Modulators of myc family proto-oncogene protein

Abstract

Disclosed herein are compounds, such as compounds of Formula (I): and pharmaceutically acceptable salts, stereoisomers, and / or N-oxides thereof, and compositions having potency in the modulation of Myc family proteins. Such compounds and compositions can be used in the treatment of proliferative diseases, such as cancer, or in the treatment of disease where modulation of Myc family proteins is desired. Also disclosed herein are methods of using said compounds and compositions.

Description

MODULATORS OF MYC FAMILY PROTO-ONCOGENE PROTEIN CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, U.S. Provisional Patent Application No.63 / 455,773, filed March 30, 2023, U.S. Provisional Patent Application No. 63 / 534,500, filed August 24, 2023, and U.S. Provisional Patent Application No.63 / 546,637, filed October 31, 2023, the contents of each of which are incorporated by reference herein in their entirety. BACKGROUND

[0002] The MYC proto-oncogene family comprises three members: C-MYC, MYCN, and MYCL. These oncogenes encode c-Myc, N-Myc, and L-Myc oncoproteins, respectively, which belong to a family of “super-transcription factors” that regulate the transcription of more than 15% of the entire genome. Recent studies in mouse models have suggested that the regulation of oncogenic Myc proteins could potentially lead to the development of cancer therapeutics, as it has been demonstrated that even transient inactivation of Myc causes tumor regression. However, the development of drugs and therapeutics that directly targets Myc proteins has met with two major challenges. First, Myc proteins lack a well-defined active site for the binding of small molecules, thus providing challenges for the functional modulation or inhibition of their activities. Second, Myc proteins are predominantly located in cell nuclei, and targeting nuclear Myc proteins with antibodies can be technically challenging. These challenges have spawned strategies for indirect regulation of Myc proteins.

[0003] For example, amplification and overexpression of N-Myc can lead to tumorigenesis. Excess N-Myc is associated with a variety of tumors, e.g., neuroblastomas. MYCN can also be activated in tumors through somatic mutation.

[0004] C-Myc can also be constitutively expressed in various cancers such as cervix, colon, breast, lung and stomach cancers. Such constitutive expression can lead to increased expression of other genes that are involved in cell proliferation.

[0005] Amplification of the, e.g., N-Myc gene in patients frequently results in poor health outcomes. However, strategies for direct modulation of Myc proteins remain elusive, as the Myc proteins are not easily targeted.

[0006] Therefore, an ongoing need exists for small-molecule therapeutic modulators of Myc proteins for the treatment of various ailments, diseases and disorders, e.g., cancer. SUMMARY

[0007] The present disclosure provides compounds and compositions that are useful as Myc protein modulators, and methods of using the same. Furthermore, the present disclosure contemplates using disclosed compounds and compositions as direct modulators of Myc proteins in the treatment of proliferative disease, such as cancer, or in the treatment of diseases where modulation of Myc family proteins is desired.

[0008] For example, provided herein is a compound represented by Formula I-A:(Formula I-A) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, C-H, and C-F; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2, CH(CH3), C(CH3)2, C(CH2CH2), CFH, CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); ring Z is a 4-10 membered N-bound heterocyclic, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted by one, two or three halogens), oxo, C1-C4 alkoxy, and cyano; L1is selected from the group consisting of bond, C1-C6 alkylene (optionally substituted by one, two or three R4), and -C(=O)-;when L1is bond or C1-C6 alkylene (optionally substituted by one, two or three R4), R3is OR”, -CN, S(O)C1-4alkyl, or P(O)(C1-4alkyl)2; when L1is -C(=O)-, R3is NR’R’ or OR”; R4is each independently selected from the group consisting of halogen and C1-C6 alkyl (optionally substituted by one, two or three halogens), or two R4together with the carbon to which the R4are attached form a C3-C5carbocyclyl; R’ and R” for each occurrence are each independently selected from the group consisting of H and C1-C6 alkyl (optionally substituted by one, two or three halogens); RHis selected from the group consisting of H, C1-C4alkyl, -C(O)-C1-C3alkyl, and C(O)- O-C1-C3alkyl; R1is selected from the group consisting of C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; wherein C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents each independently selected from halo and C1-C4alkyl (optionally substituted by one, two or three halogens); R2is selected from the group consisting of H, F, methyl, CF3, -C(O)-O-methyl, - C(O)OH, -O-methyl, -O-ethyl, C3-C7cycloalkyl, and heterocyclyl optionally substituted by one, two, or three substituents each independently selected from the group consisting of halogen and C1-4alkyl; and R5is selected from the group consisting of H, F, methyl, and CF3, or R2and R5together with the contiguous carbon atoms to which R2and R5are attached to form a phenylene ring.

[0009] Also provided herein is a compound represented by Formula I-IA:(Formula I-IA) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein:W is selected from the group consisting of N, C-H, and C-F; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2, CH(CH3), C(CH3)2, C(CH2CH2), CFH, CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); ring Z is a 4-10 membered N-bound heterocyclic, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4alkyl (optionally substituted by one, two or three halogens), oxo, C1-C4alkoxy, and cyano; L1is selected from the group consisting of bond, C1-C6alkylene (optionally substituted by one, two or three R4), and -C(=O)-; when L1is bond or C1-C6 alkylene (optionally substituted by one, two or three R4), R3is OR”, -CN, S(O)C1-4alkyl, or P(O)(C1-4alkyl)2; when L1is -C(=O)-, R3is NR’R’ or OR”; R4is each independently selected from the group consisting of halogen and C1-C6 alkyl (optionally substituted by one, two or three halogens), or two R4together with the carbon to which the R4are attached form a C3-C5carbocyclyl; R’ and R” for each occurrence are each independently selected from the group consisting of H and C1-C6 alkyl (optionally substituted by one, two or three halogens); RHis selected from the group consisting of H, C1-C4alkyl, -C(O)-C1-C3alkyl, and C(O)- O-C1-C3alkyl; R1is selected from the group consisting of C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; wherein C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents each independently selected from halo and C1-C4alkyl (optionally substituted by one, two or three halogens); and R2is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O- methyl, -O-ethyl, C3-C7 cycloalkyl, and heterocyclyl.

[0010] Also contemplated herein are compounds represented by Formula II-A:(Formula II-A) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, C-H, and C-F; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2, CH(CH3), C(CH3)2, C(CH2CH2), CFH, CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); ring Z is selected from the group consisting of 4, 5, or 7-10-membered N-bound monocyclic heterocyclyl, 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged heterocycle, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted by one, two or three halogens), oxo, C1-C4 alkoxy, and cyano; L1is selected from the group consisting of bond, C1-C6alkylene (optionally substituted by one, two or three R4), and -C(=O)-; when L1is bond or C1-C6 alkylene (optionally substituted by one, two or three R4), R3is OR”, -CN, S(O)C1-4alkyl, or P(O)(C1-4alkyl)2; when L is -C(=O)-, R3is NR’R’ or OR”; R4is each independently selected from the group consisting of halogen and C1-C6 alkyl (optionally substituted by one, two or three halogens), or two R4together with the carbon to which the R4are attached form a C3-C5carbocyclyl; R’ and R” for each occurrence are each independently selected from the group consisting of H and C1-C6alkyl (optionally substituted by one, two or three halogens); RHis selected from the group consisting of H, C1-C4alkyl, -C(O)-C1-C3alkyl, and C(O)- O-C1-C3alkyl;R1is selected from the group consisting of C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; wherein C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents each independently selected from halo and C1-C4alkyl (optionally substituted by one, two or three halogens); R2is selected from the group consisting of H, F, methyl, CF3, -C(O)-O-methyl, - C(O)OH, -O-methyl, -O-ethyl, C3-C7cycloalkyl, and heterocyclyl optionally substituted by one, two, or three substituents each independently selected from the group consisting of halogen and C1-4alkyl; and R5is selected from the group consisting of H, F, methyl, and CF3, or R2and R5together with the contiguous carbon atoms to which R2and R5are attached to form a phenylene ring.

[0011] Also contemplated herein are compounds represented by Formula II-IA:(Formula II-IA) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, C-H, and C-F; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2, CH(CH3), C(CH3)2, C(CH2CH2), CFH, CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); ring Z is selected from the group consisting of 4, 5, or 7-10-membered N-bound monocyclic heterocyclyl, 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged heterocycle, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted by one, two or three halogens), oxo, C1-C4 alkoxy, and cyano;L1is selected from the group consisting of bond, C1-C6 alkylene (optionally substituted by one, two or three R4), and -C(=O)-; when L1is bond or C1-C6alkylene (optionally substituted by one, two or three R4), R3is OR”, -CN, S(O)C1-4alkyl, or P(O)(C1-4alkyl)2; when L is -C(=O)-, R3is NR’R’ or OR”; R4is each independently selected from the group consisting of halogen and C1-C6alkyl (optionally substituted by one, two or three halogens), or two R4together with the carbon to which the R4are attached form a C3-C5carbocyclyl; R’ and R” for each occurrence are each independently selected from the group consisting of H and C1-C6alkyl (optionally substituted by one, two or three halogens); RHis selected from the group consisting of H, C1-C4alkyl, -C(O)-C1-C3alkyl, and C(O)- O-C1-C3alkyl; R1is selected from the group consisting of C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; wherein C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents each independently selected from halo and C1-C4alkyl (optionally substituted by one, two or three halogens); and R2is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O- methyl, -O-ethyl, C3-C7cycloalkyl, and heterocyclyl.

[0012] Pharmaceutical compositions comprising a disclosed compound or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, as described herein, for example a disclosed pharmaceutical composition may include least one or more pharmaceutically acceptable carriers, diluents, stabilizers, excipients, dispersing agents, suspending agents, and / or thickening agents. The present disclosure also provides a method of manufacturing of the compounds described herein, or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

[0013] A method of modulating the amount and activity of a Myc family protein (i.e., C- Myc, N-Myc, L-Myc, or human Myc) is also provided, for example, an activity of a Myc family protein may be modulated in a cell by contacting a cell with an effective amount of a compound as described herein, or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

[0014] The present disclosure also provides a method of treating a Myc family protein associated disease in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, including embodiments in any examples, tables, or figures. In some embodiments, the subject is a human subject and the disease is a proliferative disease, such as cancer. DETAILED DESCRIPTION Definitions

[0015] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0016] It is understood that the definitions provided herein are not intended to be mutually exclusive. Accordingly, some chemical moieties may fall within the definition of more than one term.

[0017] The term “alkoxy” as used herein refers to a straight or branched alkyl group attached to oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as C1-6alkoxy, and C2-6alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, etc.

[0018] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C1-6alkyl, C1-4alkyl, and C1-3alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4- methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[0019] As used herein, the term “alkylene” refers to a di-radical alkyl group. Examples include, methylene (–CH2–), ethylene (–CH2CH2–), propylene (–CH2CH2CH2–), 2- methylpropylene (–CH2–CH(CH3) –CH2–), hexylene (–(CH2)6–) and the like.

[0020] The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkenyl groups include, but are not limited to, a straight or branched group of 2-6 or 3-4 carbon atoms, referred to herein as C2-6alkenyl, and C3-4alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

[0021] The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, or 3-6 carbon atoms, referred to herein as C2-6alkynyl, and C3-6alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.

[0022] As used herein, the terms “alkenylene,” “alkynylene,” “arylene,” “arylalkylene,” and “alkylarylene” refer to di-radical alkenyl, alkynyl, aryl, arylalkyl, and alkylaryl groups, respectively.

[0023] As used herein, the term “azido” refers to group –N3.

[0024] As used herein, the term “carboxyl,” “carboxy” or “carboxylate” refers to –CO2H or salts thereof.

[0025] As used herein, the term “carbamoyl” refers to the group NH2CO–.

[0026] The terms “cycloalkyl” or a “carbocyclic group” as used herein refers to a saturated or partially unsaturated hydrocarbon group of, for example, 3-10, 3-6, or 4-6 carbons, referred to herein as C3-10cycloalkyl, C3-6cycloalkyl, or C4-6cycloalkyl, respectively, and which may be monocyclic or bicyclic ring structures, e.g.4-9 or 4-6 membered saturated ring structures, including bridged, fused or spirocyclic rings. Exemplary cycloalkyl groups include, but are not limited to, adamantanyl, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl, cyclopropyl, and indanyl.

[0027] As used herein, the groupsare used interchangeably and refer to a cyclohexyl group.

[0028] As used herein, the term “cyano” and “carbonitrile” refer to the group –CN.

[0029] As used herein, the term “formyl” refers to the group –C(O)H.

[0030] As used herein, the term “guanidino” refers to the group –NHC(=NH)NH2.

[0031] As used herein, the terms “halo” and “halogen” are used in the conventional sense to refer to a chloro, bromo, fluoro or iodo substituent.

[0032] As used herein, the terms “hydroxy” and “hydroxyl” refer to the group -OH.

[0033] The terms “heteroaryl” or “heteroaromatic group” as used herein refers to a monocyclic aromatic 5-6 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine or pyrimidine etc.

[0034] The terms “heterocyclyl” or “heterocyclic group” are art-recognized and refer to e.g. saturated or partially unsaturated, 4-10 membered monocyclic or bicyclic ring structures, or e.g. 4-9 or 4-6 membered saturated ring structures, including bridged, fused or spirocyclic rings, and whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran or dihydrofuran etc.

[0035] As used herein, the term “nitro” refers to the group –NO2.

[0036] As used herein, the term “oxo” refers to the group (=O) or (O).

[0037] As used herein, the term “isomers” refers to compounds comprising the same numbers and types of atoms or components, but with different structural arrangement and connectivity of the atoms.

[0038] As used herein, the term “tautomer” refers to one of two or more structural isomers which readily convert from one isomeric form to another and which exist in equilibrium.

[0039] The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “(-),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof.Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.

[0040] The compounds of the disclosure may contain one or more double bonds and, therefore, exist as geometric isomers resulting from the arrangement of substituents around a carbon-carbon double bond. The symbol denotes a bond that may be a single, double or triple bond as described herein. Substituents around a carbon-carbon double bond are designated as being in the “Z” or “” configuration wherein the terms “Z” and “” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the “” and “Z” isomers. Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.

[0041] Compounds of the disclosure may contain a carbocyclic or heterocyclic ring and therefore, exist as geometric isomers resulting from the arrangement of substituents around the ring. Substituents around a carbocyclic or heterocyclic ring may be referred to as “cis” or “trans”, where the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring. Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated “cis / trans.”

[0042] Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms anunequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations, and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0043] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the present disclosure embrace both solvated and unsolvated forms. In one embodiment, a disclosed compound is amorphous. In one embodiment, a disclosed compound is a single polymorph. In another embodiment, a disclosed compound is a mixture of polymorphs. In another embodiment, a disclosed compound is in a crystalline form.

[0044] The present disclosure also embraces isotopically labeled compounds of the disclosure which are identical to those recited herein, except 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. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[0045] Certain isotopically-labeled disclosed compounds (e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes are particularly preferred 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. Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent

[0046] As used herein, singular articles such as “a,” “an” and “the” and similar referents in the context of describing the elements are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of rangesof values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, including the upper and lower bounds of the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (i.e.,“such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated.

[0047] In some embodiments, where the use of the term "about" is before a quantitative value, the present disclosure also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term "about" refers to a ±10% variation from the nominal value unless otherwise indicated or inferred. Where a percentage is provided with respect to an amount of a component or material in a composition, the percentage should be understood to be a percentage based on weight, unless otherwise stated or understood from the context.

[0048] Where a molecular weight is provided and not an absolute value, for example, of a polymer, then the molecular weight should be understood to be an average molecule weight, unless otherwise stated or understood from the context.

[0049] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present disclosure remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0050] As used herein, a dash (“”) that is not between two letters or symbols refers to a point of bonding or attachment for a substituent. For example, –NH2is attached through the nitrogen atom.

[0051] As used herein, the terms “active agent,” “drug,” “pharmacologically active agent” and “active pharmaceutical ingredient” are used interchangeably to refer to a compound or composition which, when administered to a subject, induces a desired pharmacologic or physiologic effect by local or systemic action or both.

[0052] As used herein, the term “prodrug” refers to compounds that are transformed in vivo to provide a compound or pharmaceutically acceptable salt, hydrate or solvate of the compound described herein. The transformation can occur by various mechanisms (i.e., esterase, amidase,phosphatase, oxidative and / or reductive metabolism) in various locations (i.e., in the intestinal lumen or upon transit into the intestine, blood, or liver).

[0053] As used herein, the term “modulator” refers to a compound or composition that increases or decreases the level of a target or the function of a target, which may be, but is not limited to, a Myc family protein, such as c-Myc, N-Myc, L-Myc and human Myc.

[0054] As used herein, the term “degrader” refers to a compound or composition that decreases the amount of a target or the activity of a target. In some embodiments, the target may be, but is not limited to, a Myc family protein comprising c-Myc, N-Myc, L-Myc and human Myc.

[0055] As used herein, the term “degrading” refers to a method or process that decreases the amount of a target or the activity of a target. In some embodiments, the target may be, but is not limited to, a Myc family protein comprising c-Myc, N-Myc, L-Myc and human Myc.

[0056] As used herein, the term “Myc family protein” refers to any one of the proteins c- Myc, N-Myc, or L-Myc as described herein. In some embodiments, a Myc protein is a c-Myc protein. In some embodiments, a Myc protein is a N-Myc protein. In some embodiments, a Myc protein is a L-Myc protein. In some embodiments, a Myc protein is a human c-Myc protein. In some embodiments, a Myc protein is a human N-Myc protein. In some embodiments, a Myc protein is a human L-Myc protein. In some embodiments, a Myc family protein is a human Myc family protein.

[0057] As used herein, the terms “N-Myc” and “MycN” can be used interchangeably and refer to the protein “V-Myc myelocytomatosis viral related oncogene, neuroblastoma derived” and include the wildtype and mutant forms of the protein. In some embodiments, MycN refers to the protein associated with one or more of database entries of Entrez Gene 4613, OMIM 164840, UniProt P04198, and RegSeq NP_005369.

[0058] As used herein, the term “c-Myc” refers to the protein “V-Myc myelocytomatosis viral oncogene” and include the wildtype and mutant forms of the protein. In some embodiments, c-Myc refers to the protein associated with one or more of database entries of Entrez Gene 4609, OMIM 190080, UniProt P01106, and RegSeq NP_002458.

[0059] As used herein, the term “L-Myc” refers to the protein “V-Myc myelocytomatosis viral oncogene homolog, lung carcinoma derived” and include the wildtype and mutant forms of the protein. In some embodiments, L-Myc refers to the protein associated with one or more ofdatabase entries of Entrez Gene 4610, OMIM 164850, UniProt P12524, and RegSeq NP_001028253.

[0060] The terms “individual,” “host,” “subject,” and “patient” are used interchangeably herein, and refer to an animal, including, but not limited to, human and non-human primates, including simians and humans; rodents, including rats and mice; bovines; equines; ovines; felines; canines; and the like. "Mammal" means a member or members of any mammalian species, and includes, by way of example, canines, felines, equines, bovines, ovines, rodentia, etc. and primates, i.e., non-human primates, and humans. Non-human animal models, i.e., mammals, non-human primates, murines, lagomorpha, etc. may be used for experimental investigations.

[0061] As used herein, the terms “treating,” “treatment,” and the like, refer to obtaining a desired pharmacologic and / or physiologic effect, such as reduction of tumor burden. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or may be therapeutic in terms of a partial or complete cure for a disease and / or adverse effect attributable to the disease. “Treatment,” as used herein, covers any treatment of a disease in a mammal, particularly in a human and includes: (a) preventing the disease or a symptom of a disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it (i.e., including diseases that may be associated with or caused by a primary disease); (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease (i.e., reduction in of tumor burden). In some embodiments, certain methods described herein treat cancer associated with the signaling pathway of a Myc family protein, such as c-Myc, N-Myc, L-Myc or human Myc.

[0062] As used herein, the term “pharmaceutically acceptable salt” refers to a salt which is acceptable for administration to a subject. It is understood that such salts, with counter ions, will have acceptable mammalian safety for a given dosage regime. Such salts can also be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids, and may comprise organic and inorganic counter ions. The neutral forms of the compounds described herein may be converted to the corresponding salt forms by contacting the compound with a base or acid and isolating the resulting salts.

[0063] Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like.

[0064] Other examples of salts include anions of the compounds of the present disclosure compounded with a suitable cation such as N+, NH4+, and NW4+(where W can be a C1-C8alkyl group), and the like. For therapeutic use, salts of the compounds of the present disclosure can be pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0065] Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1'-methylene-bis-(2- hydroxy-3-naphthoate )) salts.

[0066] Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.

[0067] Compounds included in the present compositions that include a basic or acidic moiety can also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure can contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.

[0068] As used herein, the terms “determining,” “measuring,” “assessing,” and “assaying” are used interchangeably and include both quantitative and qualitative determinations.

[0069] As used herein, the phrase “signaling pathway” refers to a series of interactions between cellular components, both intracellular and extracellular, that conveys a change to one or more other components in a living organism, which may cause a subsequent change to additional component. Optionally, the changes conveyed by one signaling pathway may propagate to other signaling pathway components. Examples of cellular components include, but are not limited to, proteins, nucleic acids, peptides, lipids and small molecules.

[0070] As used herein, the terms “effective amount” and “therapeutically effective amount” are used interchangeably and refer to the amount of a compound that, when administered to a mammal or other subject for treating a disease, condition, or disorder, is sufficient to affect such treatment for the disease, condition, or disorder. The “effective amount” or "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated.

