection. After completion, the reaction mixture was filtrated and the filtrate was concentrated. The material was purified by column chromatography (40% EtOAc in w-hexane) to give the crude product, which was furtherpurified via prep HPLC (Welch Xtimate C18 150 x 30 mm, 5 μm) using 0.2% FA in water with a gradient of 37-67% MeCN at 25 mL / min) to afford Compound 53 ( 10.7 mg, 7% yield) as a yellow solid. 'H NMR (400 MHz, DMSO): 37.94 (s, 1H), 7.55 (d, J= 8.8 Hz, 1H), 7.23 (d, J= 7.2 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 5.20 - 5.08 (m, 1H), 3.70 (s, 3H), 2.17 (s, 6H), 1.42 (d, J= 6.4 Hz, 3H). LCMS (ESI, m / z) [M+H]+= 366.0.Example 54: (5)-5-chloro-A-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyI)-6-(3- chl oro- 1H- 1,2,4-triazol- 1 -y l)pyridin-2-amineCul (0.2equiv) DMEDA(04 equiv) K2CO3(2 equiv) DMF (0.2 M)

[0313] To a mixture of (< S)-6-bromo-5-chloro-A-(l-(4-chloro-l,5-dimethyl-l / 7-pyrazol-3-yl)ethyl)pyridin-2-amine (150 mg, 0.41 mmol) and 3-chloro-17 / -l,2,4-triazole (47 mg, 0.45 mmol) in DMF (2 mL, 0.2 M) were added K2CO3 (114 mg, 0.82 mmol), Cui (16 mg, 0.08 mmol) and DMEDA (0.02 mL, 0.1 mmol). Then the reaction mixture was heated at 120 °C for 16 hours under nitrogen atmosphere. Upon completion as detennined by LCMS, the reaction was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified via prep HPLC (Welch Xtimate Cl 8 column 150 x 30 mm, 5 pm) using 10 mM NH4HCO3 in water with a gradient of 55-85% MeCN at 25 mL / min) to afford Compound 54 (21.5 mg, 13% yield) as yellow oil.1H NMR (400 MHz, DMSO): δ 9.04 (s, 1H), 7.76 - 7.60 (m, 2H), 6.74 (d, J= 8.8 Hz, 1H), 5.09 - 4.95 (m, 1H), 3.70 (s, 3H), 2.17 (s, 3H), 1.43 (d, J= 6.8 Hz, 3H). LCMS (ESI, m / z) [M+H]+= 386.0.Example 55: (X)-5-chloro-A-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-6-(3- chloro- IH-pyrazol- l-yl)pyridin-2-amineCuI (0.2 equiv) DMEDA (0.4 equiv) K₂CO₃ (2 equiv) DMF (0.14 M)

[0314] To a solution of (. S)-6-bromo-5-chloro-A-(l-(4-chloro-l,5-dimethyl-l / 7-pyrazol-3-yl)ethyl)pyridin-2-amine (100 mg, 0.27 mmol, 1 equiv) and 3-chloro- IH-pyrazole (40 mg, 0.3 mmol) in DMF (2 mL. 0.14 M) were added Cui (10.5 mg, 0.05 mmol), K2CO3 (76 mg, 0.54 mmol) and DMEDA (0.01 mL, 0.11 mmol). Then the reaction mixture was stirred at120 °C for 16 hours under nitrogen protection. Upon completion as determined by LCMS, the reaction was diluted with water and extracted with ethyl acetate (3 x 10 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified via prep HPLC (Phenomenex Gemini-NX C18 column 150 x 40 mm, 5 pm) using 0.05% HC1 in water with a gradient of 60-90% MeCN at 25 mL / min) to afford Compound 55 (16.5 mg, 16% yield) as colorless oil.1H NMR (400 MHz, DMSO): δ 8.22 (d, J= 2.4 Hz. 1H), 7.62 (d. J= 8.8 Hz. 1H), 7.58 - 7.42 (m, 1H), 6.69 - 6.57 (m, 2H). 5.10 - 4.98 (m, 1H), 3.71 (s, 3H), 2.18 (s, 3H), 1.44 (d, J= 6.8 Hz, 3H). LCMS (ESI, m / z) [M+H]’ = 385.0.Example 56; (X)-5-chloro-7V-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-6-(3- (difluoromethyl)- lH-pyrazol-l-yl)pyridin-2-amineCuI (0.2 equiv) DMEDA (0.4 equiv) K2CO3(2 equiv) DMF (0.2 M)

[0315] To a solution of (S)-6-bromo-5-chloro-N-(1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethyl)pyridin-2-amine (100 mg, 0.41 mmol, 1 equiv) and 3-(difluoromethyl)-1H-pyrazole (73 mg, 0.62 mmol, 1.5 equiv) were added Cui (16 mg, 0.08 mmol, 0.2 equiv), DMEDA (0.02 mL, 0.16 mmol, 0.4 equiv) and K.2CO3 (114 mg, 0.82 mmol) in DMF (2 mL, 0.2 M ). Then the reaction was heated at 120 °C for 16 hours under nitrogen protection. After completion, the reaction was filtered and the filtrate was purified via prep HPLC (Phenomenex Gemini-NX Cl 8 column 50 x 30 mm, 3 pm) using 0.05% NH3 H2O + 10 mM NH4HCO3 in water with a gradient of 50-80% MeCN at 25 mL / min) to afford Compound 56 (10.6 mg, 6% yield) as a yellow solid. 'H NMR (400 MHz, DMSO): 88.24 (d, J= 2.4 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.52 (d, J= 8.0 Hz, 1H), 7.09 (t, J= 54.4 Hz, 1H), 6.76 (d, J = 2.8 Hz, 1H), 6.66 (d, J= 8.8 Hz, 1H), 5.05 - 4.95 (m, 1H), 3.70 (s, 3H), 2.17 (s, 3H), 1.43 (d, J = 6.8 Hz. 3H). LCMS (ESI, m / z) [M+H]+= 401.1.Example 57; (5)-5-chloro-AL(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-6-(2- methyloxazol-4-yl)pyridin-2-aminePd(dppf)Cl₂ (0.1 equiv) K₂CO₃ (3 equiv) dioxane / H₂O (0.2 M)

[0316] To a solution of (< S)-6-bromo-5-chloro-A-(l-(4-chloro-l,5-dimethyl-l / 7-pyrazol-3-yl)ethyl)pyridin-2-amine (120 mg, 0.33 mmol, 1 equiv) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (103 mg, 0.49 mmol, 1.5 equiv) in 1,4-dioxane (1 mL) and H2O (0.35 mL) were added Pd(dppf)Cl₂ (24 mg, 0.03 mmol, 0.1 equiv) and K2CO3 (137 mg, 0.99 mmol, 3 equiv). The reaction was stirred at 100 °C for 1 hour under nitrogen protection. After completion, the reaction mixture was filtrated and the filtrate was concentrated. The material was purified via prep HPLC (WePure Biotech XP tC 18 column 150 x 30 mm, 7 pm) using 0.225% FA in water with a gradient of 35-65% MeCN at 25 mL / min) to afford Compound 57 (85.7 mg, 71% yield) as a white solid.1H NMR (400 MHz, DMSO): δ 8.31 (s, 1H), 7.44 (d, J= 8.8 Hz, 1H), 7.01(d, J= 7.6 Hz, 1H), 6.52 (d, J = 8.8 Hz, 1H), 5.18 - 5.07 (m, 1H), 3.70 (s, 3H), 2.46 (s, 3H), 2.18 (s, 3H), 1.43 (d, J= 6.8 Hz, 3H). LCMS (ESI, m / z) [M+H]+= 366.1.Example 58; (X)-5-chloro-A / -(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-6-(2- methyloxazol-5-yl)pyridin-2-aminePd(dppf)Cb (01 equiv) K2CO3(3 equiv) dioxane / H2O (0.15 M)

[0317] To a solution of (S)-6-bromo-5-chloro-A-(l-(4-chloro-l,5-dimethyl-17f-pyrazol-3-yl)ethyl)pyridin-2-amine (100 mg, 0.27 mmol, 1 equiv) and 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)oxazole (69 mg, 0.33 mmol. 1.2 equiv) in 1,4-dioxane (1 mL) and H2O (0.3 mL) were added Pd(dppf)Cl₂ (20 mg, 0.03 mmol, 0.1 equiv) and K2CO3 (114 mg, 0.82 mmol, 3 equiv). The reaction was stirred at 100 °C for 1 hour under nitrogen protection. After completion, the reaction mixture was filtrated and the filtrate was concentrated. The material was purified via prep HPLC (WePure Biotech XP tC 18 column 150 x 30 mm, 7 pm) using 0.225% FA in water with a gradient of 49-79% MeCN at 25 mL / min) to afford Compound 58 (40.7 mg, 40% yield) as a yellow solid. ’HNMR (400 MHz, DMSO): d 7.63 (s, 1H), 7.49 (d, J= 8.8 Hz, 1H), 7.19 (d, J= 7.6 Hz, 1H), 6.52 (d, J= 8.8 Hz, 1H), 5.22 - 5.08 (m, 1H). 3.69 (s, 3H). 2.49 (s, 3H), 2.18 (s. 3H), 1.43 (d. J= 7.2 Hz, 3H). LCMS (ESI, m / z) [M+H]+= 366.1.Example 59: (N)-5-chloro- / V-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-6-(oxazol- 2-yl)pyridin-2-amine

[0318] To a solution of (< S)-6-bromo-5-chloro-jV-(l-(4-chloro-l,5-dimethyl-l / f-pyrazol-3-yl)ethyl)pyridin-2-amine (150 mg, 0.41 mmol, 1 equiv) and 2-(tributylstannyl)oxazole (162 mg, 0.45 mmol, 1.1 equiv) in 1,4-dioxane (2 mL, 0.2 M) was added Pd(PPh3)4 (48 mg, 0.04 mmol, 0.1 equiv). The reaction was stirred at 100 °C for 16 hours under nitrogen protection. After completion, the reaction mixture was filtrated and the filtrate was concentrated. The material was purified via prep HPLC (Phenomenex Gemini-NX C18 column 150 x 30 mm, 3 pm) using 0.05% NH3 H2O + 10 mM NH4HCO3 in water with a gradient of 43-73% MeCN at 25 mL / min) to afford Compound 59 (28.8 mg, 20% yield) as a yellow solid. 'H NMR (400 MHz, DMSO): 68.27 (s, 1H). 7.57 (d, J= 9.2 Hz, 1H), 7.43 (s, 1H), 7.27 (d, J= 8.0 Hz, 1H), 6.69 (d, J= 8.8 Hz, 1H), 5.24 - 5.10 (m, 1H), 3.71 (s, 3H), 2.18 (s, 3H), 1.43 (d, J= 6.8 Hz, 3H). LCMS (ESI, m / z) [M+H]+= 352.0.Example 60: (5)-5-chloro-A-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-6-(l- methyl-lH-l,2,4-triazol-3-yl)pyridin-2-aminePd(PPh3)₄ (0.1 equiv) dioxane (0.2 M)

[0319] To a solution of (< S)-6-bromo-5-chloro-A-(l-(4-chloro-l,5-dimethyl-17f-pyrazol-3-yl)ethyl)pyridin-2-amine (150 mg, 0.41mmol) and tributyl-(l -methyl- 1,2,4-triazol-3-yl)stannane (169 mg, 0.45 mmol, 1.1 equiv) in 1,4-dioxane (2 mL, 0.2 M) was added Pd(PPh₃)₄ (48 mg, 0.04 mmol, 0.1 equiv). Then the reaction was heated at 100 °C for 2 hours under nitrogen atmosphere. Upon completion as determined by LCMS, the reaction mixture was filtered and the filtrate was concentrated. The material was purified via prep-TLC (10% Methanol / DCM) to give 70 mg crude product, which was further purified via prep HPLC (Welch Xtimate C18 column 150 x 30 mm, 5 pm) using 0.2% formic acid in water with a gradient of 25-55% MeCN at 25 mL / min) to afford Compound 60 (44 mg, 29% yield) as a yellow solid. 'H NMR (400 MHz. DMSO): d 8.52 (s. 1H), 7.51 (d. J = 8.8 Hz. 1H), 7.03 (d. J= 8.0 Hz, 1H), 6.63 (d, J= 8.8 Hz, 1H), 5.15 - 5.05 (m, 1H), 3.94 (s, 3H), 3.71 (s, 3H), 2.19 (s, 3H), 1.41 (d, J = 6.8 Hz. 3H). LCMS (ESI, m / z) [M+H]+= 366.1.Example 62: (5)-7V-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-l-(5- fluoropyrimidin-2-yl)-lH-pyrazol-3- amineci. IM-

[0320] To a mixture of (S)-jV-(l-(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)ethyl)-17f-pyrazol-3-amine (80 mg, 0.33 mmol, 1 equiv) and t-BuOK (94 mg, 0.83 mmol, 2.5 equiv) in DMF (2 mL, 0.16 M) was added 2-chloro-5-fluoropyrimidine (49 mg, 0.37 mmol, 1.1 equiv) at 0 °C under nitrogen protection. Then, the reaction was stirred at room temperature for 2 h. After completion, the reaction was diluted with water (12 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The material was purified via prep HPLC (Phenomenex Gemini -NX C18 column 150 x 40 mm, 5 pm) using 0.05% HC1 in water with a gradient of 40-70% MeCN at 25 mL / min) to afford Compound 62 (35 mg, 31% yield) as a yellow solid. 'H NMR (400 MHz, DMSO): d 8.80 (s, 2H), 8.27 (d, J= 2.8 Hz, 1H), 5.96 (d, J= 2.8 Hz, 1H), 4.84 (q, J = 6.8 Hz, 1H), 3.69 (s, 3H), 2.20 (s, 3H), 1.45 (d, J= 6.8 Hz, 3H). LCMS (ESI, m / z) [M+H]+= 336.0.Example 63a & Example 63b: (7?)-N-(l-(4-chloroisothiazol-5-yl)ethyI)-l-(5- chloropyrimidin-2-yl)-lH-pyrazol-3-amine & (5)-N-(l-(4-chloroisothiazol-5-yl)ethyl)-l- (5-chloropyrimidin-2-yl)-lH-pyrazol-3-amineci Step 4Step 1: Synthesis of 4-chloro-N-methoxy-N-methylisothiazole-5-carboxamide