[0071] As used herein, the terms “pharmaceutically acceptable excipient,” “pharmaceutically acceptable diluent,” “pharmaceutically acceptable carrier,” and “pharmaceutically acceptable adjuvant” refer to an excipient, diluent, carrier, and adjuvant that are useful in preparing a pharmaceutical composition that are generally safe, non-toxic and neither biologically nor otherwise undesirable, and include an excipient, diluent, carrier, and adjuvant that are acceptable for veterinary use as well as human pharmaceutical use. The phrase “a pharmaceutically acceptable excipient, diluent, carrier and adjuvant” as used in the specification and claims includes both one and more than one such excipient, diluent, carrier, and adjuvant.

[0072] As used herein, the term “pharmaceutical composition” is meant to encompass a composition suitable for administration to a subject, such as a mammal, especially a human. In general a “pharmaceutical composition” is sterile, and free of contaminants that are capable of eliciting an undesirable response within the subject (i.e., the compound(s) in the pharmaceutical composition is pharmaceutical grade). Pharmaceutical compositions can be designed for administration to subjects or patients in need thereof via a number of different routes of administration including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, intracheal, intramuscular, subcutaneous, and the like.

[0073] Generally, reference to or depiction of a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Compounds comprising radioisotopes such as tritium,14C,32P and35S are thus within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those skilled in the art based on the disclosure herein.

[0074] Unless the specific stereochemistry is expressly indicated, all chiral, diastereomeric, and racemic forms of a compound are intended. Thus, compounds described herein include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Racemic mixtures of (R)-enantiomer and (S)-enantiomer, and enantio-enriched stereomeric mixtures comprising of (R)- and (S)-enantiomers, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology.

[0075] The compounds described herein may exist as solvates, especially hydrates, and unless otherwise specified, all such solvates and hydrates are intended. Hydrates may form during manufacture of the compounds or compositions comprising the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds. Compounds of the present technology may exist as organic solvates as well, including DMF, ether, and alcohol solvates, among others. The identification and preparation of any particular solvate is within the skill of the ordinary artisan of synthetic organic or medicinal chemistry.

[0076] As described herein, the text refers to various embodiments of the present compounds, compositions, and methods. The various embodiments described are meant to provide a variety of illustrative examples and should not be construed as descriptions of alternative species. Rather, it should be noted that the descriptions of various embodiments provided herein may be of overlapping scope. The embodiments discussed herein are merely illustrative and are not meant to limit the scope of the present technology. Compounds

[0077] The disclosure is generally directed to compounds that modulate (e.g., degrade) MycN and / or MycC, and may therefore have significant antineoplastic properties. The disclosed compounds and pharmaceutical compositions thereof find use in a variety of applications inwhich the modulation of the amount and activity of a Myc protein is desired, including use as potent antineoplastic agents.

[0078] Thus, provided herein, in part, is a compound represented by Formula I:(Formula I) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, C-H, and C-F; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2, CH(CH3), C(CH3)2, C(CH2CH2), CFH, CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); ring Z is a 4-10 membered N-bound heterocyclic, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4alkyl (optionally substituted by one, two or three halogens), oxo, C1-C4alkoxy, and cyano; L1is selected from the group consisting of bond, C1-C6 alkylene (optionally substituted by one, two or three R4), and -C(=O)-; when L1is bond or C1-C6alkylene (optionally substituted by one, two or three R4), R3is OR”, -CN, S(O)C1-4alkyl, NR’R’, or P(O)(C1-4alkyl)2; when L1is -C(=O)-, R3is NR’R’ or OR”; R4is each independently selected from the group consisting of halogen and C1-C6alkyl (optionally substituted by one, two or three halogens), or two R4together with the carbon to which the R4are attached form a C3-C5carbocyclyl; R’ and R” for each occurrence are each independently selected from the group consisting of H and C1-C6alkyl (optionally substituted by one, two or three halogens); RHis selected from the group consisting of H, C1-C4alkyl, -C(O)-C1-C3alkyl, and C(O)- O-C1-C3alkyl;R1is selected from the group consisting of C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; wherein C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents each independently selected from halo and C1-C4alkyl (optionally substituted by one, two or three halogens); R2is selected from the group consisting of H, F, methyl, CF3, -C(O)-O-methyl, - C(O)OH, -O-methyl, -O-ethyl, C3-C7cycloalkyl, and heterocyclyl optionally substituted by one, two, or three substituents each independently selected from the group consisting of halogen and C1-4alkyl; and R5is selected from the group consisting of H, F, methyl, and CF3, or R2and R5together with the contiguous carbon atoms to which R2and R5are attached to form a phenylene ring.

[0079] In some embodiments, provided herein is a compound of Formula I-I:(Formula I-I) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, C-H, and C-F; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2, CH(CH3), C(CH3)2, C(CH2CH2), CFH, CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); ring Z is a 4-10 membered N-bound heterocyclic, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4alkyl (optionally substituted by one, two or three halogens), oxo, C1-C4alkoxy, and cyano; L1is selected from the group consisting of bond, C1-C6 alkylene (optionally substituted by one, two or three R4), and -C(=O)-;when L1is bond or C1-C6 alkylene (optionally substituted by one, two or three R4), R3is OR”, -CN, S(O)2C1-4alkyl, NR’R’, or P(O)(C1-4alkyl)2; when L1is -C(=O)-, R3is NR’R’ or OR”; R4is each independently selected from the group consisting of halogen and C1-C6 alkyl (optionally substituted by one, two or three halogens), or two R4together with the carbon to which the R4are attached form a C3-C5carbocyclyl; R’ and R” for each occurrence are each independently selected from the group consisting of H and C1-C6 alkyl (optionally substituted by one, two or three halogens); RHis selected from the group consisting of H, C1-C4alkyl, -C(O)-C1-C3alkyl, and C(O)- O-C1-C3alkyl; R1is selected from the group consisting of C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; wherein C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents each independently selected from halo and C1-C4alkyl (optionally substituted by one, two or three halogens); and R2is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O- methyl, -O-ethyl, C3-C7cycloalkyl, and heterocyclyl.

[0080] In some embodiments, provided herein a compound of Formula I-A:(Formula I-A) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, C-H, and C-F; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2, CH(CH3), C(CH3)2, C(CH2CH2), CFH, CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3);ring Z is a 4-10 membered N-bound heterocyclic, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4alkyl (optionally substituted by one, two or three halogens), oxo, C1-C4alkoxy, and cyano; L1is selected from the group consisting of bond, C1-C6 alkylene (optionally substituted by one, two or three R4), and -C(=O)-; when L1is bond or C1-C6alkylene (optionally substituted by one, two or three R4), R3is OR”, -CN, S(O)2C1-4alkyl, or P(O)(C1-4alkyl)2; when L1is -C(=O)-, R3is NR’R’ or OR”; R4is each independently selected from the group consisting of halogen and C1-C6alkyl (optionally substituted by one, two or three halogens), or two R4together with the carbon to which the R4are attached form a C3-C5carbocyclyl; R’ and R” for each occurrence are each independently selected from the group consisting of H and C1-C6 alkyl (optionally substituted by one, two or three halogens); RHis selected from the group consisting of H, C1-C4alkyl, -C(O)-C1-C3alkyl, and C(O)- O-C1-C3alkyl; R1is selected from the group consisting of C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; wherein C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents each independently selected from halo and C1-C4alkyl (optionally substituted by one, two or three halogens); R2is selected from the group consisting of H, F, methyl, CF3, -C(O)-O-methyl, - C(O)OH, -O-methyl, -O-ethyl, C3-C7cycloalkyl, and heterocyclyl optionally substituted by one, two, or three substituents each independently selected from the group consisting of halogen and C1-4alkyl; and R5is selected from the group consisting of H, F, methyl, and CF3, or R2and R5together with the contiguous carbon atoms to which R2and R5are attached to form a phenylene ring.

[0081] In some embodiments, provided herein a compound of Formula I-IA:(Formula I-IA) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, C-H, and C-F; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2, CH(CH3), C(CH3)2, C(CH2CH2), CFH, CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); ring Z is a 4-10 membered N-bound heterocyclic, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4alkyl (optionally substituted by one, two or three halogens), oxo, C1-C4alkoxy, and cyano; L1is selected from the group consisting of bond, C1-C6 alkylene (optionally substituted by one, two or three R4), and -C(=O)-; when L1is bond or C1-C6alkylene (optionally substituted by one, two or three R4), R3is OR”, -CN, S(O)2C1-4alkyl, or P(O)(C1-4alkyl)2; when L1is -C(=O)-, R3is NR’R’ or OR”; R4is each independently selected from the group consisting of halogen and C1-C6alkyl (optionally substituted by one, two or three halogens), or two R4together with the carbon to which the R4are attached form a C3-C5carbocyclyl; R’ and R” for each occurrence are each independently selected from the group consisting of H and C1-C6alkyl (optionally substituted by one, two or three halogens); RHis selected from the group consisting of H, C1-C4alkyl, -C(O)-C1-C3alkyl, and C(O)- O-C1-C3alkyl; R1is selected from the group consisting of C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; wherein C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents eachindependently selected from halo and C1-C4alkyl (optionally substituted by one, two or three halogens); and R2is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O- methyl, -O-ethyl, C3-C7 cycloalkyl, and heterocyclyl.

[0082] In some embodiments, Y is NH, N-CH3, O, S, CH2, CF2, CH(CH3), or C(CH3)2, C(CH2CH2). In some embodiments, Y is NH, N-CH3, or O. In some embodiments, Y is NH or N-CH3. In some embodiments, Y is NH.

[0083] In some embodiments, RHis H, -C(O)-C1-C3alkyl, or C(O)-O-C1-C3alkyl. In some embodiments, RHis H or C1-C4alkyl. In some embodiments, RHis H.

[0084] In some embodiments, W is C-H or C-F. In other embodiments, W is N.

[0085] For example, W is N, Y is NH, RHis H, and the compound is represented by the Formula Ia:(Formula Ia) or a pharmaceutically acceptable salt, stereoisomer and / or N-oxide thereof.

[0086] In some embodiments, W is N, Y is NH, RHis H, and the compound is represented by the Formula Iaa:(Formula Iaa) or a pharmaceutically acceptable salt, stereoisomer and / or N-oxide thereof.

[0087] In some embodiments, R1is a 5-6 membered heterocyclyl or C3-C6cycloalkyl optionally substituted by one or two substituents each independently selected from halo and C1- C4alkyl (optionally substituted by one, two or three halogens). In some embodiments, R1is a 5-6membered heterocyclyl or C3-C6 cycloalkyl. In some embodiments, R1is C3-C6 cycloalkyl optionally substituted by one or two substituents each independently selected from halo and C1- C4alkyl (optionally substituted by one, two or three halogens). In some embodiments, R1is C3-C6cycloalkyl optionally substituted by one or two halo. In some embodiments, R1is a C3-C6 cycloalkyl. For example, R1is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R1is cyclopropyl or cyclopentyl. In some embodiments, R1is cyclopropyl. In some embodiments, R1is cyclopentyl.

[0088] In some embodiments, ring Z is selected from the group consisting of 4-6 membered monocyclic heterocycle, 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged heterocycle. In some embodiments, ring Z is selected from the group consisting of 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocyclyl, and 6-10 membered bridged heterocycle. In other embodiments, ring Z is selected from the group consisting of 4-6 membered monocyclic heterocycle and 6-10 membered bridged heterocycle. In some embodiments, ring Z is 6-10 membered bridged heterocycle. For example, ring Z is selected from the group consisting of:.

[0089] In some embodiments, ring Z is selected from the group consisting of:.

[0090] In some embodiments, ring Z is selected from the group consisting of:.

[0091] In some embodiments, ring Z is selected from the group consisting of:.

[0092] In some embodiments, ring Z is selected from the group consisting of:.

[0093] Exemplary contemplated compounds are represented by Formula Ib:(Formula Ib) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

[0094] In some embodiments, the compound is a compound of Formula Ibb:(Formula Ibb) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

[0095] Also contemplated herein are compounds represented by Formula Ic:(Formula Ic) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

[0096] In other embodiments, contemplated compounds are represented by Formula Icc:(Formula Icc) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

[0097] In other embodiments, contemplated compounds are represented by Formula Id:(Formula Id) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

[0098] In other embodiments, contemplated compounds are represented by Formula Idd:(Formula Idd) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

[0099] In some embodiments, the compound is a compound of Formula Ie:or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0100] In some embodiments, the compound is a compound of Formula Iee:(Formula Iee) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0101] In some embodiments, L1is C1-C6alkylene substituted by one or two R4. For example, L1may be methylene substituted by one or two R4. In some embodiments, R4is C1-C4 alkyl (optionally substituted by one, two or three halogens). For example, R4may be methyl, ethyl, or propyl. In other embodiments, two R4s together with the carbon to which the R4are attached form a C3-C4carbocyclyl. For example, two R4s together with the carbon to which the R4are attached may form a cyclopropylene. In some embodiments, R3is OR”, -CN, S(O)C1-4alkyl, or P(O)(C1-4alkyl)2. In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, O-tert-butyl, CN, SO2CH3, NH2, NHMe, N(Me)2, P(O)(CH3)2. In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, O-tert-butyl, CN, SO2CH3, P(O)(CH3)2. In some embodiments, R3is OR”, S(O)C1-4alkyl, or P(O)(C1-4alkyl)2. In some embodiments, R3is OR” or P(O)(C1-4alkyl)2. In some embodiments, R3is OR”. In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, O-tert-butyl, P(O)(CH3)2, and S(O)2(CH3). In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n- butyl, and O-tert-butyl.

[0102] In some embodiments, L1is C1-C6alkylene. For example, L1may be methylene, ethylene, or propylene. In some embodiments, L1is methylene. In some embodiments, R3isOR”, -CN, S(O)C1-4alkyl, or P(O)(C1-4alkyl)2. In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, O-tert-butyl, CN, SO2CH3, NH2, NHMe, N(Me)2, P(O)(CH3)2. In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, O-tert-butyl, CN, SO2CH3, P(O)(CH3)2. In some embodiments, R3is OR”, S(O)C1-4alkyl, or P(O)(C1-4alkyl)2. In some embodiments, R3is OR” or P(O)(C1-4alkyl)2. In some embodiments, R3is OR”. In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, O-tert-butyl, P(O)(CH3)2, and S(O)2(CH3). In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n- butyl, and O-tert-butyl.

[0103] In other embodiments, L1is bond. In some embodiments, R3is OR”, -CN, S(O)C1- 4alkyl, or P(O)(C1-4alkyl)2. In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, O-tert-butyl, CN, SO2CH3, NH2, NHMe, N(Me)2, P(O)(CH3)2. In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, O-tert-butyl, CN, SO2CH3, P(O)(CH3)2. In some embodiments, R3is OR”, S(O)C1-4alkyl, or P(O)(C1-4alkyl)2. In some embodiments, R3is OR” or P(O)(C1-4alkyl)2. In some embodiments, R3is OR”. In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, O-tert-butyl, P(O)(CH3)2, and S(O)2(CH3). In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n- butyl, and O-tert-butyl.

[0104] In other embodiments, L1is -C(=O)-. In some embodiments, R3is OR”. In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, and O-tert-butyl. In other embodiments, R3is NR’R’ such as NH2, NHMe, and N(Me)2.

[0105] In some embodiments, R2is H, F, methyl, CF3, -C(O)-O-methyl, -C(O)OH, -O- methyl, -O-ethyl, or heterocyclyl optionally substituted by C1-4alkyl. In some embodiments, R2is H, F, methyl, -O-methyl, -O-ethyl, or piperazine optionally substituted by C1-4alkyl.

[0106] In some embodiments, R2is H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O-methyl, or -O- ethyl. In some embodiments, R2is H, F, or -O-methyl. In some embodiments, R2is H or F. In some embodiments, R2is H.

[0107] In some embodiments, R5is H or methyl. In some embodiments, R5is H.

[0108] In some embodiments, R2and R5together with the contiguous carbon atoms to which R2and R5are attached to form a phenylene ring.

[0109] Also provided herein, in some embodiments, are compounds represented by Formula II:(Formula II) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, C-H, and C-F; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2, CH(CH3), C(CH3)2, C(CH2CH2), CFH, CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); ring Z is selected from the group consisting of 4, 5, or 7-10-membered N-bound monocyclic heterocyclyl, 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged heterocycle, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4alkyl (optionally substituted by one, two or three halogens), oxo, C1-C4alkoxy, and cyano; L1is selected from the group consisting of bond, C1-C6 alkylene (optionally substituted by one, two or three R4), and -C(=O)-; when L1is bond or C1-C6alkylene (optionally substituted by one, two or three R4), R3is OR”, -CN, S(O)C1-4alkyl, NR’R’, or P(O)(C1-4alkyl)2; when L is -C(=O)-, R3is NR’R’ or OR”; R4is each independently selected from the group consisting of halogen and C1-C6alkyl (optionally substituted by one, two or three halogens), or two R4together with the carbon to which the R4are attached form a C3-C5carbocyclyl;R’ and R” for each occurrence are each independently selected from the group consisting of H and C1-C6 alkyl (optionally substituted by one, two or three halogens); RHis selected from the group consisting of H, C1-C4alkyl, -C(O)-C1-C3alkyl, and C(O)- O-C1-C3alkyl; R1is selected from the group consisting of C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; wherein C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents each independently selected from halo and C1-C4alkyl (optionally substituted by one, two or three halogens); R2is selected from the group consisting of H, F, methyl, CF3, -C(O)-O-methyl, - C(O)OH, -O-methyl, -O-ethyl, C3-C7 cycloalkyl, and heterocyclyl optionally substituted by one, two, or three substituents each independently selected from the group consisting of halogen and C1-4alkyl; and R5is selected from the group consisting of H, F, methyl, and CF3, or R2and R5together with the contiguous carbon atoms to which R2and R5are attached to form a phenylene ring.

[0110] In some embodiments, provided herein is a compound represented by Formula II-I:(Formula II-I) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, C-H, and C-F; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2, CH(CH3), C(CH3)2, C(CH2CH2), CFH, CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); ring Z is selected from the group consisting of 4, 5, or 7-10-membered N-bound monocyclic heterocyclyl, 6-10 membered spiroheterocycle, 6-10 membered fused bicyclicheterocycle, and 6-10 membered bridged heterocycle, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4alkyl (optionally substituted by one, two or three halogens), oxo, C1-C4alkoxy, and cyano; L1is selected from the group consisting of bond, C1-C6 alkylene (optionally substituted by one, two or three R4), and -C(=O)-; when L1is bond or C1-C6alkylene (optionally substituted by one, two or three R4), R3is OR”, -CN, S(O)C1-4alkyl, NR’R’, or P(O)(C1-4alkyl)2; when L1is -C(=O)-, R3is NR’R’ or OR”; R4is each independently selected from the group consisting of halogen and C1-C6alkyl (optionally substituted by one, two or three halogens), or two R4together with the carbon to which the R4are attached form a C3-C5carbocyclyl; R’ and R” for each occurrence are each independently selected from the group consisting of H and C1-C6 alkyl (optionally substituted by one, two or three halogens); RHis selected from the group consisting of H, C1-C4alkyl, -C(O)-C1-C3alkyl, and C(O)- O-C1-C3alkyl; R1is selected from the group consisting of C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; wherein C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents each independently selected from halo and C1-C4alkyl (optionally substituted by one, two or three halogens); and R2is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O- methyl, -O-ethyl, C3-C7cycloalkyl, and heterocyclyl.

[0111] In some embodiments, provided herein is a compound represented by Formula II-A:or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, C-H, and C-F; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2, CH(CH3), C(CH3)2, C(CH2CH2), CFH, CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); ring Z is selected from the group consisting of 4, 5, or 7-10-membered N-bound monocyclic heterocyclyl, 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged heterocycle, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4alkyl (optionally substituted by one, two or three halogens), oxo, C1-C4alkoxy, and cyano; L1is selected from the group consisting of bond, C1-C6 alkylene (optionally substituted by one, two or three R4), and -C(=O)-; when L1is bond or C1-C6 alkylene (optionally substituted by one, two or three R4), R3is OR”, -CN, S(O)C1-4alkyl, or P(O)(C1-4alkyl)2; when L1is -C(=O)-, R3is NR’R’ or OR”; R4is each independently selected from the group consisting of halogen and C1-C6alkyl (optionally substituted by one, two or three halogens), or two R4together with the carbon to which the R4are attached form a C3-C5carbocyclyl; R’ and R” for each occurrence are each independently selected from the group consisting of H and C1-C6 alkyl (optionally substituted by one, two or three halogens); RHis selected from the group consisting of H, C1-C4alkyl, -C(O)-C1-C3alkyl, and C(O)- O-C1-C3alkyl; R1is selected from the group consisting of C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; wherein C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents each independently selected from halo and C1-C4alkyl (optionally substituted by one, two or three halogens); R2is selected from the group consisting of H, F, methyl, CF3, -C(O)-O-methyl, - C(O)OH, -O-methyl, -O-ethyl, C3-C7cycloalkyl, and heterocyclyl optionally substituted by one,two, or three substituents each independently selected from the group consisting of halogen and C1-4alkyl; and R5is selected from the group consisting of H, F, methyl, and CF3, or R2and R5together with the contiguous carbon atoms to which R2and R5are attached to form a phenylene ring.

[0112] In some embodiments, provided herein is a compound represented by Formula II-IA:(Formula II-IA) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: W is selected from the group consisting of N, C-H, and C-F; Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2,C(CH3)2, C(CH2CH2), CFH, CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); ring Z is selected from the group consisting of 4, 5, or 7-10-membered N-bound monocyclic heterocyclyl, 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged heterocycle, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted by one, two or three halogens), oxo, C1-C4 alkoxy, and cyano; L1is selected from the group consisting of bond, C1-C6alkylene (optionally substituted by one, two or three R4), and -C(=O)-; when L1is bond or C1-C6 alkylene (optionally substituted by one, two or three R4), R3is OR”, -CN, S(O)C1-4alkyl, or P(O)(C1-4alkyl)2; when L1is -C(=O)-, R3is NR’R’ or OR”;R4is each independently selected from the group consisting of halogen and C1-C6 alkyl (optionally substituted by one, two or three halogens), or two R4together with the carbon to which the R4are attached form a C3-C5carbocyclyl; R’ and R” for each occurrence are each independently selected from the group consisting of H and C1-C6 alkyl (optionally substituted by one, two or three halogens); RHis selected from the group consisting of H, C1-C4alkyl, -C(O)-C1-C3alkyl, and C(O)- O-C1-C3alkyl; R1is selected from the group consisting of C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; wherein C3-C10cycloalkyl, spiro C5-C10bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents each independently selected from halo and C1-C4alkyl (optionally substituted by one, two or three halogens); and R2is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O- methyl, -O-ethyl, C3-C7 cycloalkyl, and heterocyclyl.

[0113] In some embodiments, Y is NH, N-CH3, O, S, CH2, CF2, CH(CH3), or C(CH3)2, C(CH2CH2). In some embodiments, Y is NH, N-CH3, or O. In some embodiments, Y is NH or N-CH3. In some embodiments, Y is NH.

[0114] In some embodiments, RHis H, -C(O)-C1-C3alkyl, or C(O)-O-C1-C3alkyl. In some embodiments, RHis H or C1-C4alkyl. In some embodiments, RHis H.

[0115] In some embodiments, W is C-H or C-F. In other embodiments, W is N.

[0116] For example, when W is N, Y is NH, and RHis H, the compound may be represented by Formula IIa:(Formula IIa) or a pharmaceutically acceptable salt, stereoisomer and / or N-oxide thereof.

[0117] In some embodiments, when W is N, Y is NH, and RHis H, the compound may be represented by Formula IIaa:(Formula IIaa) or a pharmaceutically acceptable salt, stereoisomer and / or N-oxide thereof.

[0118] In some embodiments, R1is a 5-6 membered heterocyclyl or C3-C6 cycloalkyl optionally substituted by one or two substituents each independently selected from halo and C1- C4alkyl (optionally substituted by one, two or three halogens). In some embodiments, R1is a 5-6 membered heterocyclyl or C3-C6 cycloalkyl. In some embodiments, R1is C3-C6 cycloalkyl optionally substituted by one or two substituents each independently selected from halo and C1- C4alkyl (optionally substituted by one, two or three halogens). In some embodiments, R1is C3-C6cycloalkyl optionally substituted by one or two halo. In some embodiments, R1is a C3-C6 cycloalkyl. For example, R1is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R1is cyclopropyl or cyclopentyl. In some embodiments, R1is cyclopropyl. In some embodiments, R1is cyclopentyl.

[0119] In some embodiments, ring Z is selected from the group consisting of 4 or 5 membered monocyclic heterocycle, 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged heterocycle. In some embodiments, ring Z is selected from the group consisting of 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged heterocycle. In some embodiments, ring Z is selected from the group consisting of 4 or 5 membered monocyclic heterocycle and 6-10 membered bridged heterocycle. In some embodiments, ring Z is 6-10 membered bridged heterocycle. For example, ring Z may be selected from the group consisting of: .

[0120] In some embodiments, ring Z is selected from the group consisting of:.

[0121] In some embodiments, ring Z is selected from the group consisting of:.

[0122] In some embodiments, L1is C1-C6 alkylene substituted by one or two R4. For example, L1may be methylene substituted by one or two R4. In some embodiments, R4is C1-C4 alkyl (optionally substituted by one, two or three halogens). For example, R4may be methyl, ethyl, or propyl. In other embodiments, two R4s together with the carbon to which the R4are attached form a C3-C4 carbocyclyl. For example, two R4s together with the carbon to which the R4are attached may form a cyclopropylene. In some embodiments, R3is OR”, -CN, S(O)C1-4alkyl, or P(O)(C1-4alkyl). In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, O-tert-butyl, CN, SO2CH3, NH2, NHMe, N(Me)2, P(O)(CH3)2. In some embodiments, R3is selected from the group consisting of OH, O- methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, O-tert-butyl, CN, SO2CH3, P(O)(CH3)2. In some embodiments, R3is OR”, S(O)C1-4alkyl, or P(O)(C1-4alkyl). In some embodiments, R3is OR” or P(O)(C1-4alkyl)2. In some embodiments, R3is OR”. In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, O-tert- butyl, P(O)(CH3)2, and S(O)2(CH3). In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, and O-tert-butyl.

[0123] In some embodiments, L1is C1-C6alkylene. For example, L1may be methylene, ethylene, or propylene. In some embodiments, L1is methylene. In some embodiments, R3is OR”, -CN, S(O)C1-4alkyl, or P(O)(C1-4alkyl). In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, O-tert-butyl, CN, SO2CH3, NH2, NHMe, N(Me)2, P(O)(CH3)2. In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, O-tert-butyl, CN, SO2CH3, P(O)(CH3)2. In some embodiments, R3is OR”, S(O)C1-4alkyl, or P(O)(C1-4alkyl). In some embodiments, R3is OR” or P(O)(C1-4alkyl)2. In some embodiments, R3is OR”. In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl,O-n-propyl, O-n-butyl, O-tert-butyl, P(O)(CH3)2, and S(O)2(CH3). In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n- butyl, and O-tert-butyl.

[0124] In other embodiments, L1is bond. In some embodiments, R3is OR”, -CN, S(O)C1- 4alkyl, or P(O)(C1-4alkyl). In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, O-tert-butyl, CN, SO2CH3, NH2, NHMe, N(Me)2, P(O)(CH3)2. In some embodiments, R3is selected from the group consisting of OH, O- methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, O-tert-butyl, CN, SO2CH3, P(O)(CH3)2. In some embodiments, R3is OR”, S(O)C1-4alkyl, or P(O)(C1-4alkyl). In some embodiments, R3is OR” or P(O)(C1-4alkyl)2. In some embodiments, R3is OR”. In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, O-tert- butyl, P(O)(CH3)2, and S(O)2(CH3). In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, and O-tert-butyl.

[0125] In other embodiments, L1is -C(=O)-. In some embodiments, R3is OR”. In some embodiments, R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, and O-tert-butyl. In other embodiments, R3is NR’R’ such as NH2, NHMe, and N(Me)2.

[0126] In some embodiments, R2is H, F, methyl, CF3, -C(O)-O-methyl, -C(O)OH, -O- methyl, -O-ethyl, or heterocyclyl optionally substituted by C1-4alkyl. In some embodiments, R2is H, F, methyl, -O-methyl, -O-ethyl, or piperazine optionally substituted by C1-4alkyl.

[0127] In some embodiments, R2is H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O-methyl, or -O- ethyl. In some embodiments, R2is H, F, or -O-methyl. In some embodiments, R2is H or F. In some embodiments, R2is H.

[0128] In some embodiments, R5is H or methyl. In some embodiments, R5is H.

[0129] In some embodiments, R2and R5together with the contiguous carbon atoms to which R2and R5are attached to form a phenylene ring.

[0130] In some embodiments, the compound is selected from the group consisting of:44or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

[0131] Also provided herein, in some embodiments, is a compound represented by Formulaor a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: R11is H or CH3; L1is methylene or ethylene; R3is OR”; R” is H or C1-C6alkyl (optionally substituted by one, two or three halogens); RHis selected from the group consisting of H, C1-C3alkyl, -C(O)-C1-C3alkyl, and C(O)- O-C1-C3alkyl; R2is selected from the group consisting of H, F, methyl, CF3, -C(O)-O-methyl, - C(O)OH, -O-methyl, -O-ethyl, C3-C7cycloalkyl, and heterocyclyl optionally substituted by one, two, or three substituents each independently selected from the group consisting of halogen and C1-4alkyl; and R5is selected from the group consisting of H, F, methyl, and CF3, or R2and R5together with the contiguous carbon atoms to which R2and R5are attached to form a phenylene ring.

[0132] Also provided herein, in some embodiments, is a compound represented by Formula III-I:or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: R11is H or CH3; L1is methylene or ethylene; R3is OR”; R” is H or C1-C6 alkyl (optionally substituted by one, two or three halogens); RHis selected from the group consisting of H, C1-C3alkyl, -C(O)-C1-C3alkyl, and C(O)- O-C1-C3alkyl; and R2is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O- methyl, -O-ethyl, C3-C7 cycloalkyl, and heterocyclyl.

[0133] In some embodiments, RHis H or C1-C3alkyl.

[0134] In some embodiments, R2is H or F. In some embodiments, R2is H.

[0135] Also provided herein, in some embodiments, is a compound represented by Formula IV:or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: R11is H or CH3;L1is methylene or ethylene; R3is OR”; R” is H or C1-C6alkyl (optionally substituted by one, two or three halogens); RHis selected from the group consisting of H, C1-C3alkyl, -C(O)-C1-C3alkyl, and C(O)- O-C1-C3alkyl; R2is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O- methyl, -O-ethyl, C3-C7cycloalkyl, and heterocyclyl; R5is selected from the group consisting of H, F, methyl, and CF3, or R2and R5together with the contiguous carbon atoms to which R2and R5are attached to form a phenylene ring.

[0136] Also provided herein, in some embodiments, is a compound represented by Formula IV-I:(Formula IV-I) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein: R11is H or CH3; L1is methylene or ethylene; R3is OR”; R” is H or C1-C6 alkyl (optionally substituted by one, two or three halogens); RHis selected from the group consisting of H, C1-C3alkyl, -C(O)-C1-C3alkyl, and C(O)- O-C1-C3alkyl; and R2is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O- methyl, -O-ethyl, C3-C7 cycloalkyl, and heterocyclyl.

[0137] In some embodiments, RHis H or C1-C3alkyl.

[0138] In some embodiments, R2is H or F. In some embodiments, R2is H.

[0139] Without being bound by theory, the compounds disclosed herein inhibit cyclin- dependent kinase activity and may therefore have desirable properties. Pharmaceutical Compositions and Formulations

[0140] The compounds, prodrugs, and compositions described herein can be useful as pharmaceutical compositions for administration to a subject in need thereof.

[0141] Accordingly, pharmaceutical compositions are presented that can comprise at least a compound described herein, a pharmaceutically acceptable salt thereof, or a prodrug thereof, and at least one pharmaceutically acceptable carriers, diluent, stabilizers, excipients, dispersing agents, suspending agents, or thickening agents. For example, a disclosed pharmaceutical compositions may include one or more of the disclosed compounds, pharmaceutically acceptable salts, or prodrugs described herein. Contemplated compositions may include a compound, a pharmaceutically acceptable salt thereof, or a prodrug thereof in a therapeutically effective amount, for example, a disclosed pharmaceutical composition may be formulated for parenteral administration to a subject in need thereof, formulated for intravenous administration to a subject in need thereof, or formulated for subcutaneous administration to a subject in need thereof. Methods of Treatment

[0142] As described above, embodiments of the present disclosure include the use of compounds, prodrugs, and pharmaceutical compositions described herein to treat a Myc protein associated proliferative disease in a subject in need thereof. Such proliferative diseases include cancer, for example, a cancer selected from a group consisting of head and neck cancer, nervous system cancer, brain cancer, neuroblastoma, lung / mediastinum cancer, breast cancer, esophageal cancer, stomach cancer, liver cancer, biliary tract cancer, pancreatic cancer, small bowel cancer, large bowel cancer, colorectal cancer, gynecological cancer, genito-urinary cancer, ovarian cancer, thyroid gland cancer, adrenal gland cancer, skin cancer, melanoma, bone sarcoma, soft tissue sarcoma, pediatric malignancy, Hodgkin’s disease, non-Hodgkin’s lymphoma, myeloma, leukemia, and metastasis from an unknown primary site.

[0143] In some embodiments, a contemplated method of treating includes treating a cancer that is a Myc protein associated cancer, e.g., wherein the Myc protein is selected from the group consisting of a N-Myc protein, a c-Myc protein, a L-Myc protein, a human N-Myc protein, a human c-Myc protein, and a human L-Myc protein.

[0144] For example, provided herein is a method of treating a cancer selected from the group consisting of neuroblastoma, small cell lung carcinoma, breast cancer or a hematopoietic cancer.

[0145] In some embodiments, a disclosed method to treat cancer further comprises a second therapy, wherein the secondary therapy is an antineoplastic therapy, e.g., a contemplated method may further comprise administering an antineoplastic therapy such as one or more agents selected from a DNA topoisomerase I or II inhibitor, a DNA damaging agent, an immunotherapeutic agent (e.g., an antibody, cytokine, immune checkpoint inhibitor or cancer vaccine), an antimetabolite or a thymidylate synthase (TS) inhibitor, a microtubule targeted agent, ionizing radiation, an inhibitor of a mitosis regulator or a mitotic checkpoint regulator, an inhibitor of a DNA damage signal transducer, and an inhibitor of a DNA damage repair enzyme. For example, additional antineoplastic therapy may be selected from the group consisting of immunotherapy (e.g., immuno-oncologic therapy), radiation therapy, photodynamic therapy, gene-directed enzyme prodrug therapy (GDEPT), antibody-directed enzyme prodrug therapy (ADEPT), gene therapy, and controlled diets.

[0146] The present disclosure also contemplates the use of compounds, prodrugs, and pharmaceutical compositions described herein to modulate the amount and activity of a Myc protein (in vitro or in a patient), where the Myc protein may be for example a N-Myc protein, a c-Myc protein, a L-Myc protein, a human N-Myc protein, a human c-Myc protein, and / or a human L-Myc protein.

[0147] For example, the disclosure provides a method of modulating the amount (e.g., the concentration) and / or activity of a Myc protein such as (e.g. degrading a Myc protein, or modulating the rate of degradation of a Myc protein) that comprises contacting a Myc protein with an effective amount of a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, including embodiments or from any examples, tables or figures.

[0148] Contemplated methods include methods of modulating the protein-protein interactions of the Myc family protein, or a method of decreasing the amount and decreasing the level of activity of a Myc protein.

[0149] A disclosed method of modulating the amount and activity of a Myc protein may include co-administering a compound described herein, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a second agent, e.g., therapeutic agent.EXAMPLES

[0150] Below are examples of specific embodiments for carrying out the present disclosure. The examples are offered for illustrative purposes only, and are not intended to limit the scope of the present disclosure in any way. Efforts have been made to ensure accuracy with respect to numbers used (i.e., amounts, temperatures, etc.), but some experimental error and deviation should be allowed for. General Experimental

[0151] 1H and13C NMR spectra were recorded in CDCl3 (residual internal standard CHCl3 = δ 7.26), DMSO-d6(residual internal standard CD3SOCD2H = δ 2.50), methanol-d4(residual internal standard CD2HOD = δ 3.20), or acetone-d6(residual internal standard CD3COCD2H = δ 2.05). The chemical shifts (δ) reported are given in parts per million (ppm) and the coupling constants (J) are in Hertz (Hz). The spin multiplicities are reported as s = singlet, bs = broad singlet, bm = broad multiplet, d = doublet, t = triplet, q = quartet, p = pentuplet, dd = doublet of doublet, ddd = doublet of doublet of doublet, dt = doublet of triplet, td = triplet of doublet, tt = triplet of triplet, and m = multiplet.

[0152] UPLC-MS analysis was carried out on a Waters Acquity UPLC system consisting of an Acquity I-Class Sample Manager-FL, Acquity I-Class Binary Solvent Manager and an Acquity UPLC Column Manager. UV detection was afforded using an Acquity UPLC PDA detector (scanning from 210 to 400 nm), whilst mass detection was achieved using aa Acquity Qda detector (mass scanning from 100–1250 Da; positive and negative modes simultaneously). A Waters Acquity UPLC BEH C18 column (2.1 × 50 mm, 1.7 mm) was used to separate the analytes.

[0153] Samples were prepared by dissolution (with or without sonication) into 1 mL of 50% (v / v) MeCN in water. The resulting solutions were then filtered through a 0.2 mm syringe filter before submitting for analysis. All of the solvents, including formic acid and 36% ammonia solution, were purchased as the HPLC grade. Conditions (Acidic 2 min): 0.1% v / v Formic acid in water [Eluent A]; 0.1% v / v Formic acid in MeCN [Eluent B]; Flow rate 0.8mL / min; injection volume 2mL and 1.5 min equilibration time between samples. Conditions (Acidic 4 min): 0.1% v / v formic acid in water [Eluent A]; 0.1% v / v formic acid in MeCN [Eluent B]; Flow rate 0.8mL / min; injection volume 2mL and 1.5 min equilibration time between samples. Conditions(Basic 2 min): 0.1% ammonia in water [Eluent A]; 0.1% ammonia in MeCN [Eluent B]; Flow rate 0.8mL / min; injection volume 2mL and 1.5 min equilibration time between samples. Conditions (Basic 4 min): 0.1% ammonia in water [Eluent A]; 0.1% ammonia in MeCN [Eluent B]; Flow rate 0.8mL / min; injection volume 2mL and 1.5 min equilibration time between samples. General Synthetic SchemesScheme 2

[0154] In certain embodiments, a compound disclosed herein is prepared according to Scheme 1 or 2. Intermediate A1 (e.g., disclosed herein) is reacted with amine B1 (e.g., amines disclosed herein) in the presence of a base (e.g., N,N-diisopropylethylamine) at elevated temperatures to produce a compound of Formula I. In certain embodiments, amine B1 may comprise a protecting group (e.g., tert-butyloxycarbonyl (Boc), benzyl carbamate (Cbz)). In certain embodiments, when amine B1 comprises a protecting group (e.g., tert-butyloxycarbonyl (Boc), benzyl carbamate (Cbz)), the intermediate produced from the reaction thereof with intermediate A1 in the presence of a base may further be deprotected (e.g., in the presence ofreducing agents such as hydrogen (e.g., with Pd / C as catalyst) or LiAlH4 or acid such as TFA or HBr) to produce a compound of Formula I or I-I. List of Abbreviations AcOH Acetic acid aq Aqueous BCA Bicinchoninic acid Boc tert-butyloxycarbonyl (Boc)2O Di-tert-butyl dicarbonate Cbz Benzyloxycarbonyl CbzCl Benzyl chloroformate CDCl3 Deuterated chloroform CDI N,N’-carbonyldiimidazole CITTIP Chlorotriisopropoxytitanium(IV) ClTi(i-Opr)3Chlorotriisopropoxytitanium(IV) DCM Dichloromethane DIPEA Diisopropylethylamine (Hunig’s base) DMF N,N-dimethylformamide DMSO Dimethyl sulfoxide DMSO-d6Deuterated dimethyl sulfoxide e.e. Enantiomeric excess eq Equivalent(s) Et2O Diethyl ether Et3N Triethylamine EtMgBr Ethyl magnesium bromide EtOAc Ethyl acetate EtOH Ethanol h Hour(s) HPLC High-performance liquid chromatography IPA Isopropanol i-Pr2NEt Diisopropylethylamine (Hunig’s base) i-PrOH IsopropanolMe2NH Dimethylamine MeCN Acetonitrile MeI Methyl iodide MeMgBr Methyl magnesium bromide MeNH2 Methylamine MeOH Methanol Ms Methanesulfonyl (mesyl) MsCl Mesyl chloride NaHMDS Sodium bis(trimethylsilyl)amide NaOMe Sodium methoxide NaSMe Sodium thiomethoxide Na2S2O8 Sodium persulfate n-BuOH n-Butanol NMP N-Methyl-2-pyrrolidone NMR Nuclear magnetic resonance n-PrOH n-propanol PBS Phosphate buffered saline Pd / C Palladium on carbon r.t. Room temperature RIPA Radioimmunoprecipitation assay Rt Retention time SCX Strong cation exchange SFC Supercritical fluid chromatography SOCl2 Thionyl chloride STAB Sodium triacetoxyborohydride TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride THF Tetrahydrofuran Ti(Oi-Pr)4Titanium (IV) isopropoxide TMSCHN2(Trimethylsilyl)diazomethane UPLC-MS Ultra-performance liquid chromatography-mass spectrometryUV Ultraviolet Synthesis of intermediates 2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine

[0155] A solution of 5-cyclopropyl-1H-pyrazol-3-amine (4.55 g, 36.9 mmol), 2,4- dichloropyrimidine (5.00 g, 33.6 mmol) and N,N-diisopropylethylamine (8.8 mL, 50 mmol) in DMSO (50 mL) was heated to 60 °C and stirred for 16 hours. The reaction mixture was then cooled to ambient temperature, then added to ice water (ca.1 L). The precipitate was collected by filtration, then dried under reduced pressure to afford the title compound as a solid (7.41 g, 31.4 mmol, 94%).

[0156] 1H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 10.26 (s, 1H), 8.14 (s, 1H), 7.31 (s, 1H), 5.93 (s, 1H), 1.89 (tt, J = 8.7, 5.2 Hz, 1H), 1.01 – 0.88 (m, 2H), 0.68 (q, J = 3.5, 1.9 Hz, 2H).