[0321] To a solution of 4-chloroisothiazole-5-carboxylic acid (900 mg. 5.5 mmol, 1 equiv), HATU (3.14 g, 8.25 mmol, 1.5 equiv) and DIPEA (2.88 mL, 16.51 mmol, 3 equiv) in DMF (20 mL) was added N, O-dimethylhydroxylamine hydrochloride (805 mg, 8.25 mmol, 1.5 equiv). The reaction was stirred at room temperature for 16 h. Upon completion as determined by LCMS, the reaction was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (5 mL). dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (0-15% EtOAc in petroleum ether) to yield 4-chloro-A-methoxy-N-methylisothiazole-5-carboxamide (990 mg, 87% yield) as a white solid. LCMS: (ESI, m / z) [M+H]⁺ = 207.1.Step 2: Synthesis of 4-chloroisothiazole-5-carbaldehyde

[0322] To a solution of 4-chloro-7V-methoxy-JV-methyl-isothiazole-5-carboxamide (400 mg, 1.94 mmol, 1 equiv) in THF (8 mL) at -78 °C under nitrogen was added DIBAL-H (3.87 mL, 3.87 mmol, 2 equiv) dropwise. After stirring at -78 °C for 0.5 h, the mixture was gradually warmed to 0 °C. The reaction mixture was quenched with a saturated potassium sodium tartrate solution (20 mL), and extracted with EtOAc (2x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The material was purified by column chromatography (0-15% EtOAc in petroleum ether) to yield 4-chloroisothiazole-5-carbaldehyde (200 mg, 42% yield) as a yellow oil.XH NMR (400 MHz. DMSO): δ 11.40 (s, 1H), 8.87 (s, 1H).Step 3: Synthesis of (E)-l-(4-chloroisothiazol-5-yl)-N-(l-(5-chloropyrimidin-2-yl)-lH-pyrazol-3-yl)methanimine

[0323] To a mixture of 4-chloroisothiazole-5-carbaldehyde (200 mg, 0.81mmol, 1 equiv) and l-(5-chloropyrimi din-2 -yl)pyrazol-3-amine (159 mg, 0.81 mmol, 1 equiv) in MeOH (6 mL, 0.14 M) was added acetic acid (0.05 mL, 0.81 mmol, 1 equiv). The reaction was heated to 80 °C for 1 h. Upon completion as determined by LCMS, the reaction mixture was concentrated under reduced pressure to remove MeOH. The crude product was used directly in the next step without further purification. LCMS: (ESI, m / z) [M+H]+= 324.9.Step 4: Synthesis of N-(l-(4-chloroisothiazol-5-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-lH-pyrazol-3-amine

[0324] To a solution of (E)-l-(4-chloroisothiazol-5-yl)-N-(l-(5-chloropyrimidin-2-yl)-177-pyrazol-3-yl)methanimine (248 mg, 0.76 mmol, 1.0 equiv) in THF (8 mL) at -78 °C under nitrogen was added CH₃MgBr (3M, 1.27 mL, 3.81 mmol, 5 equiv) dropwise. After stirring at -78 °C for 0.5 h, the mixture was gradually warmed to 0 °C and stirred at 0 °C for 0.5 h. The reaction was quenched with saturated NH₄Cl solution (10 mL) and extracted with DCM / MeOH (10 / 1, 3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified via prep HPLC (Welch Xtimate Cl 8 column 150 x 30 mm, 5 pm) using 0.75%TFA in water with a gradient of 40-70% MeCN at 25 mL / min) to yield A-(l-(4-chloroisothiazol-5-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-17T-pyrazol-3-amine (60 mg, 23% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+= 340.8.Step 5: Synthesis of (R)-N-(l-(4-chloroisothiazol-5-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-lH-pyrazol-3-amine & (S)-N-(l-(4-chloroisothiazol-5-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-lH-pyrazol-3-amine

[0325] N-( l-(4-chloroisothiazol-5-yl)ethyl)-l-(5-chloropyrimidin-2-yl)- l / / -pyrazol-3-amine (60 mg, 0.18 mmol) was separated by chiral SFC (Dai cel Chiralpak AD (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH3H2O = 50 / 50; 150 mL / min) to afford Compound 63a (peak 1, Rt = 0.711 min, 5.2 mg, 9% yield) and Compound 63b (peak 2, Rt = 1.336 min, 8.0 mg, 15% yield) both as white solids.

[0326] Compound 63a (stereoisomer 1): 'H NMR (400 MHz, DMSO): 5 8.79 (s, 2H), 8.52 (s, 1H), 8.34 (d, J= 3.2 Hz, 1H), 6.98 (d, J= 6.4 Hz, 1H), 5.97 (d. J= 2.8 Hz. 1H), 5.13 - 5.05 (m. 1H), 1.55 (d. J= 7.2 Hz. 3H). LCMS (ESI, m / z) [M+H]+= 341.0.

[0327] Compound 63b (stereoisomer 2): 'H NMR (400 MHz, DMSO): 5 8.79 (s, 2H), 8.52 (s, 1H), 8.34 (d, J = 2.8 Hz, 1H), 6.98 (d, J = 6.4 Hz, 1H), 5.97 (d, J = 2.8 Hz, 1H), 5.13 - 5.05 (m, 1H), 1.55 (d, J= 7.2 Hz, 3H). LCMS (ESI, m / z) [M+H]+= 341.0.Example 64; (5)-l-(5-chloropyrimidin-2-yl)- / V-(l-(4-fluoro-l,5-dimethyl-lH-pyrazol-3- yl)ethyl)-lH-pyrazol-3-amineStep 1: Synthesis of (4 fluoro- l,5-dimethyl-lH-pyrazol-3-yl)methanol

[0328] To a solution of (l,5-dimethyl-l / 7-pyrazol-3-yl)methanol (4.1 g, 32.5mmol, 1 equiv) in MeCN (160 mL, 0.2 M) was added Selectfluor (12.6 g. 35.7 mmol, 1.1 equiv) portionwise. The reaction was stirred at room temperature for 3 h. Upon completion as determined by LCMS, the reaction mixture was concentrated. Ethyl acetate (50 mL) and water (50 mL) were added. The water layer was extracted with DCM (50 mL x 2). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The material was purified by column chromatography (10% MeOH in DCM) to yield (4-fluoro-l,5-dimethyl- IW-pyrazol-3-yl [methanol (1.4 g, 30% yield) as a yellow solid. 'H NMR (400 MHz, CD3CI): 54.65 (s, 2H), 3.71 (s, 3H), 2.21 (s, 3H). LCMS: (ESI, m / z) [M+H]+= 145.1.Step 2: Synthesis of 4-fluoro-l,5-dimethyl-lH-pyrazole-3-carbaldehyde

[0329] To a solution of (4-fluoro-l,5-dimethyl-lH-pyrazol-3-yl)methanol (1.4 g, 9.71 mmol, 1 equiv) in dioxane (60 mL, 0.14 M) was added MnO₂ (12.6 g, 145 mmol, 15 equiv). The reaction was stirred at 100 °C for 2 h. Upon completion as determined by LCMS, the mixture was filtered and the filtrate was concentrated. The material was purified by column chromatography (30% ethyl acetate in w-hexane) to yield 4-fluoro-l,5-dimethyl-177-pyrazole-3-carbaldehyde (550 mg, 39% yield) as a white solid.JH NMR (400 MHz, CD3CI): 59.88 (s, 1H), 3.84 (s, 3H), 2.27 (s, 3H). LCMS (ESI, m / z) [M+H]+= 143.1.Step 3: Synthesis of (S, E)-N-((4-fluoro-1.5-dimethyl-lH-pyrazol-3-yl)methylene)-2-methylpropane-2-sulfinamide

[0330] To a solution of 4-fluoro-l,5-dimethyl-l / f-pyrazole-3-carbaldehyde (460 mg, 3.23 mmol, 1 equiv) and (< S)-2-methylpropane-2-sulfinamide (783 mg, 6.46 mmol, 2 equiv) inTHF (14 mL) was added Ti(0iPr)4 (4.8 mL, 16.1 mmol, 5 equiv). The reaction was stirred at 70 °C for 2 h. Upon completion as determined by LCMS, water (30 mL) and ethyl acetate (60 mL) were added. The mixture was filtered and the filtrate was separated. The organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (30% ethyl acetate in n-hexane) to yield S, E)-N-((4-fluoro-l,5-dimethyl-17 / -pyrazol-3-yl)methylene)-2-methylpropane-2-sulfmamide (650 mg, 82% yield) as yellow oil. 'H NMR (400 MHz, CD3C1): 5 8.57 (s, 1H), 3.82 (s, 3H), 2.27 (s, 3H), 1.26 (s, 9H). LCMS: (ESI, m / z) [M+H]+= 246.1.Step 4: Synthesis of (S)-N-((S)-l-(4-fluoro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulflnamide

[0331] To a solution of (S,£')-A-((4-fluoro-L5-dimethyl-l / / -pyrazol-3-yl)methylene)-2-methylpropane-2-sulfinamide (650 mg, 2.64 mmol) in THF (13 mL, 0.2 M) at -78 °C under nitrogen was added CH₃MgBr (3 M, 3.5 mL, 10.6 mmol) dropwise. The reaction was stirred at -78 °C for 1 h and then at room temperature for 1 h. Upon completion as determined by LCMS, the reaction was quenched with saturated NH4CI solution (10 mL) and extracted with ethyl acetate (40 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (5% MeOH in dichloromethane) to yield (S)-JV-((S)-l-(4-fluoro-l,5-dimethyl-l / 7-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (600 mg, 87% yield) as yellow oil. LCMS: (ESI, m / z) [M+H]+= 262.1.Step 5: Synthesis of (S)-l-(4-fluoro-l,5-dimethyl-lH-pyrazol-3-yl)ethan-l-amine

[0332] To a solution of (5)- / V-((< S')-l-(4-fluoro-l,5-dimethyl-l / 7-pyrazol-3-yl)ethyl)-2-methylpropane-2-sulfinamide (400 mg, 1.53 mmol, 1 equiv) in MeOH (4 mL, 0.38 M) was added 2 M HC1 in dioxane (8 mL, 16 mmol, 10 equiv). The reaction was stirred at room temperature for 2 h. Upon completion as determined by LCMS, the reaction mixture was concentrated. The residue was dissolved in MeOH (10 mL) and Amberlyst A26(OH) ion exchange resin (1.7 g) was added. After stirring at room temperature for 2 h, the mixture was filtered and the filtrate was concentrated to yield (S)-l-(4-fluoro-l,5-dimethyl-lE7-pyrazol-3-yl)ethan-l -amine (200 mg, 83% yield) as colorless oil. 'H NMR (400 MHz, DMSO): 6 3.92 (q, J= 6.8 Hz, 1H), 3.60 (s, 3H), 2.14 (s, 3H), 1.27 (d, J= 6.8 Hz, 3H).Step 6: Synthesis of (S)-N-(l-(4-fluoro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-lH-pyrazol-3-amine

[0333] To a solution of (S -l-(4-fluoro-L5-dimethyl-l / / -pyrazol-3-yl)ethan-l-amine (200 mg, 1.27 mmol, 1.0 equiv) and 3-iodo-lEf-pyrazole (296 mg, 1.53 mmol, 1.2 equiv) in THF (2 mL, 0.22 M) was added tBuBrettPhos (61 mg, 0.13 mmol, 0.1 equiv) and / BuBrettPhos Pd G3 (108 mg. 0.13 mmol, 0.1 equiv). The mixture was purged with nitrogen, and then LiHMDS (3.8 mL. 3.8 mmol. 3 equiv) was added at 0 °C. The mixture was stirred at room temperature for 2 h. Upon completion as determined by LCMS, the reaction was quenched with NH₄Cl solution (0.4 mL). The mixture was dried over sodium sulfate, filtered and concentrated. The material was purified by column chromatography (10% MeOH in di chloromethane) to yield (S)- / V-(l-(4-fluoro-l,5-dimethyl-l / 7-pyrazol-3-yl)ethyl)-l / f-pyrazol-3-amine (180 mg, 63% yield) as a brown solid.!H NMR (400 MHz, DMSO): 5 11.42 (s, 1H), 7.38 - 7.16 (m, 1H), 5.56 - 5.31 (m, 1H), 5.15 - 4.90 (m, 1H), 4.65 - 4.39 (m, 1H), 3.61 (s, 3H). 2.13 (s, 3H), 1.39 (d, J = 6.8 Hz, 3H). LCMS: (ESI. m / z) [M+H]+= 224.1.Step 7: (S)-l-(5-chloropyrimidin-2-yl)-N-( l-(4-fluoro-l, 5-dimethyl-lH-pyrazol-3-yl)ethyl)-lH-pyrazol-3-amine

[0334] To a solution of (< S)- / V-(l-(4-fluoro-l,5-dimethyl-177-pyrazol-3-yl)ethyl)-17 / -pyrazol-3-amine (180 mg, 0.81 mmol, 1 equiv) in DMF (4 mL, 0.20 M) were added / -BuOK (226 mg. 2.02 mmol, 2.5 equiv) and 2,5-dichloropyrimidine (144 mg, 0.97 mmol. 1.2 equiv). The reaction was stirred at room temperature for 3 h. Upon completion as determined by LCMS, the reaction was purified via prep HPLC (Phenomenex Gemini-NX C18 column 75 x 30 mm, 3 pm) using 0.225% FA in water with a gradient of 20-50% MeCN at 25 mL / min) to yield 70 mg product, which was separated by chiral SFC (Regis (R, R) Whelk-Ol (250 mm x 25 mm, 10 um). Supercritical CO2 / EtOH + 0.1% NH4OH = 30 / 70; 80 mL / min) to afford Compound 64 (peak 1, Rt = 1.291 min, 30.8 mg, 11% yield) as a white solid. 'H NMR (400 MHz, DMSO): 8 8.78 (s, 2H), 8.28 (d, J= 2.8 Hz, 1H), 6.22 (d, J= 8.4 Hz, 1H), 5.95 (d, J = 2.8 Hz. 1H), 4.88 - 4.79 (m. 1H), 3.64 (s, 3H), 2.16 (d. J= 1.2 Hz, 3H). 1.45 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 336.1.Example 65a & Example 65b: (A)-l-(5-chloropyrimidin-2-yl)-A-(l-(4,5-dichloro-l-methyl-lH-imidazol-2-yl)ethyl)-lH-pyrazol-3- amine and ( / ?)-l-(5-chloropyrimidin-2-yl)- 7V-(l-(4,5-dichloro-l-methyl-lH-imidazol-2-yl)ethyl)-lH-pyrazol-3- amineStep 1Step 1: Synthesis of 4,5-dichloro-l -methyl-imidazole-2-carbaldehyde

[0335] To a solution of 4.5-dichloro-l-methyl-imidazole (800 mg.5.3 mmol, 1 equiv) in THF (30 mL, 0.18 M) at -78 °C under nitrogen was added n-BuLi (3.18 mL, 7.95 mmol, 1 equiv) dropwise. The reaction mixture was stirred at -78 °C for 1 h, and then DMF (0.82 mL, 10.6 mmol, 1 equiv) was added dropwise. After stirring at -78 °C for 1 h, the reaction was quenched with water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (10% ethyl acetate in petroleum ether) to yield 4,5-dichloro-l -methyl-imidazole-2-carbaldehy de (730 mg, 77% yield) as a white solid. 'H NMR (400 MHz, DMSO): 5 = 9.55 (s, 1H), 3.90 (s, 3H).Steps 2-3: Synthesis of l-(5-chloropyrimidin-2-yl)-N-(l-(4,5-dichloro-l-methyl-lH-imidazol-2-yl)ethyl)-lH-pyrazol-3-amine

[0336] l-(5-Chloropyrimidin-2-yl)-A-(l-(4,5-dichloro-l-methyl-17F-imidazol-2-yl)ethyl)-IH-pyrazol-3-amine was prepared using the general procedure described for the preparation of 7V-(1 -(4-chloroisothia / ol-5-yl)ethyl)-l-(5-chloropyrimidin-2-yl)- IH-pyra / ol-3-amine (Ex. 63a & Ex. 63b) by replacing 4-chloroisothiazole-5-carbaldehyde with 4,5-dichloro-l-methyl-imidazole-2-carbaldehyde in Step 3. LCMS: (ESI, m / z) [M+H]+= 372.0.Step 4: Synthesis of 1 -(5-chloropyrimidin-2-yl)-N-(l -(4,5-dichloro-l -methyl- lH-imidazol-2-yl)ethyl)-lH-pyrazol-3-amine and l-(5-chloropyrimidin-2-yl)-N-(l-(4,5-dichloro-l-methyl-! H-imidazol-2-yl)ethyl)-lH-pyrazol-3-amine

[0337] l-(5-Chloropyrimidin-2-yl)-JV-(l-(4,5-dichloro-l-methyl-17F-imidazol-2-yl)ethyl)-17 / -pyrazol-3-amine (43.0 mg, 0.12 mmol) was separated by chiral SFC (DaicelChiralpak IC (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH3H2O = 70 / 30; 150 mL / min) to afford Compound 65a (peak 1, Rt = 2.921 min, 9.1 mg. 21% yield) and Compound 65b (peak 2, Rt = 3.309 min, 8.3 mg, 19%) both as white solid.

[0338] Compound 65a (stereoisomer 1):JH NMR (400 MHz, DMSO): 5 8.81 (s, 2H), 8.31 (d, J= 2.8 Hz, 1H), 6.58 (d, J= 8.8 Hz, 1H), 5.92 (d, J= 2.8 Hz, 1H), 4.97 - 4.91 (m. 1H), 3.74 (s, 3H), 1.49 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 372.0.

[0339] Compound 65b (stereoisomer 2): 'H NMR (400 MHz, DMSO): 6 8.81 (s.2H), 8.31 (d, J= 2.8 Hz, 1H), 6.58 (d, J= 8.8 Hz, 1H), 5.92 (d, J= 2.8 Hz, 1H), 4.97 - 4.91 (m, 1H), 3.74 (s, 3H), 1.49 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 372.0.Example 66a & Example 66b: (7?)-l-(5-chloropyrimidin-2-yl)- / V-(l-(4,5-dichlorothiazol- 2-yl)ethyl)-lH-pyrazol-3- amine & (5)-l-(5-chloropyrimidin-2-yl)-7V-(l-(4,5- dichlorothiazol-2-yl)ethyl)-lH-pyrazol-3- amineci ciSteps 1-2: Synthesis of l-(5-chloropyrimidin-2-yl)-N-(l-(4,5-dichlorothiazol-2-yl)ethyl)-lH-pyrazol-3-amine

[0340] l-(5-Chloropyrimidin-2-yl)- / V-(l-(4,5-dichlorothiazol-2-yl)ethyl)-177- pyrazol-3-amine (150 mg, 40% yield) as a white solid was prepared using the general procedure described for the preparation of / V-(l-(4-chloroisothiazol-5-yl)ethyl)-1-(5-chloropyrimidin-2-yl)-1H-pyrazol-3-amine (Ex.63a & Ex.63b) by replacing 4-chloroisothiazole-5-carbaldehyde with 4,5-dichlorothiazole-2-carbaldehyde in Step 3. LCMS: (ESI, m / z) [M+H]+= 375.0.Step 3: Synthesis of (R)-l-(5-chloropyrimidin-2-yl)-N-(l-(4,5-dichlorothiazol-2-yl)ethyl)-lH-pyrazol-3-amine & (S)-l-(5-chloropyrimidin-2-yl)-N-(l-(4.5-dichlorothiazol-2-yl)ethyl)-lH-pyrazol-3-amine

[0341] l-(5-Chloropyrimidin-2-yl)- / V-(l-(4,5-dichlorothiazol-2-yl)ethyl)-177- pyrazol-3-amine (120 mg. 0.32 mmol) was separated by chiral SFC (Regis (R. R) Whelk-01 (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0.1% NH3H2O = 60 / 40; 80 mL / min) toafford Compound 66a (peak 1, Rt = 2.216 min, 23.3 mg, 20% yield) and Compound 66b (peak 2, Rt = 4.629 min, 33.7 mg, 28% yield) both as white solid.

[0342] Compound 66a (stereoisomer 1): 'H NMR (400 MHz, DMSO): 5 8.80 (s, 2H), 8.37 (d, J = 2.8 Hz, 1H), 7.03 (d, J= 6.8 Hz, 1H), 6.04 (d, J= 2.4 Hz, 1H), 5.04 - 4.91 (m, 1H), 1.54 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 374.9.

[0343] Compound 66b (stereoisomer 2): 'H NMR (400 MHz, DMSO): 6 8.80 (s, 2H), 8.37 (d, J = 3.2 Hz, 1H). 7.03 (d, J = 6.8 Hz, 1H), 6.04 (d, J = 2.4 Hz. 1H), 5.04 - 4.91 (m, 1H), 1.54 (d, J = 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 375.0.Example 67; (5)-5-chloro-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-4-(l- methyl-lH-pyrazol-3-yl)thiazol-2-amineStep 1: Synthesis of tert-butyl (4-(l-methyl-lH-pyrazol-3-yl)thiazol-2-yl)carbamate

[0344] To a stirred solution of tert-butyl (4-bromothiazol-2-yl)carbamate (4 g, 14 mmol, 1 equiv) and I-methyl-3-(4,4,5,5-tetramethyl-I,3.2-dioxaborolan-2-yl)-l / 7-pyrazole (3.6 g, 17 mmol, 1.2 equiv) in dioxane (80 mL, 0.15 M) and water (16 mL) were added Pd(dppf)Ch (1 g, 0.1 mmol, 0.1 equiv) and K2CO3 (5.9 g, 43 mmol, 3 equiv). The reaction was stirred at 100 °C for 16 hours under nitrogen. Upon completion as determined by LCMS, the mixture was concentrated. The residue was purified by column chromatography (40% ethyl acetate in / r-hexane) to yield tert-butyl (4-(l -methyl- I H-pyra / ol-3-y I )thiazol-2-yl [carbamate (2.9 g, 72% yield) as a yellow oil. 'H NMR (400 MHz, DMSO): 5 11.55 (s, 1H), 7.69 (d, J = 2.4 Hz, 1H) 7.26 (s, 1H), 6.47 (d, J= 2.4 Hz, 1H), 3.86 (s, 3H), 1.49 (s, 9H).Step 2: Synthesis of 4-(l-methyl-lH-pyrazol-3-yl)thiazol-2-amine

[0345] To a solution of / e / 7-butyl (4-(l -methyl- l / / -pyrazol-3-yl)thiazol-2-yl)carbamate (3.49 g, 12 mmol, 1 equiv) in DCM (50 mL, 0.24 M) was added TFA (10 mL). The reaction was stirred at room temperature for 2 h. Upon completion as determined by LCMS. the mixture was concentrated and the reaction mixture was adjusted to pH = 8 with NaHCCh solution. The resulting solution was extracted with DCM (3 x 10 mL). The combinedorganics were washed with brine, dried over sodium sulfate, filtered, and concentrated to yield 4-(l -methyl- 17 / -pyrazol-3-yl)thiazol-2-amine (2.2 g, 98% yield).rH NMR (400 MHz, DMSO): 5 7.63 (d, J= 2.0 Hz, 1H), 6.96 (s, 2H), 6.70 (s, 1H), 6.37 (d, J= 2.0 Hz, 1H), 3.82 (s, 3H).Step 3: Synthesis of 2-bromo-4-(l -methyl- IH-pyr azol- 3-yl) thiazole

[0346] To a stirred solution of 4-(l-methyl-l / 7-pyrazol-3-yl)thiazol-2-amine (500 mg, 2.7 mmol, 1 equiv) in MeCN (20 mL, 0.1 M) was added CuBr (744 mg, 3.3 mmol, 1.2 equiv) and t-BuONO (0.4 mL, 3.3 mmol, 1.2 equiv). The reaction was stirred at room temperature for 1 h under nitrogen. Upon completion as determined by LCMS, the mixture was diluted in water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (10% ethyl acetate in w-hexane) to yield 2-bromo-4-(l-methyl- 1 H-pyrazol-3-yl (thiazole (240 mg, 35% yield) as a yellow oil. 'H NMR (400 MHz, DMSO): 57.85 (s, 1H), 7.75 (d, J= 2.4 Hz, 1H), 6.59 (d, J= 2.4 Hz, 1H), 3.88 (s, 3H).Step 4: Synthesis of (S)-N-(l-(4-chloro-lf -dimethyl- lH-pyrazol-3-yl)ethyl)-4-(l-methyl-lH-pyr azol- 3-yl) thiazol-2-amine

[0347] To a stirred solution of 2-bromo-4-(l -methyl- 177-pyrazol-3-yl)thiazole (99 mg, 0.4 mmol, 1 equiv) and (S)- l-(4-chloro-l,5-dimethyl-l / 7-pyrazol-3-yl)ethan-l -amine hydrochloride (100 mg, 0.4 mmol, 1 equiv) in dioxane (2 mL, 0.2 M) was added Pd-PEPPSI-IHeptCl (39 mg, 0.04 mmol, 0.1 equiv), CS2CO3 (396 mg, 1.2 mmol, 3 equiv). The reaction was stirred at 110 °C for 16 hours under nitrogen. Upon completion as determined by LCMS, the mixture was filtered and concentrated. The residue was purified by column chromatography (50% ethyl acetate in w-hexane) to yield (S)-N-(l-(4-chloro-l,5-dimethyl-17 / -pyrazol-3-yl)ethyl)-4-(l -methyl- lE7-pyrazol-3-yl)thiazol-2-amine (100 mg, 73% yield) as a yellow oil. 'H NMR (400 MHz, DMSO): 57.91 (d, J= 7.6 Hz, 1H), 7.63 (d, J= 2.0 Hz, 1H), 6.71 (s, 1H), 6.41 (d, J= 2.0 Hz, 1H). 4.98 - 4.85 (m, 1H), 3.82 (s, 3H), 3.70 (s, 3H), 2.19 (s, 3H), 1.46 (d, J= 6.8 Hz. 3H). LCMS (ESI, m / z) [M+H]+= 337.1.Step 5: Synthesis of (S)-5-chloro-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-4-(l-methyl- 1 H-pyr azol- 3-yl) thiazol-2-amine