[0157] UPLC-MS (basic method, 2 min): Rt: 0.87 min, m / z: 236.2 [M+H]+. Synthesis of 2-Chloro-N-(5-cyclopentyl-1H-pyrazol-3-yl)pyrimidin-4-amine

[0158] A solution of 2,4-dichloropyrimidine (450 mg, 3.0 mmol, 1.0 eq) in anhydrous DMSO (10.0 mL) was treated sequentially with 5-cyclopentyl-1H-pyrazol-3-amine (502 mg, 3.2 mmol, 1.10 eq) and N,N-diisopropylethylamine (0.79 mL, 4.5 mmol, 1.50 eq), and the resulting solution was stirred at 60 °C for 20 h. The reaction mixture was cooled to ambient temperature and poured into ice water, affording a suspension, which was stirred for 5 min. The mixture wasfiltered to afford a solid, which was washed with water (50 mL) before being dried under vacuum to constant weight to give the desired compound as a solid (675 mg, 2.56 mmol, 85%). UPLC-MS (Basic Method, 2 min): rt 0.98 min, m / z = 263.3 [M+H]+.1H NMR (400 MHz, DMSO) δ 12.19 (s, 1H), 10.31 (s, 1H), 8.16 (s, 1H), 3.02 (q, J = 8.3 Hz, 1H), 2.05 – 1.94 (m, 2H), 1.74 – 1.66 (m, 2H), 1.58 (ddt, J = 20.3, 15.7, 7.0 Hz, 4H). t -Butyl 4-(methylsulfonyloxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate  Diisopropyl 3-hydroxyiminocyclobutane-1,1-dicarboxylate

[0159] Diisopropyl 3-oxocyclobutane-1,1-dicarboxylate (9.69 g, 40.0 mmol) and hydroxylamine hydrochloride (5.56 g, 80.0 mmol) were dissolved in ethanol (250 mL) and water (250 mL) mixture. Sodium carbonate (12.72 g, 120 mmol) was added and the mixture was heated at reflux for 1 hour. The reaction mixture was allowed to cool to room temperature, then the solvent was removed under reduced pressure. The residue was suspended in water (100 mL), then the precipitate was isolated by filtration. The filter cake was washed with water (50 mL), then dried under vacuum to afford the title compound as a solid (7.84 g, 28.9 mmol, 72%).

[0160] 1H NMR (400 MHz, Chloroform-d) δ 6.98 (s, 1H), 5.08 (hept, J = 6.3 Hz, 2H), 3.47 – 3.36 (m, 4H), 1.25 (d, J = 6.3 Hz, 12H). Diisopropyl 3-(tert-butoxycarbonylamino)cyclobutane-1,1-dicarboxylate

[0161] To diisopropyl 3-hydroxyiminocyclobutane-1,1-dicarboxylate (4.74 g, 18.4 mmol) in a mixture 1,4-dioxane (250 mL) and methanol (125 mL) was added di-tert-butyl dicarbonate(8.04 g, 36.8 mmol) and nickel(II) chloride (1.19 g, 9.21 mmol) . The reaction was cooled to 0 °C and sodium borohydride (2.79 g, 73.7 mmol) was added portion-wise. The reaction was stirred for 2 hours before diethylene triamine (4.6 mL, 42.6 mmol) was added and the reaction mixture was stirred for one hour. The reaction mixture was diluted with water (800 mL) Then extracted with EtOAc (800ml then 2 × 400 mL). The combined organic extracts were washed with a saturated aqueous brine solution (100 mL) and dried over Na2SO4, then concentrated to dryness under reduced pressure. The crude material was purified by column chromatography over silica (80 g cartridge) eluting with a gradient of EtOAc (0 % to 100%; v / v) in iso-hexane to afford the title compound as an oil (5.60 g, 14.7 mmol, 80%).

[0162] 1H NMR (400 MHz, Chloroform-d) δ 5.13 – 4.98 (m, 2H), 4.76 (s, 1H), 4.32 – 4.15 (m, 1H), 2.98 – 2.82 (m, 2H), 2.41 – 2.29 (m, 2H), 1.43 (s, 9H), 1.24 (dd, J = 6.3, 4.2 Hz, 12H).

[0163] UPLC MS (4 minute, basic method, ELSD) rt = 2.15 min, m / z = 342.0 [M-H]–. Tert-Butyl N-[3,3-Bis(hydroxymethyl)cyclobutyl]carbamate

[0164] Diisopropyl 3-(tert-butoxycarbonylamino)cyclobutane-1,1-dicarboxylate (5.25 g, 15.3 mmol) dissolved in THF (300 mL), cooled in ice bath, then lithium borohydride (1.33 g, 61.1 mmol) added, then reaction heated under reflux for 45 min, cooled to 40 °C, then added methanol (30 mL) dropwise. Once addition was complete and effervescence had subsided heated at 60 ºC for 20 minutes. The mixture was cooled to r.t, citric acid (500 mL, 5%) was added, and stirred for 30 min. The biphasic mixture was transferred to a separatory funnel with DCM (500 mL), partitioned, and further extracted aqueous with DCM (2 × 300 mL). The washed organic phase was dried over sodium sulfate, filtered, and concentrated to give the crude product in 2.07 g. Purification by crystallization was attempted by dissolving the crude product in DCM (30 mL) and adding heptane (20 mL), then removing the DCM under vacuum but the product remained stickly oily solid. The crude product was slurried in EtOAc (about 40 mL), sonicated, and filtered. The liquors were purified by column chromatography over silica (40 g cartridge) eluting with a gradient of EtOAc (50% to 100%; v / v) in iso-hexane to provide the desired product (1.00 g, 4.32 mmol, 28.28% yield) as a solid.

[0165] 1H NMR (400 MHz, DMSO-d6, 70 °C) δ 6.64 (s, 1H), 4.29 (s, 1H), 4.18 (s, 1H), 3.84 (q, J = 8.0 Hz, 1H), 3.39 (s, 2H), 3.32 (s, 2H), 2.04 – 1.94 (m, 2H), 1.74 – 1.62 (m, 2H), 1.38 (s, 9H).[3-(tert-Butoxycarbonylamino)-1-(methylsulfonyloxymethyl)cyclobutyl]methyl methanesulfonate

[0166] To a solution of tert-butyl N-[3,3-bis(hydroxymethyl)cyclobutyl]carbamate (661 mg, 2.86 mmol) and triethylamine (1.2 mL, 8.6 mmol) in chloroform (9.5 mL) was added methanesulfonyl chloride (0.46 mL, 6.0 mmol) dropwise at 0 °C. The rection mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with water (10 mL) and diluted with dichloromethane (20 mL). Reaction mixture was extracted with dichloromethane (2 x 20 mL), then the combined organic extracts were washed with a saturated aqueous brine solution (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was triturated with diethyl ether to afford the title compound as a solid (918 mg, 2.37 mmol, 83%).

[0167] 1H NMR (400 MHz, Chloroform-d) δ 5.34 – 5.08 (m, 1H), 4.50 – 3.93 (m, 4H), 3.76 – 3.47 (m, 1H), 3.05 – 2.95 (m, 6H), 2.35 – 2.23 (m, 2H), 1.91 (s, 2H), 1.36 (d, J = 2.3 Hz, 9H). tert-Butyl 4-(methylsulfonyloxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

[0168] In a round bottom flask was taken [3-(tert-butoxycarbonylamino)-1- (methylsulfonyloxymethyl)cyclobutyl]methyl methanesulfonate (7.00 g, 18.1 mmol) in DCM ( 100 mL). Methanesulfonic acid (3.6 mL, 54.2 mmol) was added and reaction mixture was stirred for 2 hours at room temperature. THF (30 mL) was added and stirring was continued for another 2 hours. Afterwards, volatiles were removed under reduced pressure to afford semi-solid residue. The residue was taken in toluene (50 mL) and N,N-diisopropylethylamine (14 mL, 81 mmol) was added. IPA (25 mL) was added, and reaction was heated to reflux and stirred for 16 hours. The reaction mixture was cooled to room temperature, then N,N-diisopropylethylamine (6.3 mL, 36 mmol) and di-tert-butyl dicarbonate (5.91 g, 27.1 mmol) added successively. After stirring for 20 hours at room temperature, the reaction mixture was transferred to separatory funnel with water (400 mL) and EtOAc (200 mL). The organic layer was separated and the aqueous layer was further extracted with EtOAc (300 mL). The combined organics were washed with brine (400 mL), dried over Na2SO4 and concentrated under reduced pressure to afford oily residue. The crude material was purified by column chromatography over silica (80 g cartridge) eluting with a gradient of EtOAc (50% to 100%; v / v) in iso-hexane to afford the title compound as a solid (2.50 g, 8.58 mmol, 48%).1H NMR (400 MHz, Chloroform-d) δ 4.42 – 4.34 (m, 3H), 3.28 (s, 2H), 3.02 (s, 3H), 1.92 – 1.82 (m, 2H), 1.63 – 1.47 (m, 2H), 1.46 (s, 9H). Example 1. Synthesis of [2-[4-[(5-Cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.1.1]hexan-4-yl]methanol (Compound 1)2-Azabicyclo[2.1.1]hexan-4-ylmethanol;hydrochloride

[0169] To a solution of tert-butyl 4-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2- carboxylate (600 mg, 2.81 mmol) in 1,4-dioxane (5 mL) was added 4 M hydrogen chloride solution in 1,4-dioxane (5.0 mL, 20.0 mmol) and the reaction mixture was stirred for 4 hours. The reaction mixture was then concentrated to dryness under reduced pressure to afford 2- azabicyclo[2.1.1]hexan-4-ylmethanol;hydrochloride (420 mg, 2.81 mmol, 99%) as a solid.

[0170] 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 2H), 4.09 (s, 1H), 3.61 (s, 2H), 3.09 – 3.02 (m, 2H), 1.89 – 1.78 (m, 2H), 1.54 – 1.39 (m, 2H).

[0171] UPLC-MS (basic method, 2 min): Rt: 0.20 min, m / z = 114.0 [M–Cl]+. [2-[4-[(5-Cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexan-4- yl]methanol

[0172] A solution of 2-chloro-N-(5-cyclopentyl-1H-pyrazol-3-yl)pyrimidin-4-amine (620 mg, 2.35 mmol), 2-azabicyclo[2.1.1]hexan-4-ylmethanol;hydrochloride (422 mg, 2.82 mmol) and N,N-diisopropylethylamine (1.8 mL, 11 mmol) in NMP (6 mL) was heated to 120 °C and stirred for 72 hours. The reaction mixture was then loaded onto a C18 cartridge. The purified by reversed-phase column chromatography, eluting with a gradient of 4:1 water (0.1% v / v NH3):MeCN (0.1% v / v NH3) to 4:6 water (0.1% v / v NH3):MeCN (0.1% v / v NH3). The residue was further purified by reversed-phase basic preparative HPLC to afford the title compound as a solid (275 mg, 0.808 mmol, 34%).

[0173] 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.34 (s, 1H), 7.84 (d, J = 5.7 Hz, 1H), 6.46 – 6.05 (m, 2H), 4.70 (t, J = 1.7 Hz, 1H), 4.67 (t, J = 5.4 Hz, 1H), 3.64 (d, J = 5.4 Hz, 2H), 3.32 (s, 2H), 3.00 (p, J = 7.9 Hz, 1H), 2.03 – 1.92 (m, 2H), 1.84 – 1.74 (m, 2H), 1.74 – 1.51 (m, 6H), 1.38 – 1.31 (m, 2H).

[0174] UPLC-MS (basic method, 4 min): Rt: 1.33 min, m / z = 341.3 [M+H]+. Example 2. Synthesis of N-(5-Cyclopentyl-1H-pyrazol-3-yl)-2-[4-(methoxymethyl)-2- azabicyclo[2.1.1]hexan-2-yl]pyrimidin-4-amine (Compound 2)[2-[4-[(5-Cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexan-4- yl]methanol

[0175] A solution of 2-azabicyclo[2.1.1]hexan-4-ylmethanol;hydrochloride (722 mg, 4.82 mmol), 2-chloro-N-(5-cyclopentyl-1H-pyrazol-3-yl)pyrimidin-4-amine (1.06 g, 4.02 mmol) and N,N-diisopropylethylamine (3.2 mL, 18 mmol) in NMP (10 mL) was heated to 120 °C in a sealed tube, and stirred for 48 hours. The reaction mixture was cooled to room temperature, then loaded onto a 20 g SCX-2 cartridge. The SCX cartridge was washed with water (100 mL), followed by methanol (100 mL). All eluents from both washings were combined then concentrated under reduced pressure. The crude material was purified by automated flash column chromatography, over C18-modified silica, eluting with a gradient of 1:19 MeCN:H2Owith 0.1% v / v NH3 to 19:1 MeCN:H2O with 0.1% v / v NH3 to afford the title compound as a solid (950 mg, 2.79 mmol, 69%).

[0176] 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.35 (s, 1H), 7.84 (d, J = 5.7 Hz, 1H), 6.48 – 6.10 (m, 2H), 4.70 (d, J = 1.7 Hz, 1H), 4.67 (t, J = 5.4 Hz, 1H), 3.64 (d, J = 5.3 Hz, 2H), 3.32 (s, 2H), 3.01 (p, J = 8.0 Hz, 1H), 2.05 – 1.94 (m, 2H), 1.82 – 1.76 (m, 2H), 1.75 – 1.52 (m, 6H), 1.39 – 1.30 (m, 2H).

[0177] UPLC-MS (basic method, 2 min): Rt: 0.90 min, m / z = 341.3 [M+H]+. 2-[4-(Chloromethyl)-2-azabicyclo[2.1.1]hexan-2-yl]-N-(5-cyclopentyl-1H-pyrazol-3- yl)pyrimidin-4-amine

[0178] To a solution of [2-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.1.1]hexan-4-yl]methanol (1.01 g, 2.97 mmol) in CH2Cl2 (30 mL) was added thionyl chloride (646 µL, 8.90 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 20 hours. The reaction was quenched with water (50 mL), then extracted with a 1:3 mixture of IPA:CHCl3 (3 × 100 mL). The combined organic extracts were dried over Na2SO4, then concentrated to dryness under reduced pressure to afford the title compound as a solid (937 mg, 2.61 mmol, 88%).

[0179] 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.43 (s, 1H), 7.85 (d, J = 5.7 Hz, 1H), 6.47 – 6.07 (m, 2H), 4.73 (t, J = 1.8 Hz, 1H), 3.99 (s, 2H), 3.42 (s, 2H), 3.01 (p, J = 7.8 Hz, 1H), 2.03 – 1.93 (m, 2H), 1.92 – 1.83 (m, 2H), 1.76 – 1.53 (m, 6H), 1.50 – 1.45 (m, 2H).

[0180] UPLC-MS (basic method, 2 min): Rt: 1.11 min, m / z = 359.3 [M+H]+.N-(5-Cyclopentyl-1H-pyrazol-3-yl)-2-[4-(methoxymethyl)-2-azabicyclo[2.1.1]hexan-2- yl]pyrimidin-4-amine

[0181] A suspension of 2-[4-(chloromethyl)-2-azabicyclo[2.1.1]hexan-2-yl]-N-(5- cyclopentyl-1H-pyrazol-3-yl)pyrimidin-4-amine (150 mg, 0.418 mmol), sodium iodide (63 mg, 0.42 mmol) and 5.4 M solution of sodium methoxide in methanol (1.0 mL, 5.40 mmol) in methanol (2 mL) was heated to 80 °C in a sealed tube and stirred for 24 hours. The reaction mixture was then diluted with a 0.5 M aqueous NaOH solution (20 mL), then extracted with 3:1 CHCl3:IPA (3 × 20 mL). The combined organic extracts were dried over Na2SO4, then concentrated to dryness under reduced pressure. The residue was purified by reversed-phase basic preparative HPLC to afford the title compound as a solid (25 mg, 71 µmol, 17%).

[0182] 1H NMR (400 MHz, chloroform-d) δ 8.00 (d, J = 5.8 Hz, 1H), 6.86 (s, 1H), 6.14 (s, 1H), 6.04 (s, 1H), 4.88 (s, 1H), 3.63 (s, 2H), 3.51 (s, 2H), 3.40 (s, 3H), 3.06 (p, J = 8.0 Hz, 1H), 2.16 – 2.02 (m, 2H), 1.98 – 1.90 (m, 2H), 1.85 – 1.61 (m, 6H), 1.61 – 1.50 (m, 2H).

[0183] UPLC-MS (basic method, 4 min): Rt: 1.62 min, m / z = 355.4 [M+H]+. Example 3. Synthesis of Ethyl 2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2- yl]-2-azabicyclo[2.1.1]hexane-4-carboxylate (Compound 3)

[0184] A solution of ethyl 2-azabicyclo[2.1.1]hexane-4-carboxylate hydrochloride (498 mg, 2.60 mmol), 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (510 mg, 2.16 mmol) and N,N-diisopropylethylamine (1.1 mL, 6.5 mmol) in NMP (4 mL) was heated to 120 °C, and stirred for 18 hours. The reaction mixture was then then loaded on to a C18cartridge then purified by basic reversed-phase column chromatography, eluting with a gradient of 1:4 MeCN:water (0.1% NH3) to 6:4 MeCN:water (0.1% NH3) to afford the title compound as a solid (500 mg, 1.41 mmol, 64% yield).

[0185] 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 9.41 (s, 1H), 7.86 (d, J = 5.7 Hz, 1H), 6.41 – 6.04 (m, 2H), 4.72 – 4.67 (m, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.61 (s, 2H), 2.25 – 2.14 (m, 2H), 1.92 – 1.81 (m, 1H), 1.74 – 1.63 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H), 0.96 – 0.87 (m, 2H), 0.70 – 0.62 (m, 2H).

[0186] UPLC-MS (basic method, 4 min): Rt: 1.49 mins, m / z = 355.2 [M+H]+. Example 4. Synthesis of 2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.1.1]hexane-4-carboxamide (Compound 4)

[0187] To ethyl 2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.1.1]hexane-4-carboxylate (10 mg, 28 µmol) was added in 7 M NH3in MeOH (3 mL) and the reaction stirred at room temperature for 42 hours. The reaction mixture was concentrated to dryness to afford the title compound as a solid (9.3 mg, 28 µmol, 99%).

[0188] 1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 9.33 (s, 1H), 7.82 (d, J = 5.7 Hz, 1H), 7.37 (s, 1H), 7.07 (s, 1H), 6.33 – 6.00 (m, 2H), 4.61 (s, 1H), 3.50 (s, 2H), 2.09 – 2.04 (m, 2H), 1.89 – 1.77 (m, 1H), 1.62 – 1.52 (m, 2H), 0.91 – 0.84 (m, 2H), 0.66 – 0.58 (m, 2H).

[0189] UPLC-MS (basic method, 4 min): Rt: 1.00, m / z = 326.1 [M+H]+. Example 5. Synthesis of N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[4-(methoxymethyl)-2- azabicyclo[2.1.1]hexan-2-yl]pyrimidin-4-amine (Compound 6)tert-Butyl 4-(methoxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

[0190] tert-Butyl 4-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (550 mg, 2.58 mmol) was dissolved in THF (5 mL) and cooled to 0 °C. Sodium hydride (60% in mineral oil,123 mg, 3.09 mmol) was added and the reaction mixture was stirred for 15 min. Methyl iodide (0.16 mL, 2.6 mmol) was added, then the reaction was stirred for 4 hours. The reaction mixture was quenched by adding saturated aqueous ammonium chloride solution (15mL) and extracted with ethyl acetate (2 × 20mL). The combined organic extracts were washed with water (20 mL), saturated brine solution (20 mL), dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain the title compound as an oil (540 mg, 2.38 mmol, 92%).

[0191] 1H NMR (400 MHz, DMSO-d6) δ 4.17 (t, J = 1.8 Hz, 1H), 3.51 (s, 2H), 3.31 (s, 2H), 3.26 (s, 3H), 1.76 (dt, J = 4.2, 1.8 Hz, 2H), 1.39 (s, 9H), 1.32 (dd, J = 4.4, 1.9 Hz, 2H). 4-(Methoxymethyl)-2-azabicyclo[2.1.1]hexane;2,2,2-trifluoroacetic acid

[0192] tert-Butyl 4-(methoxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (540 mg, 2.38 mmol) was dissolved in DCM (10 mL) and trifluoroacetic acid (0.91 mL, 12 mmol) was added to it at 0 °C and the reaction mixture was stirred for 5 min. The reaction mixture was then warmed to room temperature and stirred for a further 4 h. The reaction mixture was then concentrated to dryness under reduced pressure to afford the title compound as an oil (560 mg, 2.32 mmol, 98%).

[0193] 1H NMR (400 MHz, DMSO-d6): δ 8.90 (s, 2H), 4.09 (td, J = 1.7, 0.9 Hz, 1H), 3.52 (s, 2H), 3.24 (s, 3H), 3.09 – 3.03 (m, 2H), 1.86 (d, J = 5.7 Hz, 2H), 1.47 – 1.38 (m, 2H). N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[4-(methoxymethyl)-2-azabicyclo[2.1.1]hexan-2- yl]pyrimidin-4-amine

[0194] 2-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (490 mg, 2.08 mmol), 4-(methoxymethyl)-2-azabicyclo[2.1.1]hexane;2,2,2-trifluoroacetic acid (502 mg, 2.08 mmol), and N,N-diisopropylethylamine (1.1 mL, 6.2 mmol) were dissolved in 1-butanol (10 mL) and the reaction mixture was heated at 115 °C and stirred for 24 h. The solvent was then evaporated under reduced pressure, and the crude material was extracted with 20% MeOH in DCM (2 × 50 mL). The combined organic extracts were washed with water (30 mL) followed by saturated aqueous brine solution (30 mL), dried over Na2SO4, then concentrated to dryness under reduced pressure. The residue was purified by reversed-phase basic preparative HPLC. The residue was dissolved in MeOH, then loaded onto an SCX-2 cartridge. The cartridge was washed with MeOH (20 mL), then the compound was eluted with 2 M NH3in MeOH (20 mL). The eluent was concentrated to dryness under reduced pressure to afford the title compound as a solid (150 mg, 0.460 mmol, 22%).