[0348] To a solution of (N)-N-(l-(4-chloro-l,5-dimethyl-l / / -pyrazol-3-yl)ethyl)-4-(l-methyl-17 / -pyrazol-3-yl)thiazol-2-amine (100 mg, 0.29 mmol, 1 equiv) in DMF (1 mL,0.3M) was added NCS (48 mg, 0.35 mmol, 1.2 equiv). The reaction was stirred at room temperature for 2 h under nitrogen. Upon completion as determined by LCMS, the reaction was diluted with saturated NaHCO? solution (4 mL) and extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified by via prep HPLC (WePure Biotech XPt C18 column 150 x 30 mm, 7 pm) using 0.225% FA in water with a gradient of 40-70% MeCN at 25 mL / min) to afford Compound 67 (20.1 mg, 18% yield) as a white solid.!H NMR (400 MHz, DMSO): 5 8.11 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 6.53 (d, J = 2.0 Hz, 1H), 4.97 -4.88 (m, 1H), 3.86 (s, 3H), 3.71 (s, 3H), 2.19 (s, 3H), 1.45 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 370.9.Example 68a & Example 68b; ( / ?)- / V-(l-(5-chloro-l,2-dimethyl-1H-imidazol-4-yl)ethyl)- l-(5-chloropyrimidin-2-yl)-lH-pyrazol-3-amine & (5)-7V-(l-(5-chloro-l,2-dimethyl-lH- imidazol-4-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-lH-pyrazol-3-amineStep 1 Step 2 Step 3Step 4Step 1: Synthesis of 5-chloro- 1,2-dimethyl-4-vinyl- IH-imidazole

[0349] To a mixture of 4-bromo-5 -chloro- 1,2-dimethyl-imidazole (3.8 g, 18.14 mmol and potassium trifluoro(vinyl)borate (7.29 g, 54.42 mmol) in 1.4-dioxane (100 mL) and water (20 mL) was added CS2CO3 (17.73 g, 54.42 mmol) and Pd(dppf)Ch (1.33 g, 1.81 mmol). The reaction was stirred at 100 °C for 16 h under a nitrogen atmosphere. Upon completion as determined by LCMS, the reaction was diluted with water and extracted with ethyl acetate (3 x 30 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (10% ethyl acetate in ii-hexane) to yield 5-chloro-l,2-dimethyl-4-vinyl-imidazole (1.9 g, 67% yield) as yellow oil.’H NMR (400 MHz, DMSO): 5 6.47 (dd, J= 17.6, 11.2 Hz, 1H), 5.70 (dd, J= 17.2, 2.4 Hz, 1H), 5.08 (dd, J= 11.2, 2.4 Hz, 1H). 3.45 (s, 3H). 2.29 (s. 3H).Step 2: Synthesis of 5-chloro-l,2-dimethyl-lH-imidazole-4-carbaldehyde

[0350] To a solution of 5-chloro-l,2-dimethyl-4-vinyl-imidazole (1.8 g, 11.49 mmol) inTHF (60 mL) and water (15 mL) was added K₂OsO₄·2H₂O (423 mg, 1.15 mmol) and sodium periodate (7.38 g, 34.48 mmol). The mixture was stirred at room temperature for 1 h. After completion, the reaction was diluted with water and extracted with ethyl acetate (3 x 30 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield 5-chloro-l.2-dimethyl-l / 7-imidazole-4-carbaldehyde (1.4 g, 77% yield) as a black oil. 'H NMR (400 MHz, DMSO): 5 9.70 (s. 1H), 3.55 (s, 3H), 2.37 (s, 3H).Steps 3-4: Synthesis of N-(l-(5-chloro-l,2-dimethyl-lH-imidazol-4-yl)ethyl)-l-(5-chloropyrimidin-2-yl) - lH-pyrazol-3-amine

[0351] / V-(l-(5-chloro-L2-dimethyl-177-imidazol-4-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-lL7-pyrazol-3-amine (120 mg, 14% yield) as a white solid was prepared using the general procedure described for the preparation of 7V-(l-(4-chloroisothiazol-5-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-l / 7-pyrazol-3-amme (Ex. 63a & Ex. 63b) by replacing 4-chloroisothiazole-5-carbaldehyde with 5-chloro-l.2-dimethyl-l / 7-imidazole-4-carbaldehyde in Step 3. LCMS: (ESI, m / z) [M+H]+= 352.1.Step 5: Synthesis of (R)-N-(l-(5-chloro-l,2-dimethyl-lH-imidazol-4-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-lH-pyrazol-3-amine & (S)-N-( 1 -(5-chloro-l, 2-dimethyl-lH-imidazol-4-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-lH-pyrazol-3-amine

[0352] , V-( l-(5-chloro-l.2-dimethyl-l / / -imidazol-4-yl)ethyl)-l -(5-chloropyrimidin-2-yl)- l / / -pyrazol-3-amine (120 mg, 0.34 mmol) was separated by chiral SFC (Daicel Chiralcel OD (250 mm x 30 mm, 10 um), Supercritical CO2 / EtOH + 0. 1% NH3H2O = 55 / 45; 80mL / min) to afford Compound 68a (peak 1. Rt =2.939 mm, 37.3 mg, 30% yield) and Compound 68b (peak 2, Rt = 3.256 min, 35.0 mg, 29% yield) both as white solid.

[0353] Compound 68a (stereoisomer 1): 'H NMR (400 MHz, DMSO): 5 8.78 (s, 2H), 8.26 (d, J = 2.8 Hz, 1H), 6.06 (d, J = 8.4 Hz, 1H), 5.96 (d, J = 2.8 Hz, 1H), 4.76 - 4.70 (m. 1H), 3.43 (s, 3H), 2.29 (s, 3H). 1.38 (d. J= 6.4 Hz. 3H). LCMS (ESI, m / z) [M+H] = 352.1.

[0354] Compound 68b (stereoisomer 2): ’H NMR (400 MHz, DMSO): 5 8.78 (s, 2H), 8.26 (d. J = 2.8 Hz, 1H). 6.06 (d, J = 8.0 Hz, 1H), 5.96 (d, J = 2.8 Hz. 1H), 4.76 - 4.70 (m, 1H), 3.43 (s, 3H), 2.29 (s, 3H), 1.38 (d, J= 6.8 Hz, 3H). LCMS (ESI, m / z) [M+H]’ = 352.1.Example 69a & Example 69b: ( / ?)- / V-(l-(4-chloro-5-fluoropyridin-3-yl)ethyl)-l-(5- chloropyrimidin-2-yl)- lH-pyrazol-3- amine & (5)-7V-(l-(4-chloro-5-fluoropyridin- 3-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-lH-pyrazol-3- amineSteps 1-2: Synthesis ofN-( l-(4-chloro-5-fluoropyridin-3-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-lH-pyrazol-3-amine

[0355] jV-(l-(4-chloro-5-fluoropyridin-3-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-lH-pyrazol-3-amine (100 mg, 23% yield) as a white solid was prepared using the general procedure described for the preparation of A-(l-(4-chloroisothiazol-5-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-lE7-pyrazol-3-amine (Ex.63a & Ex.63b) by replacing 4-chloroisothiazole-5-carbaldehyde with 4-chloro-5-fluoronicotinaldehyde in Step 3. LCMS (ESI, m / z) [M+H]+= 353.0.Step 3: Synthesis of (R)-N-( l-(4-chloro-5-fluoropyridin-3-yl)ethyl)- 1 -(5-chloropyrimidin-2-yl)-lH-pyrazol-3-amine & (S)-N-( 1 -(4-chloro-5-fluoropyridin-3-yl)ethyl)-l-(5-chloropyrimidin-2-yl) - lH-pyrazol-3-amine

[0356] jV-(l-(4-chloro-5-fluoropyridin-3-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-l / / -pyrazol-3-amine (100 mg, 0.22 mmol) was separated by chiral SFC (Daicel Chiralpak AD (250 mmx 30 mm, 10 um), Supercritical CO2 / IPA + 0.1%NHsH2O = 50 / 50; 150 mL / min) to afford Compound 69a (peak 1, Rt = 1.597 min, 36.5 mg, 36% yield) and Compound 69b (peak 2, Rt = 3.391 min, 29.2 mg, 29% yield) both as white solids.

[0357] Compound 69a (stereoisomer 1): ¹H NMR (400 MHz, DMSO): δ 8.77 (s, 2H), 8.58 (s, 1H), 8.56 (s, 1H), 8.30 (d, J = 2.8 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 5.95 (d, J = 2.8 Hz, 1H), 5.13 - 4.99 (m, 1H), 1.49 (d, J = 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 353.0.

[0358] Compound 69b (stereoisomer 2): ’H NMR (400 MHz, DMSO): 5 8.77 (s, 2H), 8.58 (s, 1H), 8.56 (s, 1H), 8.30 (d, J = 2.8 Hz, 1H), 6.90 (d, J= 8.0 Hz, 1H), 5.95 (d, J = 2.8 Hz, 1H), 5.14 - 4.96 (m, 1H), 1.49 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 353.0.Example 70a & Example 70b: (7?)-N-(l-(4-chloro-5-fluoro-l-methyl-lH-pyrazol-3- yl)ethyl)- l-(5-chloropy rimidin-2-yl)- lH-pyrazol-3-amine & (5)-N-(l-(4-chloro-5-fluoro- l-methyl-lH-pyrazol-3-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-lH-pyrazol-3-amineStep 1: Synthesis of 4-chloro-5-fluoro-l-methyl-3-vinyl-lH-pyrazole

[0359] To a solution of 3-bromo-4-chloro-5-fluoro- 1 -methyl- l / 7-pyrazole (900 mg, 4.22 mmol), potassium trifluoro(vinyl)borate (1.69 g, 12.66 mmol) in dioxane (20 mL) and water (4 mL) was added CS2CO3 (4.12 g, 12.66 mmol) and Pd(dppf)C12 (308 mg, 0.42 mmol). The reaction was stirred at 100 °C for 16 h under nitrogen. Upon completion as determined by LCMS. the reaction was diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The material was purified by column chromatography (5% ethyl acetate in n-hexane) to yield 4-chloro-5-fluoro-l-methyl-3-vinyl-177-pyrazole (480 mg, 71% yield) as colorless oil. ’H NMR (400 MHz, CDCh): 56.56 (dd, J= 18.0, 11.6 Hz, 1H), 6.08 (d, J= 18.0 Hz. 1H), 5.41 (d. J= 11.6 Hz, 1H), 3.74 (s, 3H). LCMS: (ESI, m / z) [M+H]+= 161.0.Step 2: Synthesis of 4-chloro-5-fl.uoro-l-methyl-lH-pyrazole-3-carbaldehyde

[0360] To a solution of 4-chloro-5-fluoro-l-methyl-3-vinyl-177-pyrazole (450 mg, 2.8 mmol) in THF (16 mL) and water (4 mL) were added K2OSO4 2H2O (103 mg, 0.28 mmol) and NaIO4 (1.8 g. 8.41 mmol). The reaction was stirred at room temperature for 1 h. Upon completion as determined by TLC, the reaction was diluted with water and extracted with ethylacetate (50 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (100% ethyl acetate) to yield 4-chloro-5-fluoro-l -methyl- l / / -pyrazole-3-carbaldehy de (380 mg, 83% yield) as brown oil. ¹H NMR (400 MHz, CDCl₃): δ 9.84 (d, J = 1.6 Hz, 1H), 3.89 (s, 3H).Steps 3-4: Synthesis of N-(l-(4-chloro-5-fluoro-l-methyl-lH-pyrazol-3-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-IH-pyrazol-3-amine

[0361] 7V-(l-(4-chloro-5-fluoro-l-methyl-177-pyrazol-3-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-17f-pyrazol-3-amine (170 mg, 21% yield) as a white solid was prepared using the general procedure described for the preparation of JV-(l-(4-chloroisothiazol-5-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-17 / -pyrazol-3-amine (Ex.63a & Ex.63b) by replacing 4-chloroisothiazole-5-carbaldehyde with 4-chloro-5-fluoro-l -methyl- 17f-pyrazole-3-carbaldehyde in Step 3. LCMS: (ESI, m / z) [M+H]+= 356.1.Step 5: Synthesis of (R)-N-(l-(4-chloro-5-fluoro-l-methyl-lH-pyrazol-3-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-lH-pyrazol-3-amine & (2)-N-(l-(4-chloro-5fluoro-l-methyl-lH-pyrazol-3-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-lH-pyrazol-3-amine

[0362] 7V-(l-(4-chloro-5-fluoro-l-methyl-17f-pyrazol-3-yl)ethyl)-1-(5-chloropyrimidin-2-yl)-1H-pyrazol-3-amine (170 mg, 0.48 mmol) was separated by chiral SFC (Daicel Chiralpak AD (250 mm x 30 mm, 10 um). Supercritical CO2 / MeOH + 0.1 % NH3H2O = 65 / 35; 150 mL / min) to afford Compound 70a (peak 1, Rt = 1.125 min, 49.5 mg, 28% yield) and Compound 70b (peak 2, Rt = 1.439 min, 61.7 mg, 36% yield) both as white solids.

[0363] Compound 70a (stereoisomer 1): ¹H NMR (400 MHz, DMSO): δ 8.79 (s, 2H), 8.29 (d, J = 2.8 Hz, 1H), 6.32 (d, J = 8.4 Hz, 1H), 5.96 (d, J = 3.2 Hz, 1H), 4.87 - 4.78 (m, 1H), 3.70 (s, 3H), 1.45 (d, J = 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 356.1.