[0195] 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.31 (s, 1H), 7.80 (d, J = 5.7 Hz, 1H), 6.21 (s, 2H), 4.66 (t, J = 1.8 Hz, 1H), 3.55 (s, 2H), 3.30 (s, 2H), 3.26 (s, 3H), 1.82 (ddd, J = 16.1, 6.8, 3.8 Hz, 3H), 1.35 (dd, J = 4.3, 1.8 Hz, 2H), 0.92 – 0.84 (m, 2H), 0.66 – 0.57 (m, 2H).

[0196] UPLC-MS analysis: (4 min, basic method): R.t.: 1.36 min, m / z = 327.3 [M+H]+. Example 6. Synthesis of [2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.1.1]hexan-4-yl]methanol (Compound 5)

[0197] A solution of 2-azabicyclo[2.1.1]hexan-4-ylmethanol;hydrochloride (369 mg, 2.47 mmol), 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (485 mg, 2.06 mmol) and N,N-diisopropylethylamine (1.6 mL, 9.3 mmol) in NMP (8 mL) was heated to 120 °C, and stirred for 18 hours. The reaction mixture was then loaded on to a C18 cartridge then purified by basic reversed-phase column chromatography, eluting with a gradient of 1:4 MeCN:water (0.1% NH3) to 6:4 MeCN:water (0.1% NH3) to afford a solid.65 mg of this material was further purified by reversed-phase basic preparative HPLC to afford the title compound as a solid (22 mg, 70 µmol, 3%).

[0198] 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.32 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.38 – 6.05 (m, 2H), 4.72 – 4.64 (m, 2H), 3.64 (d, J = 4.9 Hz, 2H), 3.34 – 3.27 (m, 2H), 1.92 – 1.80 (m, 1H), 1.80 – 1.73 (m, 2H), 1.39 – 1.29 (m, 2H), 0.96 – 0.86 (m, 2H), 0.70 – 0.62 (m, 2H).

[0199] UPLC-MS (basic method, 4 min): Rt: 1.12 min, m / z = 313.2 [M+H]+. Example 7. Synthesis of 2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-N- methyl-2-azabicyclo[2.1.1]hexane-4-carboxamide (Compound 7)

[0200] To ethyl 2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.1.1]hexane-4-carboxylate (25 mg, 0.0705 mmol) was added 2.0 M methylamine in MeOH (8.0 mL) and the reaction mixture was stirred overnight at room temperature for 16 hours. The reaction mixure was then concentrated to dryness under reduced pressure to afford the title compound as a solid (24 mg, 70 µmol, 99%).

[0201] 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.34 (s, 1H), 7.85-7.78 (m, 2H), 6.33 – 6.03 (m, 2H), 4.64 – 4.59 (m, 1H), 3.50 (s, 2H), 2.58 (d, J = 4.6 Hz, 3H), 2.13 – 2.01 (m, 2H), 1.89 – 1.77 (m, 1H), 1.62 – 1.52 (m, 2H), 0.92 – 0.83 (m, 2H), 0.66 – 0.54 (m, 2H).

[0202] UPLC-MS (basic method, 4 min): Rt: 1.06 min, m / z = 340.3 [M+H]+. Example 8. Synthesis of N-(5-Cyclopentyl-1H-pyrazol-3-yl)-2-[1-(methoxymethyl)-3- azabicyclo[3.1.1]heptan-3-yl]pyrimidin-4-amine (Compound 8)tert-Butyl 1-(Methoxymethyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate

[0203] To a solution of tert-butyl 1-(hydroxymethyl)-3-azabicyclo[3.1.1]heptane-3- carboxylate (500 mg, 2.20 mmol) in dry THF (18 mL) under N2was added 60% w / w dispersionof sodium hydride in mineral oil (106 mg, 2.64 mmol), and the mixture was allowed to stir at RT for 15 minutes. To this mixture was added methyl iodide (0.14 mL, 2.2 mmol), and the reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL) followed by brine (50 mL). The organic layer was separated, dried over Na2SO4, then concentrated to dryness under reduced pressure to afford the title compound as an oil (477 mg, 1.98 mmol, 90%).

[0204] 1H NMR (400 MHz, Chloroform-d) δ 3.56 – 3.37 (m, 5H), 3.35 – 3.18 (m, 3H), 2.49 – 2.30 (m, 1H), 1.99 – 1.85 (m, 2H), 1.51 – 1.44 (m, 9H), 1.43 – 1.29 (m, 2H), 1.29 – 1.18 (m, 1H). 1-(Methoxymethyl)-3-azabicyclo[3.1.1]heptane

[0205] To tert-butyl 1-(methoxymethyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate (477 mg, 1.98 mmol) was added 4 M HCl in 1,4-dioxane (4.9 mL, 20 mmol). The resulting mixture was stirred at room temperature for 2 hours. The volatiles were removed under reduced pressure to afford an oil. The crude product was dissolved in methanol (5 mL) and loaded onto an SCX-2 cartridge. The cartridge was washed with MeOH (20 mL) then the compound was eluted with 2 M NH3in MeOH (20 mL). The eluent was concentrated to dryness under reduced pressure to afford the title compound as a solid (80 mg, 0.57 mmol, 29%).

[0206] 1H NMR (400 MHz, Chloroform-d) δ 3.46 (s, 1H), 3.35 (s, 1H), 3.30 (s, 2H), 3.12 (s, 1H), 3.07 – 3.02 (m, 2H), 3.00 – 2.95 (m, 2H), 2.30 – 2.23 (m, 1H), 1.95 – 1.84 (m, 2H), 1.56 – 1.40 (m, 2H).

[0207] UPLC-MS (basic method, 2 min): rt = 0.67 min, m / z = 142.0 [M+H]+N-(5-Cyclopentyl-1H-pyrazol-3-yl)-2-[1-(methoxymethyl)-3-azabicyclo[3.1.1]heptan-3- yl]pyrimidin-4-amine

[0208] To a solution of 2-chloro-N-(5-cyclopentyl-1H-pyrazol-3-yl)pyrimidin-4-amine (133 mg, 0.504 mmol) and 1-(methoxymethyl)-3-azabicyclo[3.1.1]heptane (82 mg, 0.58 mmol) in DMSO (4 mL) was added N,N-diisopropylethylamine (0.26 mL, 1.5 mmol). The resulting solution was then heated to 90 °C and stirred for 21 h. The reaction mixture was allowed to cool to room temperature and was then poured into ice water (200 mL), forming a precipitate. The precipitate was collected by filtration, then the filter cake was washed with water (10 mL), the dried under suction. The precipitate was purified by reversed-phase basic preparative HPLC to afford the title compound as a solid (22 mg, 60 µmol, 12%).

[0209] 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.42 (s, 1H), 7.87 (d, J = 5.7 Hz, 1H), 6.46 (s, 1H), 6.22 (s, 1H), 3.73 – 3.51 (m, 4H), 3.30 – 3.28 (m, 2H), 3.27 (s, 3H), 3.01 – 2.96 (m, 1H), 2.05 – 1.87 (m, 4H), 1.75 – 1.49 (m, 8H), 1.41 – 1.34 (m, 2H).

[0210] UPLC-MS (basic method, 4 min): rt = 1.82 min, m / z: 369.4 [M+H]+. Example 9. Synthesis of [(3R)-1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2- yl]-3-piperidyl]methanol (Compound 9)

[0211] A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (100 mg, 0.424 mmol), [(3R)-piperidin-3-yl]methanol hydrochloride (68 mg, 0.45 mmol), and N,N- diisopropylethylamine (0.22 mL, 1.3 mmol) in n-butanol (1.5 mL) was heated to reflux and stirred for 2 hours. The reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was suspended in water (50 mL), then extracted with a solution of 20% v / v MeOH in CH2Cl2 (2 × 50 mL). The combined organic extracts were dried over Na2SO4 then concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography, over silica gel, eluting with a gradient of CH2Cl2to 20% v / v CH2Cl2 in MeOH to afford the title compound as a solid (60 mg, 0.19 mmol, 45%).

[0212] 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.28 (s, 1H), 7.80 (d, J = 5.6 Hz, 1H), 6.14 (s, 1H), 6.08 (s, 1H), 4.59 (d, J = 12.8 Hz, 1H), 4.53 – 4.35 (m, 2H), 3.34 – 3.29 (m, 1H), 3.24 (dd, J = 11.1, 5.2 Hz, 1H), 2.78 (t, J = 12.1 Hz, 1H), 2.54 (t, J = 11.7 Hz, 1H), 1.81 (tt, J = 8.5, 5.1 Hz, 1H), 1.71 (d, J = 12.6 Hz, 1H), 1.62 (dd, J = 13.1, 3.5 Hz, 1H), 1.33 (q, J = 12.3 Hz, 1H), 1.13 (qd, J = 12.1, 3.8 Hz, 1H), 0.91 – 0.82 (m, 2H), 0.70 – 0.59 (m, 2H).

[0213] UPLC-MS (basic method, 4 mins): Rt: 1.32 min, m / z = 315.2 [M+H]+. Example 10. Synthesis of N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[(3S)-3-(methoxymethyl)-1- piperidyl]pyrimidin-4-amine (Compound 10)

[0214] To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (100 mg, 0.424 mmol) in n-butanol (1.5 mL) was added (3S)-3-(methoxymethyl)piperidine hydrochloride (74 mg, 0.45 mmol) and N,N-diisopropylethylamine (0.22 mL, 1.3 mmol), and the reaction mixture heated to reflux and stirred for 2 hours. The reaction mixture was allowed to cool to room temperature and concentrated to dryness under reduced pressure. The residue was suspended in water (50 mL) then extracted with 20% v / v MeOH in CH2Cl2(2 × 50 mL). The combined organic extracts were dried over Na2SO4 then concentrated to dryness under reduced pressure to afford the title compound as a solid (60 mg, 0.18 mmol, 43%).

[0215] 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 9.33 (s, 1H), 7.84 (d, J = 5.7 Hz, 1H), 6.36 – 5.94 (m, 2H), 4.66 – 4.37 (m, 2H), 3.25 (s, 3H), 3.24 – 3.16 (m, 2H), 2.83 (t, J = 12.1 Hz, 1H), 2.70 – 2.57 (m, 1H), 1.85 (tt, J = 8.4, 5.1 Hz, 1H), 1.78 – 1.58 (m, 3H), 1.39 (q, J = 12.2 Hz, 1H), 1.21 (dt, J = 12.7, 9.8 Hz, 1H), 0.96 – 0.83 (m, 2H), 0.70 – 0.62 (m, 2H).

[0216] UPLC-MS (basic method, 4 mins): Rt: 1.63 min, m / z = 329.2 [M+H]+. Example 11. Synthesis of N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[(3R)-3-(methoxymethyl)-1- piperidyl]pyrimidin-4-amine(Compound 11)

[0217] A solution of (3R)-3-(methoxymethyl)piperidine hydrochloride (127 mg, 0.764 mmol), 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (120 mg, 0.509 mmol), and N,N-diisopropylethylamine (270 µL, 1.53 mmol) in n-butanol (5 mL) was heated to 100 °C and stirred for 20 hours. The reaction mixture was concentrated to dryness under reducedpressure. The residue was suspended in water (40 mL) then extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were dried over MgSO4 then concentrated to dryness under reduced pressure. The residue was dissolved in MeOH (2 mL) then loaded onto an SCX-2 cartridge. The cartridge was washed with MeOH (40 mL) then the compound was eluted with 2 M NH3 in MeOH (50 mL). The eluent was concentrated to dryness under reduced pressure to afford the title compound as a solid (98 mg, 0.28 mmol, 55%).

[0218] 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.34 (s, 1H), 7.84 (d, J = 5.7 Hz, 1H), 6.33 – 5.89 (m, 2H), 4.59 (d, J = 12.9 Hz, 1H), 4.47 (d, J = 13.0 Hz, 1H), 3.31 (s, 3H), 3.24 – 3.17 (m, 2H), 2.83 (t, J = 12.2 Hz, 1H), 2.68 – 2.55 (m, 1H), 1.85 (tt, J = 8.4, 5.0 Hz, 1H), 1.78 – 1.54 (m, 3H), 1.48 – 1.31 (m, 1H), 1.20 (dt, J = 12.6, 9.1 Hz, 1H), 0.91 (dd, J = 8.3, 2.4 Hz, 2H), 0.72 – 0.52 (m, 2H).

[0219] UPLC-MS (basic method, 4 min): Rt: 1.63 min, m / z = 329.2 [M+H]+. Example 12. Synthesis of N-(5-Cyclopentyl-1H-pyrazol-3-yl)-2-[(3S)-3-(methoxymethyl)-1- piperidyl]pyrimidin-4-amine (Compound 12)

[0220] A solution of 2-chloro-N-(5-cyclopentyl-1H-pyrazol-3-yl)pyrimidin-4-amine (100 mg, 0.379 mmol), (3S)-3-(methoxymethyl)piperidine hydrochloride (66 mg, 0.34 mmol), and N,N-diisopropylethylamine (0.19 mL, 0.16 mmol) in n-butanol (0.5 mL) was heated at reflux and stirred for 2 hours. The reaction mixture was then cooled to room temperature and concentrated to dryness under reduced pressure. The residue was suspended in water (20 mL) then extracted with 20% v / v MeOH in CH2Cl2(2 × 50 mL). The combined organic extracts were dried over Na2SO4 then concentrated to dryness under reduced pressure to afford the title compound as a solid (52 mg, 0.14 mmol, 38%).

[0221] 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.34 (s, 1H), 7.84 (dd, J = 5.7, 1.6 Hz, 1H), 6.26 (s, 1H), 6.19 (s, 1H), 4.69 – 4.35 (m, 2H), 3.23 (q, J = 2.3 Hz, 4H), 3.01 (q, J = 8.0Hz, 1H), 2.83 (t, J = 12.1 Hz, 1H), 2.64 (t, J = 11.6 Hz, 1H), 1.99 (d, J = 9.5 Hz, 2H), 1.78 – 1.50 (m, 10H), 1.39 (q, J = 12.6 Hz, 1H), 1.23 (t, J = 11.9 Hz, 1H).

[0222] UPLC-MS (basic method, 4 mins): Rt: 1.50 min, m / z = 355.3 [M+H]+. Example 13. Synthesis of N-(5-Cyclopentyl-1H-pyrazol-3-yl)-2-[(3R)-3-(methoxymethyl)-1- piperidyl]pyrimidin-4-amine (Compound 13)

[0223] A solution of (3R)-3-(methoxymethyl)piperidine hydrochloride (127 mg, 0.764 mmol), 2-chloro-N-(5-cyclopentyl-1H-pyrazol-3-yl)pyrimidin-4-amine (134 mg, 0.509 mmol), and N,N-diisopropylethylamine (270 µL, 1.53 mmol) in n-butanol (4 mL) was heated to 100 °C and stirred for 20 hours. The reaction mixture was concentrated to dryness under reduced pressure. The residue was suspended in water (40 mL) then extracted with CH2Cl2(3 × 20 mL). The combined organic extracts were dried over MgSO4 then concentrated to dryness under reduced pressure. The residue was dissolved in MeOH (2 mL) then loaded onto an SCX-2 cartridge. The cartridge was washed with MeOH (40 mL) then the compound was eluted with 2 M NH3 in MeOH (50 mL). The eluent was concentrated to dryness under reduced pressure to afford the title compound as a solid (98 mg, 0.26 mmol, 51%).

[0224] 1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 9.36 (s, 1H), 7.80 (d, J = 5.7 Hz, 1H), 6.22 (s, 2H), 4.55 (d, J = 12.9 Hz, 1H), 4.45 (d, J = 13.0 Hz, 1H), 3.28 (s, 3H), 3.19 – 3.16 (m, 1H), 2.98 (dt, J = 15.6, 7.9 Hz, 1H), 2.84 – 2.74 (m, 1H), 2.67 – 2.55 (m, 1H), 1.95 (s, 2H), 1.77 – 1.43 (m, 10H), 1.42 – 1.26 (m, 1H), 1.24 – 1.12 (m, 1H).

[0225] UPLC-MS (basic method, 4 min): Rt: 1.87 min, m / z = 357.3 [M+H]+. Example 14. Synthesis of [(3S)-1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2- yl]pyrrolidin-3-yl]methanol (Compound 14)

[0226] A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (100 mg, 0.424 mmol), (S)-pyrrolidin-3-ylmethanol (64 mg, 0.64 mmol) and N,N- diisopropylethylamine (185 µL, 1.06 mmol) in n-butanol (2 mL) was heated to 110 °C and stirred for 3 hours. The volatiles were removed under reduced pressure, and residue was dissolved CH2Cl2 (10 mL). After stirring for 20 minutes, iso-hexane was added dropwise until a precipitate was formed and left for stirring for 30 minutes. The precipitate was collected by filtration then dried under reduced pressure to afford the title compound as a solid (52 mg, 0.17 mmol, 39%).

[0227] 1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 9.28 (s, 1H), 7.79 (d, J = 5.7 Hz, 1H), 6.33 – 6.03 (m, 2H), 4.63 (t, J = 5.2 Hz, 1H), 3.62 – 3.46 (m, 2H), 3.48 – 3.29 (m, 3H), 3.23 – 3.15 (m, 1H), 2.38 – 2.27 (m, 1H), 2.00 – 1.87 (m, 1H), 1.85 – 1.75 (m, 1H), 1.72 – 1.59 (m, 1H), 0.91 – 0.80 (m, 2H), 0.64 – 0.58 (m, 2H).

[0228] UPLC-MS (basic method, 4 mins): Rt: 1.13 min, m / z = 301.1 [M+H]+. Example 15. Synthesis of N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[(3R)-3- (methoxymethyl)pyrrolidin-1-yl]pyrimidin-4-amine (Compound 15)

[0229] A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (150 mg, 0.636 mmol), (R)-3-(methoxymethyl)pyrrolidine hydrochloride (116 mg, 0.764 mmol) and N,N-diisopropylethylamine (0.39 mL, 2.2 mmol) in n-butanol (2 mL) was heated to 100 °C andstirred for 18 hours. The reaction mixture was then diluted with water (20 mL), then extracted with 3:1 CHCl3:IPA (3 × 20 mL). The combined organic extracts were dried over Na2SO4, then concentrated to dryness under reduced pressure. The residue was purified by reversed-phase basic preparative HPLC to afford the title compound as a solid (124 mg, 0.394 mmol, 62%).

[0230] 1H NMR (400 MHz, Chloroform-d) δ 8.37 (s, 1H), 7.95 (d, J = 6.0 Hz, 1H), 6.05 (d, J = 6.0 Hz, 1H), 5.97 (s, 1H), 3.78 – 3.67 (m, 2H), 3.56 (dt, J = 10.9, 7.6 Hz, 1H), 3.42 – 3.38 (m, 2H), 3.38 – 3.31 (m, 4H), 2.59 (hept, J = 6.9 Hz, 1H), 2.11 (td, J = 12.2, 7.0 Hz, 1H), 1.88 (tt, J = 8.6, 5.2 Hz, 1H), 1.83 – 1.75 (m, 1H), 1.00 – 0.93 (m, 2H), 0.78 – 0.71 (m, 2H).

[0231] UPLC-MS (basic method, 4 min): Rt: 1.43 min, m / z = 315.2 [M+H]+. Example 16. Synthesis of Ammonium;2-[4-[(5-cyclopropyl-1H-pyrazol-3- yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexane-4-carboxylate (Compound 16)

[0232] To a solution of ethyl 2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]- 2-azabicyclo[2.1.1]hexane-4-carboxylate (100 mg, 0.282 mmol) in THF (3 mL) and MeOH (1 mL) was added 1.0 M aqueous sodium hydroxide solution (1.4 mL, 1.41 mmol) and the reaction mixture allowed to stir at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in MeOH then loaded onto an SCX-2 cartridge. The cartridge was washed with 1:1 MeCN / H2O (20 mL) then the compound was eluted with 2 M NH3 in MeOH. The solvent was removed under reduced pressure to give the title compound as a solid (92 mg, 0.268 mmol, 95%).

[0233] 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 7.86 (d, J = 5.7 Hz, 1H), 6.29 (s, 1H), 6.13 (s, 1H), 4.68 (d, J = 1.8 Hz, 1H), 3.57 (s, 2H), 2.19 – 2.13 (m, 2H), 1.92 – 1.81 (m, 1H), 1.71 – 1.60 (m, 2H), 0.96 – 0.85 (m, 2H), 0.70 – 0.62 (m, 2H).

[0234] UPLC-MS (basic method, 4 min): Rt: 0.92 min, m / z = 327.1 [M+H]+.Example 17: Synthesis of 2-[4-[(5-Cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-N- methyl-2-azabicyclo[2.1.1]hexane-4-carboxamide (Compound 30)

[0235] To ethyl 2-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.1.1]hexane-4-carboxylate (20 mg, 52 µmol) was added 2 M MeNH2in MeOH (8 mL) and the reaction stirred at room temperature for 18 hours. The reaction mixture was concentrated to dryness to afford the title compound as a solid (16 mg, 42 µmol, 81%).

[0236] 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.41 (s, 1H), 7.89 – 7.81 (m, 2H), 6.57 – 5.98 (m, 2H), 4.68 – 4.63 (m, 1H), 3.54 (s, 2H), 3.01 (p, J = 7.9 Hz, 1H), 2.62 (d, J = 4.6 Hz, 3H), 2.17 – 2.05 (m, 2H), 2.03 – 1.92 (m, 2H), 1.75 – 1.67 (m, 2H), 1.65 – 1.52 (m, 6H).