[0364] Compound 70b (stereoisomer 2): ¹H NMR (400 MHz, DMSO): δ 8.79 (s, 2H), 8.29 (d, J = 2.4 Hz, 1H), 6.32 (d, J = 8.4 Hz, 1H), 5.96 (d, J = 3.2 Hz, 1H), 4.87 - 4.78 (m, 1H), 3.70 (s, 3H), 1.45 (d, J = 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 356.1.Example 71a & Example 71b; (R)- l-(5-chloropy rimidin-2-yl)- / V-(l -(4,5-dimethylthiazol- 2-yl)ethyl)-lH-pyrazol-3-amine & (5)-l-(5-chloropyrimidin-2-yl)-7V-(l-(4,5- dimethylthiazol-2-yl)ethyl)-lH-pyrazol-3-amineStep 1 Step 2Steps 1-2: Synthesis of 1 -(5-chloropyrimidin-2-yl)-N-( 1 -(4.5-dimethylthiazol-2-yl)ethyl)- 1 H-pyrazol-3-amine

[0365] l-(5-Chloropyrimidin-2-yl)-7V-(l-(4,5-dimethylthiazol-2-yl)ethyl)-177-pyrazol-3-amine (55 mg. 16% yield) as a white solid was prepared using the general procedure described for the preparation of / V-(l-(4-chloroisothiazol-5-yl)ethyl)-1-(5-chloropyrimidin-2-yl)-1H-pyrazol-3-amine (Ex.63a & Ex.63b) by replacing 4-chloroisothiazole-5-carbaldehyde with 4,5-dimethylthiazole-2-carbaldehyde in Step 3. LCMS: (ESI, m / z) [M+H]+= 335.1.Step 3: Synthesis of (R)-l-(5-chloropyrimidin-2-yl)-N-(l-(4,5-dimethylthiazol-2-yl)ethyl)-lH-pyrazol-3-amine & (S)-l-(5-chloropyrimidin-2-yl)-N-(l-(4.5-dimethylthiazol-2-yl)ethyl)-lH-pyrazol-3-amine

[0366] l-(5-Chloropyrimidin-2-yl)-7V-(l-(4,5-dimethylthiazol-2-yl)ethyl)-lE7-pyrazol-3-amine (55 mg. 0.16 mmol) was separated by chiral SFC (Regis(S, S) Whelk-01 (250 mm x 30 mm, 10 um). Supercritical CO2 / EtOH + 0.1% NH3H2O = 40 / 60; 80 mL / min) to afford Compound 71a (peak 1, Rt = 2.474 min, 10.7 mg, 19% yield) and Compound 71b (peak 2, Rt = 4.407 min, 13.6 mg, 25% yield) both as white solids.

[0367] Compound 71a (stereoisomer 1): ¹H NMR (400 MHz, DMSO): δ 8.78 (s, 2H), 8.32 (d, J = 2.4 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 5.97 (d, J = 3.2 Hz, 1H), 4.95 - 4.87 (m, 1H), 2.24 (s, 3H), 2.21 (s, 3H), 1.50 (d, J = 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 335.1.

[0368] Compound 71b (stereoisomer 2): ’H NMR (400 MHz, DMSO): 6 8.78 (s, 2H), 8.32 (d. J = 2.4 Hz, 1H). 6.75 (d, J = 7.6 Hz, 1H), 5.97 (d, J = 3.2 Hz. 1H), 4.95 - 4.88 (m, 1H), 2.24 (s, 3H), 2.21 (s, 3H), 1.50 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 335.1.Example 72a & Example 72b; ( / ?)-l-(5-chloropyrimidin-2-yl)-N-(l-(5-chlorothiazol-2- yl)ethyl)- lH-pyrazol-3- amine & (5)- l-(5-chloropyrimidin-2-yl)-N-(l-(5-chlorothiazol-2- yl)ethyl)- lH-pyrazol-3- amineSteps 1-2: Synthesis of l-(5-chloropyrimidin-2-yl)-N-(l-(5-chlorothiazol-2-yl)ethyl)-lH-pyrazol-3-amine

[0369] l-(5-Chloropyrimidin-2-yl)- / V-(l-(5-chlorothiazol-2-yl)ethyl)-177-pyrazol-3-amine (42 mg, 20% yield) as a white solid was prepared using the general procedure described for the preparation of 7V-(l-(4-chloroisothiazol-5-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-lE7-pyrazol-3-amine (Ex. 63a & Ex. 63b) by replacing 4-chloroisothiazole-5-carbaldehyde with 5-chlorothiazole-2-carbaldehyde in Step 3. LCMS: (ESI, m / z) [M+H]+= 341.0.Step 3: Synthesis of (R)-l-(5-chloropyrimidin-2-yl)-N-(l-(5-chlorothiazol-2-yl)ethyl)-lH-pyrazol-3-amine & (S)-l-(5-chloropyrimidin-2-yl)-N-(l-(5-chlorothiazol-2-yl)ethyl)-lH-pyrazol-3-amine

[0370] l-(5-Chloropyrimidin-2-yl)- / V-(l-(5-chlorothiazol-2-yl)ethyl)-177-pyrazol-3-amine (70 mg, 0.21 mmol) was separated by chiral SFC (Dai cel Chiralpak IG (250 mm x 30 mm, 10 um), Supercritical CO2 / MeOH + 0.1% NH3H2O = 40 / 60; 80 mL / min) to afford Compound 72a (peak 1, Rt = 0.838 min. 20.2 mg. 29% yield) and Compound 72b (peak 2. Rt = 1.352 min, 23.2 mg, 33% yield) both as white solids.

[0371] Compound 72a (stereoisomer 1): ¹H NMR (400 MHz, DMSO): δ 8.80 (s, 2H), 8.36 (d, J = 2.8 Hz, 1H), 7.73 (s, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.01 (d, J = 2.8 Hz, 1H), 5.01 - 4.90 (m, 1H), 1.54 (d, J = 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]⁺ = 341.0.

[0372] Compound 72b (stereoisomer 2): ‘H NMR (400 MHz, DMSO): 5 8.80 (s, 2H), 8.37 (d, J= 2.4 Hz, 1H), 7.74 (s, 1 H), 6.96 (d, J= 7.2 Hz, 1H), 6.02 (d, J= 2.8 Hz, 1H), 5.02 - 4.90 (m, 1H), 1.55 (d, J= 7.2 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 341.0.Example 73a & Example 73b: (7?)-5-chloro-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3- yl)ethyl)-l-(pyrimidin-2-yl)-lH-pyrazol-3-amine & (5)-5-chloro-N-(l-(4-chloro-l,5- dimethyl-lH-pyrazol-3-yl)ethyl)-l-(pyrimidin-2-yl)-lH-pyrazol-3-amineCl Cl ClStep 1: Synthesis of 2-(5-ch!oro-3-nitro-lH-pyrazol-l-yl)pyrimidine

[0373] To amixture of 3-chloro-5-nitro-l / / -pyrazole (2.0 g, 13.6 mmol, 1 equiv) and K2CO3 (3.7 g, 27.1 mmol, 2 equiv) in DMF (40 mL, 0.34 M) was added 2-chloropyrimidine (2.3 g, 20.3 mmol, 1.5 equiv). The reaction mixture was stirred at 120 °C for 48 h. After completion, the reaction was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic phases were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (25% ethyl acetate / hexane) to yield 2-(5-chloro-3-nitro-177-pyrazol-l-yl)pyrimidine (760 mg. 25% yield) as ayellow solid. 'H NMR (400 MHz, DMSO): <59.10 (d, J = 4.8 Hz. 2H), 7.81 (t, J = 4.8 Hz, 1H), 7.66 (s, 1H).Step 2: Synthesis of 5-chloro-l-(pyrimidin-2-yl)-lH-pyrazol-3-amine

[0374] To a mixture of 2-(5-chloro-3-nitro-1H-pyrazol-1-yl)pyrimidine (800 mg, 3.5 mmol, 1 equiv) in EtOH (20 mL) and H2O (10 mL) was added Fe dust (1.0 g, 17.7 mmol, 5 equiv) and NH4CI (950 mg, 17.7 mmol, 5 equiv). The reaction mixture was stirred at 80 °C. Upon completion as determined by LCMS, the reaction was fdtered through a Celite pad. The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic phases were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated to yield 5-chloro-l-(pyrimidin-2-yl)-127-pyrazol-3-amine (480 mg, 69% yield) as ayellow solid. LCMS: (ESI, m / z) [M+H]+= 196.1.Step 3: Synthesis of (E)-l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)-N-(5-chloro-l-(pyrimidin-2-yl)-lH-pyrazol-3-yl)methammine

[0375] To a mixture of 5-chloro-l-(pyrimidin-2-yl)-17 / -pyrazol-3-amine (410 mg, 2.1 mmol, 1 equiv) in MeOH (16 mL, 0.13 M) was added AcOH (126 mg, 2.1 mmol, 1 equiv), 4-chloro-l,5-dimethyl-177-pyrazole-3-carbaldehyde (340 mg, 2.1 mmol, 1 equiv). The reaction mixture was stirred at 80 °C for 1 h. After completion, the reaction was concentrated under reduced pressure to yield crude (E’)-l-(4-chloro-l,5-dimethyl-1 f-pyrazol-3-yl)-N-(5-chloro-l-(pyrimidin-2-yl)-lT7-pyrazol-3-yl)methanimine (720 mg, 98% yield) as a yellow solid which was used without further purification. LCMS: (ESI, m / z) [M+H]+= 336.1.Step 4: Synthesis of 5-chloro-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-l-(pyrimidin-2-yl)-lH-pyrazol-3-amine

[0376] To a suspension of (E)-l-(4-chloro-l,5-dimethyl-17 / -pyrazol-3-yl)-A-(5-chloro-l-(pyrimidin-2-yl)-177-pyrazol-3-yl)methanimine (720 mg, 2.1 mmol, 1 equiv) in THF (20 mL, 0.1M) was added 3M methylmagnesium bromide (3.58 mL, 10.7 mmol, 5 equiv) dropwise at -78 °C under nitrogen. The mixture was stirred at -78 °C for 2 h. Upon completion as determined by LCMS, the reaction mixture was quenched with saturated NH4CI solution (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organics phases were washed with brine (20 mL). dried over sodium sulfate, filtered, and concentrated. The crude was purified via prep HPLC (Phenomenex Gemini NX C18 column 150 x 30 mm. 5 pm) using 0.225% FA in water with a gradient of 28-58% MeCN at 25 mL / min) to yield 5-chloro-A-(l-(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)ethyl)-l-(pyrimidin-2-yl)-177-pyrazol-3-amine (40 mg, 5% yield) as a white solid. LCMS: (ESI, m / z) [M+H]+= 352.1.Step 5: Synthesis of (R)-5-chloro-N-(l-(4-chloro-1.5-dimethyl-lH-pyrazol-3-yl)ethyl)-l-(pyrimidin-2-yl)-lH-pyrazol-3-cimine & (S)-5-chloro-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-l-(pyrimidin-2-yl)-lH-pyrazol-3-amine

[0377] 5-Chloro-A-(l-(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)ethyl)-l-(pyrimidin-2-yl)-IT / -pyrazol-3-amine (40 mg. 0.11 mmol) was separated by chiral SFC (Daicel Chiralcel OD (250 mm x 30 mm,10 um). Supercritical CO2 / IPA + 0.1% NH3H2O = 45 / 55: 80 mL / min) to afford Compound 73a (peak 1, Rt = 1.587 min, 10.9 mg, 27% yield) and Compound 73b (peak 2, Rt = 1.912 min, 9.6 mg. 24% yield) both as white solids.

[0378] Compound 73a (stereoisomer 1):1H NMR (400 MHz, DMSO): 5 8.84 (d, J = 4.8 Hz. 2H), 7.42 (t, J= 4.8 Hz. 1H), 6.14 (d. J = 8.4 Hz, 1H), 6.01 (s. 1H), 4.82 - 4.68 (m, 1H), 3.71 (s, 3H), 2.19 (s, 3H), 1.41 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 352.1.

[0379] Compound 73b (stereoisomer 2): ¹H NMR (400 MHz, DMSO): δ 8.84 (d, J = 4.8 Hz, 2H), 7.42 (t, J = 4.8 Hz, 1H), 6.14 (d, J = 8.4 Hz, 1H), 6.01 (s, 1H), 4.82 - 4.68 (m, 1H), 3.71 (s, 3H), 2.19 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 352.1.Example 74; 5-Chloro-7V-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yI)ethyI)-4-(l-methyl- lH-pyrazol-4-yl)thiazol-2-amineStep 1: Synthesis of l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethan-l-ol

[0380] To a solution of 4-chloro-l,5-dimethyl-pyrazole-3-carbaldehyde (500 mg, 3.15 mmol, 1 equiv) in THF (10 mL, 0.3 M) was added CIEMgBr (1.58 mL, 4.73 mmol, 1.5 equiv) at 0 °C under nitrogen. The reaction was warmed up to room temperature and stirred at room temperature for 2 h. After completion, the reaction quenched with sat. aq. NH4CI ( 10 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (0-30% EtOAc in w-hexane) to yield 1-(4-chloro-1,5-dimethyl-1H-pyrazol-3-yl)ethan-1-ol (400 mg, 73% yield) as colorless oil. 'H NMR (400 MHz, DMSO): 5 4.97 (d, J= 4.8 Hz, 1H), 4.73 - 4.64 (m, 1H), 3.69 (s, 3H), 2.19 (s, 3H), 1.38 (d, J= 6.8 Hz, 3H).Step 2: Synthesis of l-(4-chloro-1.5-dimethyl-lH-pyrazol-3-yl)ethan-l-one

[0381] To a solution of l-(4-chloro-l,5-dimethyl-17f-pyrazol-3-yl)ethan-l-ol (400 mg, 2.29 mmol, 1 equiv) in DCM (6 mL, 0.38 M) was added DMP (1.49 g, 3.44 mmol, 1.5 equiv). The reaction was stirred at room temperature for 1 h. After completion, the reactionquenched with sat. aq. Na2SO3 solution (5 mL) and extracted with DCM (20 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (0-20% EtOAc in w-hexane) to yield 1-(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)ethan-l-one (270 mg, 68% yield) as a yellow solid. 'H NMR (400 MHz, DMSO): 83.85 (s, 3H), 2.43 (s, 3H), 2.24 (s, 3H).Step 3: Synthesis of tert-butyl (4-(l-methyl-lH-pyrazol-4-yl)thiazol-2-yl)carbamate

[0382] To a solution of tert-butyl 4-bromothiazol-2-ylcarbamate (3.0 g, 10.75 mmol, 1 equiv) and l-methyl-4-(4.4.5.5-tetramethyl-l.3.2-dio.xaborolan-2-yl)-l / / -pyrazole (3.35 g, 16.12 mmol, 1.5 equiv) in 1,4-dioxane (50 mL) and water (5 mL) were added Pd(dppf)C12 (786 mg, 1.07 mmol, 0.1 equiv) and K2CO3 (4.46 g, 32.24 mmol, 3 equiv). The mixture was heated to 100 °C for 16 h under nitrogen. Upon completion as determined by LCMS, the reaction was diluted with water (40 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (0-20% EtOAc / n-hexane) to yield / c / 7-butyl (4-(l -methyl- IH-pyrazol-4-yl)thiazol-2-yl)carbamate (2 g, 82% yield) as a yellow solid. LCMS: (ESI, m / z) [M+H]+= 281.1.Step 4: Synthesis of tert-butyl (5-chloro-4-(l-methyl-lH-pyrazol-4-yl)thiazol-2-yl)carbamate

[0383] To a solution of tert-butyl (4-(l -methyl- l / / -pyrazol-4-yl)thiazol-2-yl)carbamate (1.2 g, 4.28 mmol, 1 equiv) in DMF (60 mL, 0.07 M) was added NCS (0.69 g, 5.14 mmol, 1.2 equiv). The mixture was heated to 60 °C for 2 h. Upon completion as determined by LCMS, the reaction was diluted with water (40 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (0-30% EtOAc in n-hexane) to yield tert-butyl (5 -chloro-4-(l -methyl- 17f-pyrazol-4-yl)thiazol-2-yl)carbamate (700 mg, 52% yield) as a yellow solid. LCMS: (ESI, m / z) [M+H]+= 315.1.Step 5: Synthesis of 5-chloro-4-( 1 -methyl- lH-pyrazol-4-yl)thiazol-2-amine

[0384] To a solution of tert-butyl (5 -chloro-4-(l -methyl- l / / -pyrazol-4-y l)thiazol-2-yl)carbamate (700 mg. 2.22 mmol) in DCM (10 mL) was added 2,2,2-trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 1 h. Upon completion as determined by LCMS, the reaction was concentrated and the residue was diluted with NaHCO3 (10 mL) andextracted with DCM (30 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to yield 5 -chloro-4-(l -methyl- 17f-pyrazol-4-y l)thiazol-2-amine (350 mg, 73% yield) as a yellow solid. LCMS: (ESI, m / z) [M+H]+= 215.1.Step 6: Synthesis of (E)-l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)-N-(5-chloro-4-(l-methyl-lH-pyrazol-4-yl)thiazol-2-yl)ethan-l-imme

[0385] To a solution of l-(4-chloro-l,5-dimethyl-pyrazol-3-yl)ethanone (218 mg.1.26 mmol, 1 equiv) and 5-chloro-4-(l-methylpyrazol-4-yl)thiazol-2-amine (270 mg, 1.26 mmol, 1 equiv) in toluene (5 mL) was added and titanium(IV) isopropoxide (1.07 g, 3.78 mmol). The mixture was heated to 110 °C for 2 h. Upon completion as determined by LCMS, the reaction was concentrated to yield (E)-l-(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)-jV-(5-chloro-4-(l -methyl- lL7-pyrazol-4-yl)thiazol-2-yl)ethan-l -imine (400 mg crude), which was directly used in the next step without further purification. LCMS: (ESI, m / z) [M+H]+= 369.0.Step 7: Synthesis of 5-chloro-N-(l-(4-chloro-1.5-dimethyl-lH-pyrazol-3-yl)ethyl)-4-(l-methyl-lH-pyrazol-4-yl)thiazol-2-amine

[0386] To a solution of (E)-l-(4-chloro-l,5-dimethyl-177-pyrazol-3-yl)-N-(5-chloro-4-(l -methyl- 177-pyrazol-4-yl)thiazol-2-yl)ethan-l -imine (400 mg, 1.08 mmol) in MeOH (5 mL, 0.22 M) at 0 °C under nitrogen was added NaBH4 (123 mg, 3.25 mmol). Then the reaction was stirred at room temperature for 2 h. Upon completion as determined by LCMS, the reaction was diluted with water (20 mL) and extracted with EtOAc (40 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The material was purified by purified via prep HPLC (Welch Xtimate C18 column 150 x 30 mm, 5 pm) using 10 mM NH4HCO3 in water with a gradient of 52-82% MeCN at 25 mL / min) to afford Compound 74 (12 mg, 14% yield) as a white solid. ¹H NMR (400 MHz, DMSO): δ 8.13 (d, J = 7.2 Hz, 1H), 8.06 (s, 1H), 7.78 (s, 1H), 4.99 - 4.89 (m, 1H), 3.87 (s, 3H), 3.71 (s, 3H), 2.19 (s, 3H), 1.45 (d, J = 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 371.0.Example 75a & Example 75b: (7?)-l-(5-chloropyrimidin-2-yl)-A (l-(4-chlorothiazol-2- yl)ethyl)-lH-pyrazol-3-amine & (5)-l-(5-chloropyrimidin-2-yl)-7V-(l-(4-chlorothiazol-2- yl)ethyl)- lH-pyrazol-3-amineStep 1: Synthesis of (E)-l-(2,3-difluorophenyl)-N-(l-(5-methylpyrimidin-2-yl)-lH-pyrazol-3-yl methanimine

[0387] To a mixture of l-(5-methylpyrimidin-2-yl)-177-pyrazol-3-amine (200 mg, 1.4 mmol, 1 equiv) and 2,3-difluorobenzaldehyde (247 mg, 1.4 mmol, 1 equiv) in MeOH (12 mL, 0.1 M) was added AcOH (85 mg, 1.4 mmol, 1 equiv). The reaction was stirred at 80 °C for 1 h. After completion, the mixture was concentrated under reduced pressure to yield crude ( / / )- 1 -(2, 3-di fluorophenyl )-7V-( 1 -(5-methylpyrimidin-2-yl )- 1 H-pyrazol-3-yl)methanimine (420 mg, 99% yield) as a yellow solid. 'H NMR (400 MHz, DMSO): 59.19 (s, 1H), 8.73 (s, 2H), 8.66 (d, J= 2.8 Hz. 1H), 7.93 (t, J= 6.8 Hz, 1H), 7.72 - 7.58 (m. 1H), 7.45 - 7.31 (m, 1H), 6.88 (d, J= 2.8 Hz, 1H), 2.32 (s, 3H). LCMS: (ESI, m / z) [M+H]+= 300.1.Step 2: Synthesis of N-(l-(2,3-difluorophenyl)-2,2,2-trifluoroethyl)-l-(5-methylpyrimidin-2- yl)-lH-pyrazol-3-amine

[0388] To a mixture of (E)-l-(2,3-difluorophenyl)-JV-(l-(5-methylpyrimidin-2-yl)- l / 7-pyrazol-3-yl)methanimine (420 mg. 1.4 mmol, 1 equiv) and TBAA (465 mg. 1.5 mmol, 1.1 equiv) in THF (10 rnL, 0.14 M) was added TMSCF3 (0.42 mL, 2.8 mmol, 2 equiv) at -20 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 2 h. Upon completion as determined by LCMS, the reaction was quenched by saturated NH4CI solution (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified via prep HPLC (Welch Xtimate C18 column 150 x 30 mm, 5 pm) using 10 mM NH4HCO3 in water with a gradient of 55-85% MeCN at 25 rnL / min) to yield A-(l-(2.3-difluorophenyl)-2.2.2- trifluoroethyl)-l-(5-methylpyrimidin-2-yl)-lH-pyrazol-3-amine (200 mg, 40% yield) as a white solid. LCMS: (ESI, m / z) [M+HJ+= 370.1.Step 3: Synthesis of (R)-N-(l-(2,3-difluorophenyl)-2,2,2-trifluoroethyl)-l-(5-methylpyrimidin-2-yl)-lH-pyrazol-3-amine & (S)-N-( l-(2, 3-difluorophenyl)-2.2.2-trifluoroethyl)-l-(5-methylpyrimidin-2-yl)-lH-pyrazol-3-amine

[0389] 7V-(l-(2,3-difluorophenyl)-2,2,2-trifluoroethyl)-l-(5-methylpyrimidin-2-yl)- 1H- pyrazol-3-amine (150 mg, 0.41 mmol) was separated by chiral SFC (Daicel Chiralcel OJ (250 mm x 30 mm, 10 um), Supercritical CO2 / MeOH + 0.1% NH3H2O = 85 / 15; 80 mL / min) to afford Compound 75a (peak 1, Rt = 1.577 min, 46.9 mg, 31%) and Compound 75b (peak 2, Rt = 1.803 min, 29.0 mg, 20%) both as white solids.

[0390] Compound 75a (stereoisomer 1): 'H NMR (400 MHz, DMSO): 5 8.58 (s, 2H), 8.37 (d. J = 2.8 Hz, 1H), 7.61 - 7.49 (m. 2H), 7.47 (d. J = 10.0 Hz. 1H), 7.39 - 7.30 (m, 1H), 6.04 (d, J= 2.8 Hz, 1H), 6.00 - 5.89 (m, 1H), 2.25 (s, 3H). LCMS: (ESI, m / z) [M+H]+= 370.1.

[0391] Compound 75b (stereoisomer 2): 'H NMR (400 MHz, DMSO): 5 8.58 (s, 2H), 8.37 (d, J = 2.8 Hz, 1H), 7.61 - 7.49 (m. 2H), 7.47 (d, J = 10.0 Hz, 1H), 7.39 - 7.30 (m, 1H), 6.04 (d, J= 2.8 Hz, 1H), 6.00 - 5.89 (m, 1H), 2.25 (s, 3H). LCMS: (ESI, m / z) [M+H]+= 370.1.Example 76a & Example 76b: ( / ?)-l-(5-chloropyriiiiidin-2-yl)- / V-(l-(4-chlorothiazol-2- yl)ethyl)-lH-pyrazol-3- amine & (5)-l-(5-chloropyrimidin-2-yl)-2V-(l-(4-chlorothiazol-2- yl)ethyl)- 1 H-pyrazoI-3-amineSteps 1-2: Synthesis of l-(5-chloropyrimidin-2-yl)-N-(l-(4-chlorothiazol-2-yl)ethyl)-lH-pyrazol-3-amine

[0392] l-(5-Chloropyrimidin-2-yl)-JV-(l-(4-chlorothiazol-2-yl)ethyl)-17 / -pyrazol-3-amine (10 mg, 2% yield) as a white solid was prepared using the general procedure described for the preparation of / V-(l-(4-chloroisothiazol-5-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-17f-pyrazol-3-amine (Ex. 63a & Ex. 63b) by replacing 4-chloroisothiazole-5-carbaldehyde with 4-chlorothiazole-2-carbaldehyde in Step 3. LCMS (ESI, m / z) [M+H]+= 341.1.Step 3: Synthesis of (R)-l-(5-chloropyrimidin-2-yl)-N-(l-(4-chlorothiazol-2-yl)ethyl)-lH-pyrazol-3-amine & (S)-l-(5-chloropyrimidin-2-yl)-N-(l-(4-chlorothiazol-2-yl)ethyl)-lH-pyrazol-3-amine

[0393] 1 -(5-Chloropyrimidin-2-yl)-JV-(l -(4-chlorothiazol-2-yl)ethyl)-177-pyrazol-3-amine (10 mg, 0.03 mmol) was separated by chiral SFC (Daicel Chiralcel OJ (250 mm x 30 mm, 10 urn), Supercritical CO2 / EtOH + 0.1% NH3H2O = 55 / 45; 80 mL / min) to afford Compound 76a (peak 1, Rt = 1.566 min, 4.3 mg, 43% yield) and Compound 76b (peak 2, Rt = 1.959 min, 33 mg, 33% yield) both as white solid.

[0394] Compound 76a (stereoisomer 1): 'H NMR (400 MHz, DMSO): 5 8.79 (s, 2H), 8.35 (d, J = 2.4 Hz. 1H), 7.55 (s, 1H), 6.95 (d, J= 7.2 Hz 1H), 6.02 (d, J = 2.8 Hz. 1H), 5.08 - 4.98 (m. 1H), 1.54 (d, J= 6.8 Hz. 3H). LCMS: (ESI, m / z) [M+H]+= 341.0.