[0237] UPLC-MS (basic method, 4 min): Rt: 1.23, m / z = 368.3 [M+H]+. Example 18: Synthesis of [3-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3- azabicyclo[3.1.1]heptan-1-yl]methanol (Compound 20)3-azabicyclo[3.1.1]heptan-1-ylmethanol;hydrochloride

[0238] To tert-butyl 1-(hydroxymethyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate (998 mg, 4.39 mmol) was added 4 M HCl in 1,4-dioxane (10 mL, 43.9 mmol). The resulting mixture wasstirred at room temperature for 2 h. The reaction mixture was then concentrated to dryness under reduced pressure to afford the title compound as an oil (764 mg, 4.43 mmol, 100%).

[0239] 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 2H), 3.30 – 3.23 (m, 2H), 3.21 (s, 2H), 3.17 (t, J = 5.4 Hz, 2H), 2.35 (tq, J = 7.3, 2.4 Hz, 1H), 1.91 (td, J = 6.7, 2.5 Hz, 2H), 1.56 – 1.47 (m, 2H). [3-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3-azabicyclo[3.1.1]heptan-1- yl]methanol

[0240] To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (427 mg, 1.81 mmol) and 3-azabicyclo[3.1.1]heptan-1-ylmethanol hydrochloride (406 mg, 2.36 mmol) in NMP (15 mL) was added N,N-diisopropylethylamine (1.3 mL, 7.3 mmol). The reaction mixture was heated to 120 °C and stirred for 16 h. The reaction mixture was then cooled to room temperature, then added slowly onto ice water (ca.200 mL), precipitating a solid, and the solid was collected by filtration. The crude material was purified by reversed-phase column chromatography over C18-modified silica gel eluting with a gradient of 1:19 MeCN (0.1% NH3):water (0.1% NH3) to 19:1 MeCN (0.1% NH3):water (0.1% NH3). The crude residue was further purified by reversed-phase basic preparative HPLC to afford the title compound as a solid (8.8 mg, 27 µmol, 1%).

[0241] 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.34 (s, 1H), 7.87 (d, J = 5.7 Hz, 1H), 6.25 (s, 2H), 4.60 (t, J = 5.2 Hz, 1H), 3.75 – 3.49 (m, 4H), 1.92 (s, 2H), 1.84 (s, 1H), 1.32 – 1.25 (m, 2H), 0.90 (d, J = 8.1 Hz, 2H), 0.68 – 0.60 (m, 2H).

[0242] UPLC-MS (basic method, 4 min): rt = 1.27 min, m / z: 327.2 [M+H]+. Example 19: Synthesis of N-(5-cyclopentyl-1H-pyrazol-3-yl)-2-[1-(methoxymethyl)-3- azabicyclo[3.1.1]heptan-3-yl]pyrimidin-4-amine (Compound 41)N-(5-cyclopentyl-1H-pyrazol-3-yl)-2-[1-(methoxymethyl)-3-azabicyclo[3.1.1]heptan-3- yl]pyrimidin-4-amine

[0243] To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (305 mg, 1.29 mmol) and 1-(methoxymethyl)-3-azabicyclo[3.1.1]heptane (210 mg, 1.49 mmol) in DMSO (15 mL) was added N,N-diisopropylethylamine (0.90 mL, 5.2 mmol). The resulting solution was then heated to 90 °C and stirred for 20 h. The reaction mixture was allowed to cool to room temperature then poured into ice water (200 mL), forming a precipitate that was collected by filtration. The precipitate was washed with water, then dried to give a solid. The residue was purified by basic reversed-phase preparative HPLC to afford the title compound as a solid (57 mg, 0.17 mmol, 13%).

[0244] 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.38 (s, 1H), 7.87 (d, J = 5.7 Hz, 1H), 6.25 (s, 2H), 3.73 – 3.50 (m, 4H), 3.30 (s, 5H), 1.91 (s, 2H), 1.83 (s, 1H), 1.38 (d, J = 7.2 Hz, 2H), 0.91 (d, J = 8.1 Hz, 2H), 0.68 – 0.59 (m, 2H).

[0245] UPLC-MS (basic method, 4 min): Rt: 1.57 min, m / z = 341.3 [M+H]+. Example 20: Synthesis of 1-[2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]- 2-azabicyclo[2.1.1]hexan-4-yl]cyclopropanol (Compound 23)1-[2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexan-4- yl]cyclopropanol

[0246] 1.0 M solution of ethyl magnesium bromide in THF (1.7 mL, 1.69 mmol) was added dropwise over 10 min to a solution of ethyl 2-[4-[(5-cyclopropyl-1H-pyrazol-3- yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexane-4-carboxylate (60 mg, 0.169 mmol) and titanium (IV) isopropoxide (0.33 mL, 1.10 mmol) in THF (10 mL) at 0 °C under nitrogen atmosphere. The mixture was warmed to room temperature and stirred for 16 hours. Then the mixture was quenched with saturated aqueous ammonium chloride solution (2 mL) then diluted with 1:1 EtOAc:DCM (20 mL). After stirring for 20 minutes, the organic layer was partitionedoff, dried over Na2SO4 then concentrated to dryness under reduced pressure. The residue was purified by normal-phase flash column chromatography, over silica gel, eluting with 9:1 DCM:MeOH. The residue was then loaded onto an SCX-2 cartridge. The cartridge was washed with MeOH (20 mL) then the compound was eluted with 2 M NH3 in MeOH (20 mL). The eluent was concentrated to dryness under reduced pressure to afford the title compound as a solid (33 mg, 93 µmol, 55%).

[0247] 1H NMR (400 MHz, Chloroform-d) δ 7.83 (d, J = 5.9 Hz, 1H), 6.48 – 5.58 (m, 1H), 4.69 (t, J = 1.8 Hz, 1H), 2.81 (s, 3H), 1.87 – 1.75 (m, 1H), 1.74– 1.64 (m, 2H), 1.56 – 1.43 (m, 2H), 0.95 – 0.82 (m, 2H), 0.78 – 0.70 (m, 2H), 0.70 – 0.65 (m, 2H), 0.64 – 0.50 (m, 2H).

[0248] UPLC-MS (basic method, 4 min): Rt: 1.27 min, m / z = 339.2 [M+H]+. Example 21: Synthesis of 1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2- yl]pyrrolidine-3-carboxamide (Compound 49)1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidine-3-carboxamide

[0249] A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (150 mg, 0.636 mmol), 3-pyrrolidinecarboxamide hydrochloride (144 mg, 0.955 mmol) and N,N- diisopropylethylamine (0.50 mL, 2.9 mmol) in n-butanol (2 mL) was heated to 100 °C and stirred for 16 hours. The reaction mixture was diluted with water (10 mL) then the compound was extracted with 1:3 IPA:CHCl3(3 × 10 mL). The combined organic extracts were dried over Na2SO4, then concentrated to dryness under reduced pressure. The crude material was purified by normal-phase column chromatography, over silica gel, eluting with a gradient of MeOH (0% to 20%; v / v) in CH2Cl2to afford the title compound as a solid (142 mg, 0.453 mmol, 71%).

[0250] 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.33 (s, 1H), 7.79 (d, J = 5.8 Hz, 1H), 7.42 (s, 1H), 6.88 (s, 1H), 6.37 – 5.93 (m, 2H), 3.65 (dd, J = 10.9, 8.0 Hz, 1H), 3.60 – 3.51 (m, 1H), 3.49 – 3.33 (m, 2H), 2.95 (p, J = 7.6 Hz, 1H), 2.14 – 1.93 (m, 2H), 1.81 (tt, J = 8.5, 5.1 Hz, 1H), 0.92 – 0.81 (m, 2H), 0.65 – 0.58 (m, 2H).

[0251] UPLC-MS (basic method, 4 min): Rt: 0.99 min, m / z = 314.2 [M+H]+.\ Example 22: Synthesis of 1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2- yl]piperidine-3-carboxamide (Compound 43)1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]piperidine-3-carboxamide

[0252] A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (150 mg, 0.636 mmol), piperidine-3-carboxamide (98 mg, 0.76 mmol) and N,N-diisopropylethylamine (0.50 mL, 2.9 mmol) in n-butanol (2 mL) was heated to 100 °C and stirred for 16 hours. The reaction mixture was diluted with water (10 mL) then extracted with 3:1 CHCl3:IPA (3 × 15 mL). The combined organic extracts were dried over Na2SO4, then concentrated to dryness under reduced pressure. The residue was purified by normal-phase column chromatography over silica gel, eluting with a gradient of MeOH (0% to 20%; v / v) in CH2Cl2 to afford the title compound as a solid (156 mg, 0.477 mmol, 75%).

[0253] 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.34 (s, 1H), 7.86 (d, J = 5.7 Hz, 1H), 7.32 (s, 1H), 6.83 (s, 1H), 6.23 (s, 1H), 6.06 (s, 1H), 4.69 – 4.61 (m, 1H), 4.61 – 4.54 (m, 1H), 2.89 – 2.70 (m, 2H), 2.30 – 2.18 (m, 1H), 1.93 – 1.78 (m, 2H), 1.71 – 1.52 (m, 2H), 1.44 – 1.27 (m, 1H), 0.95 – 0.85 (m, 2H), 0.70 – 0.59 (m, 2H).

[0254] UPLC-MS (basic method, 4 min): Rt: 1.09 min, m / z = 328.3 [M+H]+. Example 23: Synthesis of 1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-N- methyl-piperidine-3-carboxamide (Compound 44)1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-N-methyl-piperidine-3- carboxamide

[0255] To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (286 mg, 1.21 mmol) and piperidine-3-carboxylic acid methylamide hydrochloride (249 mg, 1.40 mmol) in n-butanol (12 mL) was added N,N-diisopropylethylamine (1.1 mL, 6.1 mmol). The reaction mixture was heated to 100 °C and allowed to stir for 20 h. The reaction mixture was concentrated under reduced pressure and diluted with water (30 mL). DCM (20 mL) was added to the resulting mixture, forming a precipitate that was filtered and isolated. The solid was dissolved in methanol (1 mL) and loaded onto an SCX-2 cartridge. The cartridge was washed with MeOH (20 mL) then the compound was eluted with 2 M NH3in MeOH (20 mL). The volatiles were removed under reduced pressure to afford the title compound as a powder (119 mg, 0.332 mmol, 27%).

[0256] 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 9.37 (s, 1H), 7.85 (dd, J = 7.2, 5.1 Hz, 2H), 6.20 (s, 1H), 6.05 (s, 1H), 4.62 (t, J = 13.8 Hz, 2H), 2.82 (t, J = 11.2 Hz, 1H), 2.74 (t, J = 12.2 Hz, 1H), 2.58 (d, J = 4.5 Hz, 3H), 2.29 – 2.18 (m, 1H), 1.88 – 1.77 (m, 2H), 1.69 – 1.55 (m, 2H), 1.42 – 1.27 (m, 1H), 0.95 – 0.86 (m, 2H), 0.70 – 0.58 (m, 2H).

[0257] UPLC-MS (basic method, 4 min): rt = 1.14 min, m / z: 342.3 [M+H]+. Example 24: Synthesis of [3-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3- azabicyclo[3.1.1]heptan-1-yl]methanol (Compound 21)[3-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3-azabicyclo[3.1.1]heptan-1- yl]methanol

[0258] To a solution of 2-chloro-N-(5-cyclopentyl-1H-pyrazol-3-yl)pyrimidin-4-amine (389 mg, 1.47 mmol) and 3-azabicyclo[3.1.1]heptan-1-ylmethanol hydrochloride (330 mg, 1.92 mmol) in NMP (15 mL) was added N,N-diisopropylethylamine (1.0 mL, 5.9 mmol). The reaction mixture was heated to 120 °C and stirred for 16 h. The reaction mixture was added slowly to ice water (ca.200 mL), precipitating a solid, and the solid was collected by filtration. The crude material was purified by reversed-phase column chromatography over C18-modified silica gel eluting with a gradient of 1:19 MeCN (0.1% NH3):water (0.1% NH3) to 19:1 MeCN (0.1% NH3):water (0.1% NH3). The crude residue was further purified by reversed-phase basic preparative HPLC to afford the title compound as a solid (56 mg, 0.16 mmol, 11%).

[0259] 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.37 (s, 1H), 7.87 (d, J = 5.7 Hz, 1H), 6.44 (s, 1H), 6.24 (s, 1H), 4.59 (s, 1H), 3.78 – 3.60 (m, 2H), 3.60 – 3.49 (m, 2H), 3.00 (t, J = 7.7 Hz, 1H), 1.96 (d, J = 17.3 Hz, 4H), 1.77 – 1.50 (m, 8H), 1.29 (s, 2H).

[0260] UPLC-MS (basic method, 4 min): rt = 1.50 min, m / z: 355.3 [M+H]+. Example 25: Synthesis of ethyl 2-[4-[(5-Cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2- yl]-2-azabicyclo[2.1.1]hexane-4-carboxylate (Compound 37)Ethyl 2-[4-[(5-Cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.1.1]hexane-4-carboxylate

[0261] To ethyl 2-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.1.1]hexane-4-carboxylate (345 mg, 1.31 mmol) in NMP (2.5 mL) was added N,N- diisopropylethylamine (0.68 mL, 3.9 mmol) and ethyl 2-azabicyclo[2.1.1]hexane-4-carboxylate hydrochloride (301 mg, 1.57 mmol) and the reaction mixture heated at 120 °C. After 18 hours the reaction mixture was allowed to cool to room temperature and purified by reversed phase automated flash column chromatography on a C18 cartridge, eluting with MeCN (1:4 to 3:2) in water to give the title compound as a solid (411 mg, 1.07 mmol, 82%).

[0262] 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 9.45 (s, 1H), 7.86 (d, J = 5.7 Hz, 1H), 6.30 (s, 2H), 4.70 (t, J = 1.8 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.62 (s, 2H), 3.01 (p, J = 7.9 Hz, 1H), 2.19 (dt, J = 4.1, 1.9 Hz, 2H), 2.06 – 1.93 (m, 2H), 1.74 – 1.67 (m, 4H), 1.65 – 1.50 (m, 5H), 1.22 (t, J = 7.1 Hz, 3H).

[0263] UPLC-MS (basic method, 4 min): Rt: 1.70, m / z = 383.4 [M+H]+. Example 26: Synthesis of [(3R)-1-[4-[(5-Cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2- yl]-3-piperidyl]methanol (Compound 70)

[0264] 2-chloro-N-(5-cyclopentyl-1H-pyrazol-3-yl)pyrimidin-4-amine (100 mg, 0.379 mmol), [(3R)-piperidin-3-yl]methanol hydrochloride (60 mg, 0.40 mmol), and N,N- diisopropylethylamine (0.20 mL, 1.1 mmol) were dissolved in n-butanol (1.5 mL) and the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled to room temperature and evaporated to dryness under reduced pressure. The residue was diluted with water (50 mL), then extracted with 20% MeOH in DCM (2 × 50 mL). The combined organic extracts were dried over Na2SO4, then concentrated to dryness under reduced pressure. The residue was dissolved in methanol, then loaded onto an SCX-2 cartridge. The cartridge was washed with methanol, then the compound was eluted with 2 M NH3 in methanol. The eluentwas concentrated to dryness under reduced pressure to afford the title compound as a solid (40 mg, 0.12 mmol, 31%).

[0265] 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.29 (s, 1H), 7.80 (d, J = 5.7 Hz, 1H), 6.21 (s, 2H), 4.58 (d, J = 12.9 Hz, 1H), 4.45 (t, J = 5.2 Hz, 2H), 3.23 (dt, J = 10.7, 5.1 Hz, 1H), 2.96 (q, J = 8.2 Hz, 1H), 2.78 (t, J = 12.1 Hz, 1H), 2.55 (t, J = 11.7 Hz, 1H), 2.02 – 1.83 (m, 2H), 1.74 – 1.42 (m, 9H), 1.32 (t, J = 12.4 Hz, 1H), 1.17 (dtd, J = 23.6, 12.1, 7.1 Hz, 1H).

[0266] UPLC-MS analysis: (4 min, basic): rt = 1.55 min, m / z = 343.2 [M+H]+. Example 27: Synthesis of 2-[2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]- 2-azabicyclo[2.1.1]hexan-4-yl]propan-2-ol (Compound 22)

[0267] To a stirred solution of ethyl 2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin- 2-yl]-2-azabicyclo[2.1.1]hexane-4-carboxylate (20 mg, 56 µmol) in THF (2 mL) was added 3.4 M solution of methylmagnesium in 2-methyltetrahydrofuran (191 µL, 0.564 mmol) under nitrogen atmosphere. The reaction mixture was stirred for 4 hours. Afterwards, the reaction was quenched with saturated aqueous ammonium chloride solution (2 mL), diluted with 1:1 ethyl acetate:DCM (10 mL), dried over sodium sulfate, then concentrated to dryness under reduced pressure.

[0268] In a separate reaction flask, to a stirred solution of ethyl 2-[4-[(5-cyclopropyl-1H- pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexane-4-carboxylate (5.0 mg, 14 µmol) in THF (1 mL) was added 3.4 M solution of methylmagnesium bromide in 2- methyltetrahydrofuran (48 µL, 0.141 mmol) under nitrogen atmosphere. Reaction mixture wasstirred for 5 hours. The reaction was quenched with water (5 mL), diluted with 1:1 v / v ethyl acetate:DCM (5 mL), dried over sodium sulfate, then concentrated to dryness under reduced pressure.

[0269] The residual products from both reactions were combined, then dissolved in methanol (2 mL) then loaded onto an SCX-2 cartridge. The cartridge was washed with MeOH (20 mL) then the compound was eluted with 2 M NH3in MeOH (20 mL). The eluent was concentrated to dryness under reduced pressure to afford the title compound as a solid (24 mg, 71 µmol, 99%).

[0270] 1H NMR (400 MHz, Methanol-d4) δ 7.79 (d, J = 6.0 Hz, 1H), 6.14 (s, 2H), 4.71 (t, J = 1.8 Hz, 1H), 3.45 (s, 2H), 2.00 – 1.92 (m, 2H), 1.91 – 1.79 (m, 1H), 1.46 (dd, J = 4.5, 1.9 Hz, 2H), 1.24 (s, 6H), 1.00 – 0.90 (m, 2H), 0.73 – 0.65 (m, 2H).

[0271] UPLC MS (2 minute, basic method) rt = 1.27 min m / z = 341.2 [M+H]+. Example 28: Synthesis of [(3R)-1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2- yl]pyrrolidin-3-yl]methanol (Compound 24)

[0272] A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (150 mg, 0.636 mmol), (R)-pyrrolidin-3-ylmethanol (99 µL, 0.96 mmol) and N,N- diisopropylethylamine (277 µL, 1.59 mmol) in n-butanol (2 mL) was heated to 100 °C and stirred for 16 hours. The reaction mixture was diluted with water (20 mL) then the compound was extracted with 1:3 IPA:CHCl3(3 × 20 mL). The combined organic extracts were dried over Na2SO4, then concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography, over silica gel, eluting with a gradient of MeOH (0% to 20%; v / v) in DCM to afford the title compound as a solid (155 mg, 0.516 mmol, 81%).

[0273] 1H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 6.27 (s, 1H), 6.12 (s, 1H), 3.76 – 3.40 (m, 5H), 3.36 – 3.29 (m, 1H), 2.52 – 2.44 (m, 1H), 2.12 – 2.06 (m, 1H), 1.91 – 1.68 (m, 2H), 0.96 – 0.92 (m, 2H), 0.72 – 0.66 (m, 2H).

[0274] UPLC-MS (4 min, basic method): Rt: 1.12 min, m / z = 301.1 [M+H]+. Example 29: Synthesis of 2-(tert-butyl) 4-methyl 2-azabicyclo[2.1.1]hexane-2,4- dicarboxylate (Compound 26)2-(tert-Butyl) 4-methyl 2-azabicyclo[2.1.1]hexane-2,4-dicarboxylate

[0275] To a solution of 2-[(tert-butoxy)carbonyl]-2-azabicyclo[2.1.1]hexane-4-carboxylic acid (500 mg, 2.20 mmol) in MeOH (5 mL) as added (trimethylsilyl)diazomethane (2 M in diethyl ether, 2.2 mL, 4.40 mmol) at room temperature. The reaction mixture was stirred for 1 hour. After 1 hour, (trimethylsilyl)diazomethane (2 M in diethyl ether, 2.2 mL, 4.40 mmol) was added again in a dropwise manner and the reaction mixture stirred for 18 hours. The reaction mixture was quenched with AcOH (1 mL) then a 2 M aqueous solution of citric acid (10 mL). After stirring for 10 minutes, reaction mixture was diluted with ethyl acetate (200 mL) and washed with saturated aqueous NaHCO3 solution (2 × 200 mL) followed by brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a solid (525 mg, 2.17 mmol, 99% yield).

[0276] 1H NMR (400 MHz, CDCl3) δ 4.25 (s, 1H), 3.65 (d, J = 0.7 Hz, 3H), 3.42 (s, 2H), 2.16 – 2.05 (m, 2H), 1.69 – 1.59 (m, 2H), 1.46 – 1.29 (m, 9H).

[0277] UPLC-MS (2 min, basic): Rt: 1.05 min, m / z = 142.0 [M-Boc+H+]. tert-Butyl 4-(1-hydroxy-1-methyl-ethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

[0278] To a solution of 2-(tert-Butyl) 4-methyl 2-azabicyclo[2.1.1]hexane-2,4-dicarboxylate (525 mg, 2.18 mmol) in THF (8 mL) was added methylmagnesium bromide 3 M in diethyl ether (4.4 mL, 13.1 mmol) in dropwise manner at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 18 hours then quenched with saturated aqueous NH4Cl solution (2 mL) and extracted with EtOAc (2 × 10 mL) and the organics washed with brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as an oil (450 mg, 1.86 mmol, 86% yield).