[0395] Compound 76b (stereoisomer 2): 'H NMR (400 MHz, DMSO): 8 8.79 (s, 2H), 8.35 (d, J = 2.8 Hz, 1H), 7.55 (s, 1H), 6.95 (d, J= 7.2 Hz 1H), 6.02 (d, J = 2.8 Hz, 1H), 5.08 - 4.98 (m, 1H), 1.54 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 340.9.Example 77: N-(1-(2,3-difluorophenyl)cyclobutyl)-1-(5-methylpyrimidin-2-yl)-1H-pyrazol-3-amineStep 1Step4Step 1: Synthesis ofN-(l-(2.3-difluorophenyl)cyclobutyl)-2-methylpropane-2-sulflnamide

[0396] To a solution of l-bromo-2,3-difluorobenzene (4.6 mL, 41 mmol, 1.5 equiv) in THF (100 mL, 0.27 M) at -78 °C under nitrogen was added n-BuLi (2.5 M, 16 mL, 41 mmol, 1.5 equiv) dropwise. The reaction was stirred at -78 °C for 30 minutes, then 7V-cyclobutylidene-2-methylpropane-2-sulfinamide (4 g, 27 mmol, 1 equiv) was added dropwise. The reaction was stirred at -78 °C for 2 h under nitrogen. Upon completion as determined by LCMS, the reaction was quenched with saturated NH4CI solution (15 mL) and then extracted with EtOAc (50 mL x 2). The combined organics were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (0-30% EtOAc in ii-Hexane) to yield JV-(l-(2,3-difluorophenyl)cyclobutyl)-2-methylpropane-2-sulfinamide (1.3 g, 17% yield) as a white solid.1H NMR (400 MH / . CDCL): 57.14 - 7.03 (m, 3H), 3.75 (s, 1H), 2.73 - 2.42 (m, 4H), 2.30 - 2.15 (m, 1H). 1.92 - 1.80 (m, 1H), 1.17 (s. 9H). LCMS: (ESI, m / z) [M+H]+= 288.1.Step 2: Synthesis of l-(2,3-difluorophenyl)cyclobutan-l-amine

[0397] To a solution of 2M HC1 in dioxane (22 mL, 45 mmol, 30 equiv) was added / V-(l-(2,3-difluorophenyl)cyclobutyl)-2-methylpropane-2-sulfmamide (1.3 g. 1.5 mmol, 1 equiv). Then the reaction was stirred at room temperature for 1 h. Upon completion as determined by LCMS, the mixture was concentrated. The crude was dissolved in MeOH (100 mL) and Amberlyst A26(OH) ion exchange resin (2 g) was added. The mixture was stirred at room temperature for 1 h, and then filtered. The filtrate was concentrated to yield l-(2,3-difluorophenyl)cyclobutan-l -amine (0.57 g, 69% yield) as a yellow oil.!H NMR (400 MHz, DMSO): 7.30 - 7.19 (m, 1H), 7.18 - 7.03 (m, 2H), 2.46 - 2.42 (m, 1H), 2.16 - 2.03 (m, 4H), 1.74 - 1.61 (m, 1H). LCMS (ESI, m / z) [M+H]+= 184.1.Step 3: Synthesis ofN-(l-(2.3-difluorophenyl)cyclobutyl)-lH-pyrazol-3-amine

[0398] To a stirred solution of l-(2,3-difluorophenyl)cyclobutan-l-amine (400 mg, 2.2 mmol, 1 equiv), 3-iodo-1H-pyrazole (508 mg, 2.6 mmol, 1.2 equiv), t-BuBrettPhos Pd G3 (187 mg, 0.22 mmol, 0.1 equid) and / -BuBrettPhos (212 mg, 0.44 mmol, 0.2 equiv) in THF (4 mL, 0.5 M) was added LiHMDS in THF (1.0 M, 6.6 mL, 6.6 mmol, 3 equiv) dropwise at 0 °C under nitrogen. The reaction was stirred at room temperature for 16 hours under nitrogen. Upon completion as determined by LCMS, the reaction was quenched with H2O (2 mL) and then extracted with EtOAc (5 mL x 2). The combined organics were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated. The material was purified by column chromatography (20% EE (Ethyl acetate / ethanol = 3 / 1) in / r-hexane) to yield 7V-(l-(2,3-difluorophenyl)cyclobutyl)-177-pyrazol-3-amine (200 mg, 37% yield) as a yellow oil. LCMS: (ESI, m / z) [M+H]+= 250.1.Step 4: Synthesis of N-(l-(2.3-difluorophenyl)cyclobuty>l)-l-(5-methylpyrimidin-2-yl)-lH-pyrazol-3-amine

[0399] To a mixture of A-(l-(2,3-difluorophenyl)cyclobutyl)-177-pyrazol-3-amine (160 mg, 0.64 mmol, 1 equiv) and CS2CO3 (627 mg, 1.9 mmol, 3 equiv) in DMF (5 mL, 0.13 M) were added 2-chloro-5-methylpyrimidine (83 mg. 0.64 mmol, 1 equiv). The reaction was stirred at 120 °C for 2 h under nitrogen. Upon completion as determined by LCMS, the mixturewas filtered and the filtrate was purified by via prep HPLC (Phenomenex Gemini NX Cl 8 column 150 x 30 mm, 5 pm) using 0.225% FA in water with a gradient of 45-75% MeCN at 25 mL / min) to yield the crude product, which was purified by chiral SFC (DAICEL Chiralcel OD (250 mm x 30 mm, 10 pm), Supercritical CO2 / EtOH + 0.1% NH3H2O = 65 / 35; 80 mL / min) to afford Compound 77 (47.8 mg. 22% yield) as a white solid. 'H NMR (400 MHz, DMSO): 58.53 (s. 2H), 8.22 (s, 1H), 7.36 (t, J= 7.2 Hz, 1H), 7.21 (q, J= 8.4 Hz, 1H), 7.13 -7.03 (m, 1H), 6.68 (s, 1H), 5.75 (s, 1H), 2.70 - 2.55 (m, 4H), 2.23 (s, 3H), 2.19 - 2.10 (m, 1H), 1.92 - 1.78 (m, 1H). LCMS (ESI, m / z) [M+H]+= 342.0.Intermediate EStep 2Step 1: Synthesis of 5-methoxy-2-(3-nitropyrazol-l-yl)pyrimidine

[0400] To a solution of 3-nitro-lEf-pyrazole (1 g, 8.84 mmol, 1 equiv) in DMF (50 mL, 0.18 M) were added CS2CO3 (8.64 g, 26.53 mmol, 3 eq) and 2-chloro-5-methoxypyrimidine (2.56 g, 17.69 mmol, 2 eq). The reaction was stirred at 120°C for 4 hours under nitrogen. Upon completion as determined by LCMS, EtOAc (50 mL) and water (100 mL) were added to the reaction mixture. A solid precipitated and the mixture was filtered to yield 5-methoxy-2-(3-nitropyrazol-l-yl)pyrimidine (1.17 g, 60% yield) as a white solid. 'H NMR (400 MHz, DMSO): 5 8.79 (d, J= 2.8 Hz, 1H), 8.72 (s, 2H), 7.32 (d, J= 3.2 Hz. 1H), 4.00 (s, 3H). LCMS (ESI, m / z) [M+H]+= 222.1.Step 2: Synthesis of l-(5-methoxypyrimidm-2-yl)pyrazol-3-amine

[0401] To a solution of 5-methoxy-2-(3-nitropyrazol-l-yl)pyrimidine (1.17 g, 5.29 mmol, 1 eq) in MeOH (100 mL, 0.05 M) and Ethyl acetate (10 mL) was added 10% Palladium on carbon (1.13 g, 1.06 mmol, 0.2 eq). The reaction was stirred at 50 °C for 24 hours under hydrogen (15 psi). Upon completion as determined by LCMS, the reaction was filtered and the filtrate was concentrated. The material was purified by column chromatography (0-9% MeOH in DCM) to yield l-(5-methoxypyrimidin-2-yl)pyrazol-3-amine (Intermediate E, 710 mg, 70% yield) as a yellow solid. 'H NMR (400 MHz, DMSO): 58.46 (s. 2H), 8.19 (d. J = 2.8 Hz, 1H), 5.80 (d, = 2.8 Hz, 1H), 5.20 (s, 2H), 3.90 (s, 3H). LCMS (ESI, m / z) [M+H]+= 192.1.Example 78a & Example 78b: (R)-N-(l-(4,5-dichlorothiazol-2-yl)ethyl)-l-(5- methoxypyrimidin-2-yl)-lH-pyrazol-3-amine & S)-N-(l-(4,5-dichlorothiazol-2-yl)ethyl)-l- (5-methoxypyrinudin-2-yl)-lH-pyrazol-3-amineSteps 1-2: Synthesis ofN-(l-(4.5-dichlorothiazol-2-yl)ethyl)-l-(5-methoxypyrimidin-2-yl)-lH-pyrazol-3-amine

[0402] jV-(l-(4,5-dichlorothiazol-2-yl)ethyl)-l-(5-methoxypyrimidin-2-yl)-177-pyrazol-3-amine (65 mg. 67% yield) as a white solid was prepared using the general procedure described for the preparation of N-(l-(4-chloroisothiazol-5-yl)ethyl)-l-(5-chloropyrimidin-2-yl)-lEf-pyrazol-3-amine (Ex.63a & Ex.63b) by replacing 4-chloroisothiazole-5-carbaldehyde and l-(5-chloropyrimidin-2-yl)-lEf-pyrazol-3-amine with 4,5-dichlorothiazole-2-carbaldehyde and l-(5-methoxypyrimidin-2-yl)-127-pyrazol-3-amine in Step 3. LCMS (ESI, m / z) [M+H]' = 371.1.Step 3: Synthesis of (R)-N-(l-(4,5-dichlorothiazol-2-yl)ethyl)-l-(5-methoxypyrimidm-2-yl)- lH-pyrazol-3-amine & (S)-N-( 1 -( 4, 5-dichlorothiazol-2-yl)ethyl)-l-(5-methoxypyrimidin-2-yl)-lH-pyrazol-3-amine

[0403] / V-(l-(4,5-dichlorothiazol-2-yl)ethyl)-l-(5-methoxypyrimidin-2-yl)-1 7-pyrazol-3-amine (60 mg, 0.16 mmol) was separated by chiral SFC (Daicel Chiralpak IM (250 mm x 30 mm, 10 um), Supercritical CO2 / MeOH + 0.1% NH3H2O = 45 / 55; 150 mL / min) to afford Compound 78a (peak 1. Rt = 1.658 min. 10.4 mg, 17% yield) and Compound 78b (peak 2, Rt = 1.839 min. 11.3 mg, 19% yield) both as white solid.

[0404] Compound 78a (stereoisomer 1):NMR (400 MHz, DMSO): 5 8.48 (s, 2H), 8.30 (d, J = 2.8 Hz, 1H), 6.85 (d, J= 6.8 Hz, 1H), 5.94 (d, J= 2.4 Hz, 1H), 4.98 - 4.89 (m, 1H), 3.90 (s, 3H), 1.53 (d, J= 6.8 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 370.9.

[0405] Compound 78b (stereoisomer 2): 'H NMR (400 MHz, DMSO): 8 8.48 (s, 2H), 8.30 (d, J= 2.8 Hz, 1H), 6.85 (d, J= 6.4 Hz, 1H), 5.94 (d, J= 2.4 Hz, 1H), 4.98 - 4.89 (m, 1H), 3.90 (s, 3H), 1.53 (d, J= 7.2 Hz, 3H). LCMS: (ESI, m / z) [M+H]+= 371.0.Example 79; (1S)-5-chloro-A-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-4- (pyrimidin-2-yl)thiazol-2-amineStep 1: Synthesis of tert-butyl (4-(pyrimidin-2-yl)thiazol-2-yl)carbamate

[0406] To a solution of tert-buty l (4-bromothiazol-2-yl)carbamate (3 g, 10 mmol, 1 equiv) and 2-(tributylstannyl)pyrimidine (4.3 g, 12 mmol, 1.1 equiv) in dioxane (30 mL, 0.33 M) was added Pd(PPh3)4 (1.2 g, 1.1 mmol, 0.1 equiv) and Cui (409 mg, 2.1 mmol. 0.2 equiv). The reaction was stirred at 110 °C for 16 h under nitrogen. Upon completion as determined by LCMS, the reaction was concentrated. The material was purified by column chromatography (10% EE (Ethyl acetate / ethanol = 3 / 1) in w-hexane) to yield tert-butyl (4-(pyrimidin-2-yl)thiazol-2-yl)carbamate (1.7 g, 57% yield) as a yellow oil. LCMS: (ESI, m / z) [M+H]+= 279.1.Step 2: Synthesis of 4-(pyrimidin-2-yl)thiazol-2-amine

[0407] To a solution of tert-butyl (4-(pyrimidin-2-yl)thiazol-2-yl)carbamate (1.7 g, 6.1 mmol, 1 equiv) in DCM (20 mL, 0.3 M) was added TFA (22 mL). Then the reaction was stirred at room temperature for 2 h. Upon completion as determined by7LCMS, the mixture was concentrated. The reaction mixture was adjusted to pH = 8 with NaHCOs solution (20 mL), and then was extracted with DCM (3 x 10 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to yield 4-(pyrimidin-2-yl)thiazol-2-amine (800 mg, 83% yield) as a yellow oil. LCMS: (ESI, m / z) [M+H]+= 179.1.Step 3: Synthesis of 2-bromo-4-(pyrimidin-2-yl)thiazole

[0408] To a stirred solution of 4-(pyrimidin-2-yl)thiazol-2-amine (900 mg, 5.1 mmol, 1 equiv) in MeCN (20 mL, 0.25 M) was added CuBr (1.1 mg, 5.1 mmol, 1 equiv) and / -BuONO (0.6 mL, 5.1 mmol, 1 equiv). The reaction was stirred at room temperature for 1 h under nitrogen. Upon completion as determined by LCMS, the mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified via prep HPLC (WePure Biotech XP tC18 column 150 x 30 mm, 7 pm using 0.225% FA in water with agradient of 20-50% MeCN at 25 mL / min) to yield 2-bromo-4-(pyrimidin-2-yl)thiazole (240 mg, 35% yield) as a yellow oil. LCMS: (ESI, m / z) [M+H]+= 242.1.Step 4: Synthesis of (S)-N-(l-(4-chloro-lf -dimethyl- IH-pyr azol-3-yl)ethyl)-4-(pyrimidin-2-yl)thiazol-2-amine

[0409] To a stirred solution of 2-bromo-4-(pyrimidin-2-yl)thiazole (80 mg, 0.33 mmol, 1 equiv) and (S)- l-(4-chloro-l,5-dimethyl-l / f-pyrazol-3-yl)ethan-l -amine hydrochloride (80 mg, 0.33 mmol, 1 equiv), in dioxane (2 mL, 0.17 M) was added Pd-PEPPSI-IHeptCl (32 mg, 0.03 mmol, 0.1 equiv), CS2CO3 (317 mg, 1.0 mmol, 3 equiv). The reaction was stirred at 110 °C for 16 h under nitrogen. Upon completion as determined by LCMS, the mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (50% ethyl acetate in / 7-hexane) to yield (S)- / V-(l-(4-chloro- 1,5 -dimethyl- 1H-pyrazol-3-yl)ethyl)-4-(pyrimidin-2-yl)thiazol-2-amine (60 mg, 55% yield) as a yellow oil. LCMS: (ESI, m / z) [M+H]+= 335.1.Step 5: Synthesis of (S)-5-chloro-N-(l-(4-chloro-l,5-dimethyl-lH-pyrazol-3-yl)ethyl)-4- (pyrimidin-2-yl)thiazol-2-amine

[0410] To a solution of (S)-JV-(l-(4-chloro-l,5-dimethyl-17 / -pyrazol-3-yl)ethyl)-4-(pyrimidin-2-yl)thiazol-2-amine (50 mg, 0.15 mmol, 1 equiv) in DMF (1 mL, 0.15 M) was added NCS (24 mg, 0.18 mmol, 1.2 equiv). The reaction was stirred at room temperature for 2 hours under nitrogen. Upon completion as determined by LCMS, the reaction was quenched with saturated NaHCCh solution (4 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The material was purified by via prep HPLC (Welch Xtimate C18 column 150 x 30 mm, 5 pm using 0.225% FA in water with a gradient of 35-65% MeCN at 25 mL / min) to afford Compound 79 (1.7 mg, 3% yield) as a white solid.NMR (400 MHz, DMSO): 5 8.88 (d, J= 4.8 Hz, 2H), 8.25 (d, J= 8.0 Hz, 1H), 7.45 (t, J= 4.8 Hz, 1H), 5.02 - 4.91 (m, 1H), 3.72 (s, 3H), 2.20 (s, 3H), 1.46 (d, J= 6.8 Hz, 3H). LCMS (ESI, m / z) [M+H]+= 368.9.Example 80a & Example 80b; ( / ?)-5-chloro- / V-(l-(4,5-dichlorothiazol-2-yl)ethyl)-6-( l- methyl-lH-l,2,4-triazol-3-yl)pyridin-2-amine & (5)-5-chloro- / V-(l-(4,5-dichlorothiazol- 2-yl)ethyl)-6-(l-methyl-lH-l,2,4-triazol-3-yl)pyridin-2-amineCl Cl Cl Step 1: Synthesis of 5-chloro-6-(l-methyl-lH-l,2,4-triazol-3-yl)pyridin-2-amine

[0411] To a solution of 6-bromo-5-chloropyridin-2-amine (2.0 g, 9.64 mmol, 1 equiv) and l-methyl-3-(tributylstannyl)-127-l,2,4-triazole (5.23 g, 10.4 mmol, 1.1 equiv) in DMF (40 rnL, 0.24 M) was added Pd(PPhs)4 (1.11 g, 0.96 mmol. 0.1 equiv). Cui (184 mg, 0.96 mmol, 0.1 equiv) and CsF (4.39 g, 28.92 mmol). The reaction was stirred at 100 °C for 2 hours under nitrogen. Upon completion as determined by LCMS, the reaction was filtered and the filtrate was concentrated. The material was purified by column chromatography (0-5% MeOH in DCM) to yield 5-chloro-6-(l-methyl-17f-1.2,4-triazol-3-yl)pyridin-2-amine (2 g, 99% yield) as a white solid. 'H NMR (400 MHz, DMSO): 5 8.51 (s, 1H), 7.51 (d, J= 8.8 Hz, 1H), 6.52 (d, J= 8.8 Hz, 1H), 6.26 (s, 2H), 3.91 (s, 3H). LCMS (ESI, m / z) [M+H]+= 210.1.Step 2: Synthesis of (E)-N-(5-chloro-6-(l-methyl-lH-l,2,...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I:(R1)Por a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,wherein:L is selected from -CH2C(O)-, -CF2C(O)-, -S(O)2-; -S(O)-, and -CR3R4-; Ring A is phenyl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl, or C5-10 cycloalkyl;Ring B is a 5- to 6-membered heteroaryl;X1is C;X2and X3are independently selected from CR2, S, N, and NR2, wherein X2and X3are not both N;each R1is independently selected from halogen, Ci-6 alkyl, Ci-6 haloalkyl, =0, Cs-6 cycloalkyl, -0(Ci-4 alkyl), COOH. CN, C0NH2, -C(=O)NH(Ci-4alkyl), -C(=O)N(Ci-4alkyl)2, -C(=O)O(Ci-4alkyl), -C(O)RC, -S(O)2Re, 5- to 10 membered heteroaryl, 5- to 10-membered heterocyclyl, and -NRaRb, wherein the C3-6 cycloalkyl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl are optionally substituted with one to four substituents, wherein each substituent is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl. C1-6 alkoxy, and cyano;each R2is independently selected from halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, -ORf, -NRaRb, 5- to 10-membered heteroaryl, and phenyl; wherein the C1-6 alkyl, 5-to 10-membered heteroaryl and phenyl are optionally substituted with 1 to 4 substituents independently selected from halo, oxo, C1-6 alkyl. C1-6 haloalkyl, C3-6 cycloalkyl. C1-6 alkoxy, C1-6 haloalkoxy, -CH2-Ci-6alkoxy, cyano, and 5- to 6-membered heterocycloalkyl;Raand Rbare independently selected from H, C1-6 alkyl, C1-6 haloalkyl and Cs-6 cycloalkyl;or Raand Rb, taken together with the nitrogen atom to which they are attached, form a 3- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl, wherein the 3- to 6-membered heterocyclyl and the 5- to 6-membered heteroaryl are optionally substituted with one to four substituents, wherein each substituent is independently selected from halo, C1-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, and cyano;Rcis a 3- to 6-membered heterocyclyl;Reis a C1-6 alkyl or a C3-6 cycloalkyl;Rfis selected from H, Ci-ealkyl, C1-6 haloalkyl and C3-6 cycloalkyl, wherein the C1-6 alkyl and C1-6 haloalkyl are optionally substituted by a phenyl or 5- to 10-membered heteroaryl;R3and R4are independently selected from hydrogen, halogen, cyano. C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, and C3-6 cycloalkyl, wherein the C1-6 alkyl is optionally substituted with C1-6 alkoxy; and wherein the C3-6 cycloalkyl is optionally substituted with one to four substituents, wherein each substituent is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, and cyano; orR3and R4taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl or a 3- to 6-membered heterocyclyl, wherein the C3-6 cycloalkyl and the 3-to 6-membered heterocyclyl is optionally substituted with one to four substituents, wherein each substituent is independently selected from halo, C1-6 alkyl. C1-6 haloalkyl, C3-6 cycloalkyl. C1-6 alkoxy, and cyano;p is 0, 1, 2, 3, or 4;q is 0, 1, 2, 3, or 4; andis a single or double bond.

2. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is -S(O)2-.

3. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein L is -CR3R4.

4. The compound of claim 3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3and R4are independently selected from the group consisting of hydrogen, C1-3 alkyl, C1-3 alkyl substituted with C1-3 alkoxy, C1-3 haloalkyl, C1-3 hydroxyalkyl, and C3-6 cycloalkyl.

5. The compound of claim 4, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3and R4areindependently selected from the group consisting of hydrogen, methyl, ethyl, -CH2OCH3, -CF3, CF2H, CFH2, -CH2OH, and cyclopropyl.

6. The compound of claim 3, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3and R4, taken together with the carbon atom to which they are attached, form a C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with one to four substituents, wherein each substituent is independently selected from halo, C1-6 alkyl, C1-6 haloalkyl. C3-6 cycloalkyl, C1-6 alkoxy, and cyano.

7. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound of Formula (I) is a compound of Formula (1-1):or a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1-7. or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein q is 1, 2, or 3.

9. The compound of any one of claims 1-8, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein q is 1, and R2is 5- to 10-membered heteroaryl or phenyl, wherein the 5- to 10-membered heteroary l and phenyl are optionally substituted with 1 to 4 substituents independently selected from halo, oxo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -CH2-C1-6alkoxy, cyano, and 5- to 6-membered heterocycloalkyl.

10. The compound of any one of claims 1-7, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein q is 2 or 3, and one R2is 5- to 10-membered heteroaryl or phenyl, wherein the 5- to 10-membered heteroaryl and phenyl are optionally substituted with 1 to 4 substituents independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, and cyano.

11. The compound of any one of claims 1-7. or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein q is 2 or 3, oneR2is 5- to 10-membered heteroaryl or phenyl, wherein the 5- to 10-membered heteroaryl and phenyl are optionally substituted with 1 to 4 substituents independently selected from halo, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, and cyano; and at least one R2is halogen or methyl.

12. The compound of any one of claims 1-11, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is phenyl, wherein the phenyl is optionally substituted with 1 to 4 substituents independently selected from halo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, and cyano.

13. The compound of any one of claims 1-11, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is optionally substituted with 1 to 4 substituents independently selected from halo, oxo, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -CH2-C1-6alkoxy, cyano, and 5- to 6-membered heterocycloalkyl.

14. The compound of any one of claims 1-11 and 13, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2isselected from the group consisting of:wherein m is 0, 1, 2, 3, or 4; and each Rdis independently selected from halogen, cyano, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, C1-6alkoxy, C1-6 haloalkoxy, -CH2-C1-ealkoxy, and 5- to 6-membered heterocycloalkyl.

15. The compound of any one of claims 1-11 and 13-14, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is16. The compound of any one of claims 1-11 and 13-14, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring17. The compound of claim 16, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring B is18. The compound of claim 17, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring B is selected from thegroup consisting of::d)mwherein m is 0, 1, 2, 3, or 4 and each Rdis independently selected from halogen, cyano, Ci-6 alkyl, Ci-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -CH₂-C₁-₆alkoxy, and 5- to 6-membered heterocycloalkyl.

19. The compound of claim 17, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring B is selected from the20. The compound of claim 16, or a stereoisomer or tautomer thereof, or apharmaceutically acceptable salt of any of the foregoing, wherein Ring Bis21. The compound of any one of claim 1-20, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein p is 1, 2, or 3.

22. The compound of any one of claim 1-21. or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is phenyl or 5- to 10-membered heteroaryl.

23. The compound of claim 22, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is phenyl.

24. The compound of claim 22, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A is 5- to 6-membered heteroaryl.

25. The compoundof any one of claim 1-24, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A and (R1)P,26. The compound of claim 25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A and (R')p. takentogether,is27. The compound of claim 25 or 26, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A and (R1)P. takentogether, is28. The compound of claim 25, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A and (R1)P. takentogether, is selected from the group consisting of:R129. The compound of claim 28, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A and (R')p. takentogether, is30. The compound of any one of claim 1-29, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R1is independently selected from the group consisting of halogen and Ci-6 alkyl.

31. The compound of claim 30, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R1is independently selected from the group consisting of halogen and methyl.

32. The compound of any one of claims 1-36, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Ring A and (R')P, taken together is selected from the group consisting of:pharmaceutically acceptable salt of any of the foregoing, wherein Ring A and (R’)P, taken34. The compound claim 1, wherein the compound of Formula (I) is a compound of Formula (II):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

35. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound of Formula (I) is a compound of Formula (III):(III)or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

36. The compound or pharmaceutically acceptable salt of claim 35, wherein the compound of Formula (III) is a compound of Formula (Illa- 1):, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

37. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound of Formula (I) is a compound of Formula (IV):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

38. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound of Formula (I) is a compound of Formula (VIII):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

39. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound of Formula (VIII) is a compound of Formula (VIII.1):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

40. A compound as provided in Table 1 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

41. A pharmaceutical composition comprising the compound of any one of claims 1-40, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable excipient.

42. A method of treating or preventing axonal degeneration comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-40, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 41.

43. A method of treating a neurodegenerative disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1-40, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 41.

44. A method of inhibiting SARM1 comprising contacting a biological sample with an effective amount of the compound of any one of claims 1-40, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, or the pharmaceutical composition of claim 41.

Images