[0279] 1H NMR (400 MHz, CDCl3) δ 4.41 – 4.06 (m, 1H), 3.20 (s, 2H), 1.82 – 1.72 (m, 2H), 1.41 (s, 9H), 1.39 – 1.33 (m, 2H), 1.24 – 1.14 (m, 6H). tert-Butyl 4-(1-methoxy-1-methyl-ethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

[0280] To a solution of tert-butyl 4-(1-hydroxy-1-methyl-ethyl)-2-azabicyclo[2.1.1]hexane- 2-carboxylate (450 mg, 1.86 mmol) in THF (4.5 mL) was added sodium hydride, 60% in mineral oil (224 mg, 5.59 mmol) in portion wise manner at 0 °C. After stirring for 20 minutes, methyl iodide (0.35 mL, 5.59 mmol) was added and the reaction mixture stirred for 18 hours at room temperature. The reaction mixture was quenched saturated aqueous NH4Cl solution (5 mL) and extracted with ethyl acetate (2 × 20 mL) and the organics washed with brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as an oil (450 mg, 1.76 mmol, 95% yield).

[0281] 1H NMR (400 MHz, CDCl3) δ 4.25 (s, 1H), 3.25 (s, 2H), 3.18 (s, 3H),1.84 – 1.74 (m, 2H), 1.44 (s, 9H), 1.42 – 1.37 (m, 2H), 1.14 (s, 6H). 4-(1-Methoxy-1-methyl-ethyl)-2-azabicyclo[2.1.1]hexane hydrochloride

[0282] To a solution of tert-butyl 4-(1-methoxy-1-methyl-ethyl)-2-azabicyclo[2.1.1]hexane- 2-carboxylate (450 mg, 1.76 mmol) in 1,4-dioxane (5 mL) was added 4 N HCl in 1,4-dioxane (4.5 mL, 1.76 mmol). The reaction mixture was stirred for 3 hours at room temperature then concentrated under reduced pressure. The residue was triturated in Et2O to afford the title compound as a solid (330 mg, 1.72 mmol, 98% yield).

[0283] 1H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 4.16 – 4.11 (m, 1H), 3.32 – 3.23 (m, 2H), 3.13 (s, 3H), 1.92 – 1.84 (m, 2H), 1.80 – 1.67 (m, 2H), 1.11 (s, 6H). N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[4-(1-methoxy-1-methyl-ethyl)-2- azabicyclo[2.1.1]hexan-2-yl]pyrimidin-4-amine

[0284] To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (300 mg, 1.27 mmol) and 4-(1-methoxy-1-methyl-ethyl)-2-azabicyclo[2.1.1]hexane;hydrochloride (293 mg, 1.53 mmol) in 1-butanol (6 mL) was added N,N-diisopropylethylamine (1.1 mL, 6.4 mmol) under a nitrogen atmosphere. The reaction mixture was heated to 120 °C and stirred for 18 hours. The reaction mixture was allowed to cool to room temperature then concentrated under reduced pressure. The residue was purified by column chromatography eluting with MeOH (0% to 10% v / v) in CH2Cl2 to afford a solid, which was subsequently purified by SCX-2 cartridge, washing with MeOH and eluting with 2 M NH3 in MeOH to afford the title compound as a solid (81 mg, 0.22 mmol, 17% yield).

[0285] 1H NMR (400 MHz, CDCl3) δ 7.83 – 7.71 (m, 1H), 5.97 (d, J = 5.6 Hz, 1H), 5.88 (s, 1H), 4.67 – 4.61 (m, 1H), 3.46 – 3.40 (m, 2H), 3.19 – 3.13 (m, 3H), 1.91 – 1.84 (m, 2H), 1.83 – 1.64 (m, 1H), 1.50 – 1.40 (m, 2H), 1.17 – 1.11 (m, 6H), 0.92 – 0.81 (m, 2H), 0.69 – 0.59 (m, 2H).

[0286] UPLC MS (4 min, basic method): Rt: 1.55 min, m / z = 355.3 [M+H+]. Example 30: Synthesis of N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[4-(1-methoxycyclopropyl)- 2-azabicyclo[2.1.1]hexan-2-yl]pyrimidin-4-amine (Compound 27)tert-Butyl 4-(1-hydroxycyclopropyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

[0287] To a solution of 2-(tert-butyl) 4-methyl 2-azabicyclo[2.1.1]hexane-2,4-dicarboxylate (370 mg, 1.53 mmol) and chlorotriisopropoxytitanium(IV) (2.40 g, 9.20 mmol) in THF was added ethylmagnesium bromide (15 mL, 15.3 mmol, 1 M in THF) in a dropwise manner over 10 min at 0 °C under nitrogen atmosphere and dark conditions. The reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was quenched with saturated aqueous NH4Cl solution (5 mL) and diluted with EtOAc (20 mL) and stirred for 15 minutes. The organic layer was separated, and aqueous layer was extracted with EtOAc (20 mL) and the combined organics were washed with brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as an oil (340 mg, 1.42 mmol, 93% yield).

[0288] 1H NMR (400 MHz, CDCl3) δ 4.25 (s, 1H), 4.12 – 4.00 (m, 1H), 3.30 – 3.16 (m, 2H), 2.05 – 1.95 (m, 2H), 1.49 – 1.32 (m, 9H), 1.27 – 1.13 (m, 2H), 0.83 – 0.67 (m, 2H), 0.61 – 0.46 (m, 2H).

[0289] UPLC-MS (2 min, basic method): Rt: 0.98 mins, m / z = 240.1 [M+H+]. tert-Butyl 4-(1-methoxycyclopropyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

[0290] To a solution of tert-butyl 4-(1-hydroxycyclopropyl)-2-azabicyclo[2.1.1]hexane-2- carboxylate (400 mg, 1.67 mmol) in THF (8 mL) was added sodium hydride, 60% in mineral oil(201 mg, 5.01 mmol) at 0 °C under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction was cooled to 0 °C and methyl iodide (0.31 mL, 5.01 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours, then quenched with saturated aqueous NH4Cl solution (10 mL) and extracted with EtOAc (3 x 20 mL). The organic layer was washed with brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as an oil (412 mg, 1.63 mmol, 97% yield).

[0291] 1H NMR (400 MHz, CDCl3) δ 4.29 (s, 1H), 3.35 (s, 2H), 3.26 (s, 3H), 1.70 – 1.60 (m, 2H), 1.50 – 1.45 (m, 2H), 1.44 (s, 9H), 0.81 – 0.73 (m, 2H), 0.61 – 0.46 (m, 2H). 4-(1-Methoxycyclopropyl)-2-azabicyclo[2.1.1]hexane;hydrochloride

[0292] To a solution of tert-butyl 4-(1-methoxycyclopropyl)-2-azabicyclo[2.1.1]hexane-2- carboxylate (412 mg, 1.63 mmol) in 1,4-dioxane (8 mL) at room temperature was added 4 N HCl in 1,4-dioxane (4.1 mL, 16.3 mmol) and the reaction mixture stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue triturated in Et2O to afford the title compound as a semi-solid (295 mg, 1.56 mmol, 96% yield).

[0293] 1H NMR (400 MHz, CDCl3) δ 3.24 (s, 3H), 1.91 – 1.81 (m, 2H), 1.81 – 1.74 (m, 2H), 0.90 – 0.81 (m, 3H), 0.82 – 0.75 (m, 2H), 0.58 – 0.50 (m, 2H). N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[4-(1-methoxycyclopropyl)-2-azabicyclo[2.1.1]hexan- 2-yl]pyrimidin-4-amine

[0294] To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (200 mg, 0.849 mmol) and 4-(1-methoxycyclopropyl)-2-azabicyclo[2.1.1]hexane hydrochloride (193 mg, 1.02 mmol) in 1-butanol (4 mL) was added N,N-diisopropylethylamine (0.74 mL, 4.24 mmol) and the reaction mixture heated to 120 °C for 18 hours under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with MeOH (0% to 3% v / v) in CH2Cl2then by SCX-2 cartridge, washing with MeOH and eluting with 2 M NH3in MeOH to afford the title compound as a solid (65 mg, 0.184 mmol, 22% yield).

[0295] 1H NMR (400 MHz, CDCl3) δ 7.94 – 7.86 (m, 1H), 6.06 (s, 2H), 4.77 – 4.71 (m, 1H), 3.57 (s, 2H), 3.30 (s, 3H), 2.02 – 1.77 (m, 1H), 1.87 – 1.63 (m, 2H), 1.60 – 1.50 (m, 2H), 0.98 – 0.88 (m, 2H), 0.85 – 0.78 (m, 2H), 0.77 – 0.66 (m, 2H), 0.65 – 0.53 (m, 2H).

[0296] UPLC MS (6 min, basic method): Rt = 2.51 min, m / z = 353.1 [M+H+].Example 31: Synthesis of [2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.2.1]heptan-4-yl]methanol (Compound 28)[2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptan-4- yl]methanol

[0297] A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (100 mg, 0.424 mmol), (±)-2-azabicyclo[2.2.1]heptan-4-ylmethanol (65 mg, 0.509 mmol) and N,N- diisopropylethylamine (0.18 mL, 1.06 mmol) in 1-butanol (16 mL) was heated to 100 °C and stirred for 24 hours. The reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with water (50 mL) then extracted with 3:1 CHCl3:IPA (3 × 50 mL). The combined organic extracts were dried over Na2SO4, then concentrated to dryness under reduced pressure. The residue was purified by column chromatography over silica gel eluting with a gradient of MeOH (0% to 20% v / v) in DCM to afford the title compound as a solid (109 mg, 0.334 mmol, 79%).

[0298] 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.31 (s, 1H), 7.80 (d, J = 5.7 Hz, 1H), 6.37 – 5.99 (m, 2H), 4.68 (s, 1H), 4.50 (s, 1H), 3.62 (s, 2H), 3.16 – 3.04 (m, 1H), 1.90 – 1.79 (m, 1H), 1.79 – 1.50 (m, 4H), 1.44 – 1.26 (m, 2H), 0.97 – 0.84 (m, 2H), 0.71 – 0.56 (m, 2H).

[0299] UPLC-MS (4 min, basic method): Rt: 1.22 min, m / z = 327.2 [M+H]+. Example 32: Synthesis of N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[4-(methoxymethyl)-2- azabicyclo[2.2.1]heptan-2-yl]pyrimidin-4-amine (Compound 29)tert-Butyl 4-(methoxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0300] To a stirred solution of tert-butyl 4-(bromomethyl)-2-azabicyclo[2.2.1]heptane-2- carboxylate (200 mg, 0.689 mmol) in methanol (2 mL) was added 5.4 M solution of sodium methoxide in methanol (4.1 mL, 22 mmol) and sodium iodide (108 mg, 0.724 mmol). The reaction mixture was heated to 80 °C and stirred for 16 hours. Another batch of 5.4 M solution of sodium methoxide in methanol (2.0 mL, 11 mmol) was added and reaction mixture was left for stirring at 80 °C for another 6 hours. The volatiles were removed under reduced pressure. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were dried over sodium sulfate and evaporated under reduced pressure to afford the title compound as an oil (146 mg, 0.605 mmol, 88%).

[0301] UPLC-MS (2 min, basic method, ELS detector), rt = 1.14 min, m / z = 242.2 [M+H]+. 4-(Methoxymethyl)-2-azabicyclo[2.2.1]heptane hydrochloride

[0302] To a stirred solution of tert-butyl 4-(methoxymethyl)-2-azabicyclo[2.2.1]heptane-2- carboxylate (146 mg, 0.605 mmol) in dichloromethane (2 mL) was added 4 M hydrogen chloride solution in 1,4-dioxane (1.5 mL, 0.61 mmol) at 0 °C. The reaction mixture was stirred for 2 hours at room temperature. The volatiles were removed under reduced pressure to afford the title compound as an amorphous solid (102 mg, 0.574 mmol, 95%).

[0303] 1H NMR (400 MHz, Methanol-d4) δ 4.05 – 3.99 (m, 1H), 3.61 – 3.51 (m, 2H), 3.34 (s, 3H), 3.16 – 3.07 (m, 1H), 3.04 – 2.97 (m, 1H), 1.97 – 1.83 (m, 2H), 1.84 – 1.74 (m, 1H), 1.73 – 1.55 (m, 3H).

[0304] UPLC MS (2 min, basic method,), rt = 0.39 min, m / z = 142.0 [M+H]+.N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[4-(methoxymethyl)-2-azabicyclo[2.2.1]heptan-2- yl]pyrimidin-4-amine

[0305] To a stirred solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4- amine (100 mg, 0.424 mmol) and 4-(methoxymethyl)-2-azabicyclo[2.2.1]heptane hydrochloride (90 mg, 0.51 mmol) in n-butanol (1 mL) was added N,N-diisopropylethylamine (0.37 mL, 2.1 mmol). The reaction mixture was heated to 120 °C and stirred for 4 hours under a nitrogen atmosphere. After 4 hours, the reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The residue obtained was diluted with dichloromethane (10 mL) and water (2 mL). The layers were partitioned, then aqueous layer was further extracted with dichloromethane (2 × 10 mL). Combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by normal-phase column chromatography, over silica gel, eluting with 93:7 v / v dichloromethane:methanol. The residue was dissolved in MeOH, then loaded onto an SCX-2 cartridge. The cartridge was washed with MeOH (10 mL) then the compound was eluted with 2 M NH3 in MeOH (20 mL). The eluent was concentrated to dryness under reduced pressure to afford the title compound as a solid (60 mg, 0.17 mmol, 39%).

[0306] 1H NMR (400 MHz, Chloroform-d) δ 7.82 – 7.72 (m, 1H), 5.96 – 5.87 (m, 2H), 4.51 (d, J = 10.3 Hz, 1H), 3.51 (d, J = 7.1 Hz, 2H), 3.38 – 3.28 (m, 3H), 3.17 (s, 1H), 1.95 – 1.87 (m, 2H), 1.84 – 1.71 (m, 3H), 1.66 – 1.57 (m, 2H), 1.48 – 1.37 (m, 2H), 0.92 – 0.78 (m, 2H), 0.71 – 0.58 (m, 2H).

[0307] UPLC MS (2 min, basic method,) rt = 0.98 min, m / z = 341.2 [M+H+]. Example 33: Synthesis of 2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]- N,N-dimethyl-2-azabicyclo[2.1.1]hexane-4-carboxamide (Compound 36)tert-Butyl 4-(dimethylcarbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

[0308] To 2-tert-butoxycarbonyl-2-azabicyclo[2.1.1]hexane-4-carboxylic acid (100 mg, 0.440 mmol) in anhydrous THF (3 mL) was added N,N'-carbonyldiimidazole (107 mg, 0.660 mmol). After 4 hours, a solution of dimethylamine (2 M in THF, 0.44 mL, 0.88 mmol) was added and the reaction mixture stirred at room temperature. After 18 hours the reaction mixture was concentrated under reduced pressure, diluted with water (15 mL) and extracted with EtOAc (2 x 20 mL), and the combined organics washed with brine (20 mL). The organics were separated, and dried over anhydrous Na2SO4to give the title compound (104 mg, 0.409 mmol, 93% yield) as a solid.

[0309] 1H NMR (400 MHz, DMSO-d6) δ 4.10 (t, J = 1.8 Hz, 1H), 3.32 (s, 3H), 2.92 (s, 3H), 2.82 (s, 3H), 2.10 – 2.04 (m, 2H), 1.71 – 1.61 (m, 2H), 1.40 (s, 9H).

[0310] UPLC-MS (basic method, 2 min): Rt: 0.91 min, m / z = 199.1 [M–t-Bu+H]+. N,N-Dimethyl-2-azabicyclo[2.1.1]hexane-4-carboxamide

[0311] To tert-butyl 4-(dimethylcarbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (99 mg, 0.39 mmol) in CH2Cl2(4 mL) was added trifluoroacetic acid (1.5 mL, 19.5 mmol) and the reaction mixture left to stir at room temperature. After 2 hours the reaction mixture was concentrated under reduced pressure. The residue was taken up in MeOH and loaded onto an SCX-2 cartridge. The cartridge was washed with MeOH, then the compound was eluted with 2 M NH3 in MeOH. The eluent was concentrated to dryness under reduced pressure to afford title compound as an oil (62 mg, 0.40 mmol, 100%).

[0312] 1H NMR (400 MHz, DMSO-d6) δ 3.40 – 3.35 (m, 1H), 2.90 (s, 3H), 2.85 (s, 2H), 2.80 (s, 3H), 1.84 – 1.79 (m, 2H), 1.51 – 1.47 (m, 2H).

[0313] UPLC-MS (basic method, 2 min): Rt: 0.37 min, m / z = 155.1 [M+H]+. 2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-N,N-dimethyl-2- azabicyclo[2.1.1]hexane-4-carboxamide

[0314] To N,N-dimethyl-2-azabicyclo[2.1.1]hexane-4-carboxamide (30 mg, 0.20 mmol) in 1- butanol (2 mL) was added N,N-diisopropylethylamine (0.10 mL, 0.58 mmol) and 2-chloro-N-(5- cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (39 mg, 0.17 mmol), and the reaction mixture heated to reflux. After 18 hours the reaction mixture was allowed to cool to room temperature and diluted with CH2Cl2(10 mL) and washed with water (10 mL) and brine (10 mL). The organics were separated and dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by reversed-phase basic preparative HPLC to give the title compound as a solid (18 mg, 50 µmol, 27%).

[0315] 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.40 (s, 1H), 7.86 (d, J = 5.7 Hz, 1H), 4.62 (s, 1H), 3.55 (s, 2H), 2.95 (s, 3H), 2.85 (s, 3H), 2.16 – 2.11 (m, 2H), 1.93 – 1.82 (m, 1H), 1.78 – 1.68 (m, 2H), 0.94 – 0.88 (m, 2H), 0.71 – 0.61 (m, 2H). (Note: 2H missing due to broad nature of the peaks, usually seen around 6 ppm.)

[0316] UPLC-MS (basic method, 4 min): Rt: 1.17 min, m / z = 354.2 [M+H]+. Example 34: Synthesis of N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[4-(isopropoxymethyl)-2- azabicyclo[2.1.1]hexan-2-yl]pyrimidin-4-amine (Compound 38)N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[4-(isopropoxymethyl)-2-azabicyclo[2.1.1]hexan-2- yl]pyrimidin-4-amine

[0317] A suspension of 2-[4-(chloromethyl)-2-azabicyclo[2.1.1]hexan-2-yl]-N-(5- cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (150 mg, 0.453 mmol), sodium isopropoxide (372 mg, 4.53 mmol) and sodium iodide (102 mg, 0.680 mmol) in i-PrOH (2 mL) was heated to 80 °C and stirred for 16 hours. The reaction mixture was then heated to 100 °C and stirred for a further 4 hours. The reaction mixture was then diluted with water (10 mL) then extracted with a 3:1 CHCl3:IPA (3 × 10 mL). The combined organic extracts were dried over Na2SO4, then concentrated to dryness under reduced pressure. The residue was purified by basic reversed- phase preparative HPLC to afford the title compound as a solid (14 mg, 40 µmol, 9%).

[0318] 1H NMR (400 MHz, Chloroform-d) δ 8.00 (d, J = 5.7 Hz, 1H), 6.84 (s, 1H), 6.05 (d, J = 5.1 Hz, 1H), 5.85 (s, 1H), 4.83 (s, 1H), 3.65 (s, 2H), 3.58 (hept, J = 6.1 Hz, 1H), 3.48 (s, 2H), 1.94 – 1.80 (m, 3H), 1.59 – 1.51 (m, 2H), 1.16 (d, J = 6.1 Hz, 6H), 1.00 – 0.90 (m, 2H), 0.77 – 0.71 (m, 2H).

[0319] UPLC-MS (basic method, 4 min): Rt: 1.64 min, m / z = 355.2 [M+H]+. Example 35: Synthesis of N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[4-(propoxymethyl)-2- azabicyclo[2.1.1]hexan-2-yl]pyrimidin-4-amine (Compound 40)[2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexan-4- yl]methanol

[0320] A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (1.60 g, 6.79 mmol), 2-azabicyclo[2.1.1]hexan-4-ylmethanol;hydrochloride (1.22 g, 8.15 mmol) and N,N- diisopropylethylamine (4.7 mL, 27 mmol) in NMP (16 mL) was heated to 120 °C and stirred for 72 hours. The reaction mixture was loaded directly onto a 130 g C18cartridge then purified by reversed-phase column chromatography eluting with a gradient of MeCN (0.1% NH3) (0% to 60%; v / v) in water (0.1% NH3) to afford the title compound as a solid (704 mg, 2.25 mmol, 33%).

[0321] 1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 9.31 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.34 – 5.96 (m, 2H), 4.69 (t, J = 1.7 Hz, 1H), 4.67 (t, J = 5.4 Hz, 1H), 3.64 (d, J = 5.5 Hz, 2H), 3.31 (s, 2H), 1.88 – 1.83 (m, 1H), 1.78 (s, 2H), 1.40 – 1.31 (m, 2H), 0.93 – 0.86 (m, 2H), 0.72 – 0.62 (m, 2H).

[0322] UPLC-MS (basic method, 2 min): Rt: 0.81 min, m / z = 313.2 [M+H]+. 2-[4-(Chloromethyl)-2-azabicyclo[2.1.1]hexan-2-yl]-N-(5-cyclopropyl-1H-pyrazol-3- yl)pyrimidin-4-amine

[0323] To a solution of [2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.1.1]hexan-4-yl]methanol (700 mg, 2.24 mmol) in DCM (20 mL) was added thionylchloride (0.49 mL, 6.7 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was then cooled to 0 °C, then quenched with water (10 mL), then extracted with CH2Cl2(2 × 30 mL). The combined organic extracts were dried over Na2SO4 then concentrated to dryness under reduced pressure to afford the title compound as a solid (726 mg, 2.19 mmol, 98%).

[0324] 1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 11.10 (s, 1H), 7.79 (d, J = 7.2 Hz, 1H), 6.38 (s, 1H), 6.31 (d, J = 7.2 Hz, 1H), 5.17 – 4.69 (m, 1H), 4.05 (s, 2H), 3.57 (s, 2H), 2.08 – 2.04 (m, 2H), 1.95 – 1.85 (m, 1H), 1.71 – 1.66 (m, 2H), 1.00 – 0.88 (m, 2H), 0.74 – 0.64 (m, 2H).

[0325] UPLC-MS (basic method, 2 min): Rt: 1.02 min, m / z = 331.1 [M+H]+. N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[4-(propoxymethyl)-2-azabicyclo[2.1.1]hexan-2- yl]pyrimidin-4-amine

[0326] A suspension of 2-[4-(chloromethyl)-2-azabicyclo[2.1.1]hexan-2-yl]-N-(5- cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (150 mg, 0.453 mmol), sodium iodide (102 mg, 0.680 mmol) and 18 wt% sodium n-propanolate in n-propanol (1.0 mL, 0.45 mmol) in n- propanol (1 mL) was heated to 80 °C and stirred for 16 hours. The reaction mixture was then heated to 100 °C and stirred for a further 4 hours. The reaction mixture was then diluted with water (10 mL) then extracted with a 3:1 CHCl3:IPA (3 × 10 mL). The combined organic extracts were dried over Na2SO4, then concentrated to dryness under reduced pressure. The residue was purified by basic reversed-phase basic preparative HPLC to afford the title compound as a solid (15 mg, 42 µmol, 9%).

[0327] 1H NMR (400 MHz, Chloroform-d) δ 8.00 (d, J = 5.7 Hz, 1H), 6.85 (s, 1H), 6.07 (d, J = 4.1 Hz, 1H), 5.85 (s, 1H), 4.83 (s, 1H), 3.65 (s, 2H), 3.50 (s, 2H), 3.43 (t, J = 6.6 Hz, 2H), 1.95 – 1.90 (m, 2H), 1.86 (tt, J = 8.4, 5.1 Hz, 1H), 1.65 – 1.54 (m, 4H), 0.98 – 0.89 (m, 5H), 0.77 – 0.71 (m, 2H).

[0328] UPLC-MS (basic method, 4 min): Rt: 1.68 min, m / z = 355.2 [M+H]+. Example 36: Synthesis of [(3S)-1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2- yl]-3-piperidyl]methanol (Compound 42)[(3S)-1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3-piperidyl]methanol

[0329] A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (100 mg, 0.424 mmol), [(3S)-piperidin-3-yl]methanol hydrochloride (77 mg, 0.51 mmol), and N,N- diisopropylethylamine (0.22 mL, 1.3 mmol) in n-butanol (5 mL) was heated to 100 °C and stirred for 20 hours. The reaction mixture was concentrated under reduced pressure and diluted with water (30 mL) then extracted with DCM (3 × 20 mL). The combined organic extracts were washed with saturated aqueous brine solution (30 mL), dried over MgSO4then concentrated to dryness under reduced pressure. The residue was dissolved in MeOH (2 mL) then loaded onto an SCX-2 cartridge. The cartridge was washed with MeOH (40 mL) and the product was eluted with 2 M NH3in MeOH (50 mL). The eluent was concentrated to dryness under reduced pressure to afford the title compound as a solid (78 mg, 0.24 mmol, 57%).

[0330] 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.33 (s, 1H), 7.84 (d, J = 5.6 Hz, 1H), 6.28 – 5.78 (m, 2H), 4.62 (d, J = 13.0 Hz, 1H), 4.51 (d, J = 5.4 Hz, 2H), 3.30 – 3.22 (m, 1H), 2.82 (t, J = 12.1 Hz, 1H), 2.58 (t, J = 11.7 Hz, 1H), 1.85 (tt, J = 8.4, 5.1 Hz, 1H), 1.75 (d, J = 12.1 Hz, 1H), 1.65 (dt, J = 13.0, 3.3 Hz, 1H), 1.53 (d, J = 10.3 Hz, 1H), 1.42 – 1.27 (m, 1H), 1.19 (td, J = 12.0, 3.7 Hz, 1H), 0.96 – 0.77 (m, 2H), 0.72 – 0.52 (m, 2H).

[0331] UPLC-MS (basic method, 4 min): Rt: 1.32 min, m / z = 315.2 [M+H]+. Example 37: Synthesis of 1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]- N,N-dimethyl-piperidine-3-carboxamide (Compound 45)1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-N,N-dimethyl-piperidine-3- carboxamide

[0332] To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (315 mg, 1.34 mmol) and N,N-dimethylpiperidine-3-carboxamide (251 mg, 1.60 mmol) in 1-butanol ( 15 mL) was added N,N-diisopropylethylamine (0.70 mL, 4.01 mmol). The reaction mixture was heated to 100 °C and allowed to stir for 20 h. The reaction mixture was concentrated under reduced pressure and diluted with water (30 mL). The resulting solution was extracted with DCM (3 × 20 mL). The combined organic fractions were washed with brine (20 mL), dried (Na2SO4) and concentrated to dryness to afford a solid, which was purified by trituration with a mixture of MeOH, MeCN, DMSO and H2O to afford the title compound as a solid (64 mg, 0.18 mmol, 13%).

[0333] 1H NMR (400 MHz, DMSO-d6) δ 11.97 (s, 1H), 9.36 (s, 1H), 7.86 (d, J = 5.7 Hz, 1H), 6.22 (s, 1H), 6.03 (s, 1H), 4.63 (d, J = 12.8 Hz, 2H), 3.00 (s, 3H), 2.87 – 2.72 (m, 5H), 2.73 – 2.60 (m, 1H), 1.83 (tt, J = 8.2, 4.9 Hz, 2H), 1.69 – 1.54 (m, 2H), 1.50 – 1.35 (m, 1H), 0.98 – 0.89 (m, 2H), 0.64 – 0.57 (m, 2H).

[0334] UPLC-MS (basic method, 4 min): rt = 1.27 min, m / z: 356.2 [M+H]+. Example 38: Synthesis of 3-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3- azabicyclo[3.1.1]heptane-1-carboxamide (Compound 46)tert-Butyl 1-carbamoyl-3-azabicyclo[3.1.1]heptane-3-carboxylate

[0335] To a solution of 3-Boc-3-azabicyclo[3.1.1]heptane-1-carboxylic acid (203 mg, 0.873 mmol) in anhydrous THF (6 mL) was added N,N'-carbonyldiimidazole (212 mg, 1.31 mmol) and the reaction mixture was stirred at room temperature for 3 hours.7 M solution of NH3in MeOH (0.25 mL, 1.8 mmol) was added, causing an immediate precipitation of a solid, and the reaction mixture was stirred overnight at ambient temperature. The precipitate was isolated by filtration and dried under reduced pressure, affording the title compound as a solid (112 mg, 0.464 mmol, 53%).

[0336] 1H NMR (400 MHz, Chloroform-d) δ 5.49 (s, 2H), 3.70 – 3.63 (m, 2H), 3.56 – 3.49 (m, 2H), 2.50 – 2.22 (m, 3H), 1.71 – 1.57 (m, 2H), 1.48 (m, 9H).

[0337] UPLC-MS (basic method, 4 min): rt = 1.23 min, m / z: 239.2 [M–H]–. 3-Azabicyclo[3.1.1]heptane-1-carboxamide

[0338] To a solution of tert-butyl 1-carbamoyl-3-azabicyclo[3.1.1]heptane-3-carboxylate (112 mg, 0.464 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.71 mL, 9.3 mmol) and the reaction mixture was stirred for 2 hours. The volatiles were removed from the reaction mixture under reduced pressure. The residue was dissolved in MeOH, then loaded onto an SCX- 2 cartridge. The cartridge was washed with MeOH, then the product was eluted with 2 M NH3in MeOH. The eluent was concentrated to dryness under reduced pressure to afford the title compound as a solid (61 mg, 0.24 mmol, 52%).

[0339] 1H NMR (400 MHz, Chloroform-d) δ 5.36 (s, 1H), 5.23 (s, 1H), 3.23 (s, 2H), 3.09 – 3.03 (m, 2H), 2.33 – 2.22 (m, 3H), 1.82 – 1.74 (m, 2H). 3-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3-azabicyclo[3.1.1]heptane-1- carboxamide

[0340] To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (88 mg, 0.373 mmol) and 3-azabicyclo[3.1.1]heptane-1-carboxamide (60 mg, 0.43 mmol) in n- butanol (4 mL) was added N,N-diisopropylethylamine (0.20 mL, 1.12 mmol). The reaction mixture was heated to 100 °C and allowed to stir for 22 h. The reaction mixture was concentrated under reduced pressure and diluted with water (30 mL). The compound was then extracted with 3:1 CHCl3:IPA (3 × 20 mL). The combined organic fractions were washed with saturated brine solution (20 mL), dried over Na2SO4 and concentrated to dryness to afford an oil. The residue was purified by basic reversed phase preparative HPLC. The residue was then dissolved in MeOH (0.5 mL), loaded onto an SCX-2 cartridge (5 g), washed with MeOH (20 mL) and the compound was eluted with 0.7 M NH3 in MeOH (20 mL). The volatiles were then removed from the eluent under reduced pressure, and the residue was freeze-dried to afford the title compound as a powder (8.4 mg, 24 µmol, 6%).

[0341] 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 9.41 (s, 1H), 7.91 – 7.85 (m, 1H), 7.31 (s, 1H), 7.07 – 6.96 (m, 1H), 6.26 (s, 2H), 3.82 – 3.56 (m, 4H), 2.47 – 2.38 (m, 1H), 2.27 – 2.20 (m, 2H), 1.88 – 1.77 (m, 1H), 1.57 – 1.50 (m, 2H), 0.92 – 0.88 (m, 2H), 0.67 – 0.63 (m, 2H).

[0342] UPLC-MS (basic method, 4 min): rt = 1.09 min, m / z: 340.2 [M+H]+. Example 39: Synthesis of 3-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-N- methyl-3-azabicyclo[3.1.1]heptane-1-carboxamide (Compound 47)tert-Butyl 1-(methylcarbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate

[0343] To a solution of 3-Boc-3-azabicyclo[3.1.1]heptane-1-carboxylic acid (203 mg, 0.873 mmol) in anhydrous THF (6 mL) was added N,N'-carbonyldiimidazole (212 mg, 1.31 mmol) and the reaction mixture was stirred at room temperature for 3 hours. A solution of methylamine solution (2.0 M in THF, 0.87 mL, 1.8 mmol) was added and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated under reduced pressure and water (20 mL) was added. The mixture was extracted with EtOAc (3 × 20 mL) and the combined organics were washed with saturated brine solution (20 mL), dried with Na2SO4and filtered. The volatiles were removed under reduced pressure to afford the title compound as an oil (190 mg, 0.559 mmol, 63.98%).

[0344] 1H NMR (400 MHz, Chloroform-d) δ 5.63 – 5.42 (m, 1H), 3.65 – 3.60 (m, 2H), 3.55 – 3.48 (m, 2H), 2.87 – 2.77 (m, 3H), 2.48 – 2.16 (m, 3H), 1.69 – 1.56 (m, 2H), 1.48 (dd, J = 3.8, 0.6 Hz, 9H).

[0345] UPLC-MS (basic method, 4 min): rt = 1.29 min, m / z: 253.2 [M+H]+. N-Methyl-3-azabicyclo[3.1.1]heptane-1-carboxamide

[0346] To a solution of tert-butyl 1-(methylcarbamoyl)-3-azabicyclo[3.1.1]heptane-3- carboxylate (190 mg, 0.745 mmol) in DCM (6 mL) was added trifluoroacetic acid (1.1 mL, 15 mmol) and the reaction mixture was stirred for 2 h. The volatiles were removed from the reaction mixture under reduced pressure. The residue was dissolved in MeOH, then loaded onto an SCX- 2 cartridge. The cartridge was washed with MeOH, then the compound was eluted with 2 M NH3in MeOH. The eluent was concentrated to dryness under reduced pressure to afford the title compound as an oil (114 mg, 0.487 mmol, 65%).

[0347] 1H NMR (400 MHz, Chloroform-d) δ 5.42 (s, 1H), 3.48 (s, 1H), 3.18 (s, 2H), 3.06 – 3.03 (m, 2H), 2.79 (d, J = 4.9 Hz, 3H), 2.27 – 2.18 (m, 3H), 1.80 – 1.72 (m, 2H). 3-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-N-methyl-3- azabicyclo[3.1.1]heptane-1-carboxamide

[0348] To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (151 mg, 0.641 mmol) and N-methyl-3-azabicyclo[3.1.1]heptane-1-carboxamide (114 mg, 0.737 mmol) in n-butanol (7 mL) was added N,N-diisopropylethylamine (0.33 mL, 1.9 mmol). The reaction mixture was heated to 100 °C and allowed to stir for 22 h. The reaction mixture was concentrated under reduced pressure and diluted with water (30 mL). The mixture was then extracted with 3:1 CHCl3:IPA (3 × 20 mL). The combined organic fractions were washed with saturated brine solution (20 mL), dried with Na2SO4and concentrated to dryness to afford an oil. The residue was purified by reversed-phase basic preparative HPLC to afford the title compound as a powder (51 mg, 0.14 mmol, 23%).

[0349] 1H NMR (400 MHz, DMSO-d6) δ 11.94 (d, J = 24.7 Hz, 1H), 9.45 (s, 1H), 7.88 (d, J = 5.7 Hz, 1H), 7.73 (s, 1H), 6.25 (s, 2H), 3.78 – 3.57 (m, 4H), 2.63 (s, 3H), 2.42 (s, 1H), 2.21 (s, 2H), 1.81 (s, 1H), 1.59 – 1.50 (m, 2H), 0.93 – 0.87 (m, 2H), 0.60 (s, 2H).

[0350] UPLC-MS (basic method, 4 min): rt = 1.15 min, m / z: 354.2 [M+H]+. Example 40: Synthesis of 3-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-N,N- dimethyl-3-azabicyclo[3.1.1]heptane-1-carboxamide (Compound 48)tert-Butyl 1-(dimethylcarbamoyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate

[0351] To a solution of 3-Boc-3-azabicyclo[3.1.1]heptane-1-carboxylic acid (200 mg, 0.861 mmol) in anhydrous THF (6 mL) was added N,N'-carbonyldiimidazole (209 mg, 1.29 mmol) and the reaction mixture was stirred at room temperature for 3 hours.2 M solution of dimethylamine in THF (0.86 mL, 1.7 mmol) was added and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated under reduced pressure and water (20 mL) was added. The organics were extracted with EtOAc (3 × 20 mL) and the combined organic extracts were washed with saturated brine solution (20 mL), dried with Na2SO4 and filtered. The volatiles were removed under reduced pressure to afford the title compound as a solid (216 mg, 0.667 mmol, 77%).

[0352] 1H NMR (400 MHz, Chloroform-d) δ 3.62 (d, J = 14.3 Hz, 2H), 3.56 – 3.47 (m, 2H), 3.01 – 2.85 (m, 6H), 2.38 – 2.25 (m, 3H), 1.80 – 1.69 (m, 2H), 1.47 (d, J = 3.1 Hz, 9H).

[0353] UPLC-MS (basic method, 4 min): rt = 1.43 min, m / z: 213.1 [M-tBu+H]+. N,N-Dimethyl-3-azabicyclo[3.1.1]heptane-1-carboxamide

[0354] To a solution of tert-butyl 1-(dimethylcarbamoyl)-3-azabicyclo[3.1.1]heptane-3- carboxylate (216 mg, 0.803 mmol) in DCM (8 mL) was added trifluoroacetic acid (1.2 mL, 16 mmol) and the reaction mixture was stirred for 2 h. The volatiles were removed from the reaction mixture under reduced pressure. The residue was dissolved in MeOH, then loaded onto an SCX- 2 cartridge. The cartridge was washed with MeOH, then the product was eluted with 2 M NH3in MeOH. The eluent was concentrated to dryness under reduced pressure to afford the title compound as a gum (133 mg, 0.789 mmol, 98.25%).

[0355] 1H NMR (400 MHz, Chloroform-d) δ 3.45 (s, 1H), 3.17 (d, J = 0.9 Hz, 2H), 3.04 (d, J = 2.7 Hz, 2H), 2.94 (s, 3H), 2.88 (s, 3H), 2.38 – 2.27 (m, 2H), 2.21 – 2.12 (m, 1H), 1.91 – 1.82 (m, 2H).

[0356] UPLC-MS (basic method, 4 min): rt = 0.43 min, m / z: 169.1 [M+H]+. 3-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-N,N-dimethyl-3- azabicyclo[3.1.1]heptane-1-carboxamide

[0357] To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (160 mg, 0.679 mmol) and N,N-dimethyl-3-azabicyclo[3.1.1]heptane-1-carboxamide (131 mg, 0.781 mmol) in n-butanol (7 mL) was added N,N-diisopropylethylamine (0.35 mL, 2.0 mmol). The reaction mixture was heated to 100 °C and allowed to stir for 24 h. The reaction mixture wasconcentrated under reduced pressure and diluted with water (30 mL). The mixture was then extracted with DCM (3 × 20 mL). The combined organic fractions were washed with saturated brine solution (20 mL), dried over Na2SO4and concentrated to dryness. The residue was purified by basic reversed phase preparative HPLC to afford the title compound as a solid (67 mg, 0.182 mmol, 26.86%).

[0358] 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 9.45 (s, 1H), 7.88 (d, J = 5.8 Hz, 1H), 6.22 (s, 2H), 3.78 – 3.60 (m, 4H), 2.91 (d, J = 42.8 Hz, 6H), 2.38 (s, 1H), 2.27 (t, J = 7.3 Hz, 2H), 1.82 (s, 1H), 1.74 (dd, J = 6.9, 2.7 Hz, 2H), 0.92 (d, J = 8.1 Hz, 2H), 0.64 (s, 1H), 0.51 (s, 1H).

[0359] UPLC-MS (basic method, 4 min): rt = 1.26 min, m / z: 368.3 [M+H]+. Example 41: Synthesis of 1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-N- methyl-pyrrolidine-3-carboxamide (Compound 50)

[0360] A stirred mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (100 mg, 0.424 mmol), N-methylpyrrolidine-3-carboxamide hydrochloride (84 mg, 0.509 mmol) and N,N-diisopropylethylamine (0.37 mL, 2.12 mmol) in n-butanol (4 mL) was heated at reflux, for 18 hours. The reaction mixture was cooled to room temperature. The solvent was removed in vacuo to leave a viscous oil. The oil was partitioned between water (10 mL) and chloroform / IPA 3:1 (3 x 10 mL). The combined organic extracts were washed with brine (10 mL) and dried over Na2SO4. The solvent was removed in vacuo. To afford the title compound as a solid (27 mg, 78 µmol, 18%).

[0361] 1H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 9.81 (s, 1H), 8.06 – 7.94 (m, 1H), 7.82 (d, J = 6.1 Hz, 1H), 6.49 – 5.96 (m, 2H), 3.74 – 3.45 (m, 4H), 3.06 – 2.98 (m, 1H), 2.61 (d, J = 4.6 Hz, 3H), 2.16 – 2.02 (m, 2H), 1.90 – 1.83 (m, 1H), 0.94 – 0.88 (m, 2H), 0.68 – 0.62 (m, 2H).

[0362] UPLC-MS (basic method, 4 min): Rt: 1.07 min, m / z = 328.2 [M+H]+.Example 42: Synthesis of 1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-N,N- dimethyl-pyrrolidine-3-carboxamide (Compound 51)

[0363] A stirred mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (165 mg, 0.700 mmol), N,N-dimethylpyrrolidine-3-carboxamide hydrochloride (150 mg, 0.840 mmol) and N,N-diisopropylethylamine (0.61 mL, 3.50 mmol) in n-butanol (7 mL) was heated, at reflux, for 20 hours. The reaction mixture was cooled to room temperature. The solvent was removed in vacuo to leave a viscous oil. The oil was partitioned between water (10 mL) and DCM (3 x 10 mL). The combined organic extracts were washed with brine (10 mL) and dried over Na2SO4, then the solvent removed in vacuo. The residue was purified by automated flash column chromatography, over silica gel, eluting with a gradient of methanol (0% to 5%; v / v) in DCM to give the title compound as a solid (76 mg ,0.218 mmol, 31%).

[0364] 1H NMR (400 MHz, DMSO-D6) δ 11.90 (s, 1H), 9.37 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.51 – 5.88 (m, 2H), 3.77 – 3.66 (m, 1H), 3.62 – 3.41 (m, 4H), 3.07 (s, 3H), 2.85 (s, 3H), 2.17 – 1.98 (m, 2H), 1.88 – 1.81 (m, 1H), 0.95 – 0.84 (m, 2H), 0.66 – 0.60 (m, 2H).

[0365] UPLC-MS (basic method, 4 min): Rt: 1.15 min, m / z = 342.3 [M+H]+. Example 43: Synthesis of N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[(3R)-3-(1-methoxy-1- methyl-ethyl)pyrrolidin-1-yl]pyrimidin-4-amine (Compound 57-1)tert-Butyl-(3R)-3-(1-methoxy-1-methyl-ethyl)pyrrolidine-1-carboxylate

[0366] To a stirred solution of 1-Boc-(3R)-3-(2-hydroxypropan-2-yl)pyrrolidine (200 mg, 0.872 mmol) in THF (5 mL) at 0 °C was added 60% w / w sodium hydride in mineral oil (105 mg, 2.62 mmol) portion wise, under nitrogen atmosphere. The mixture was allowed to warm up to room temperature and stirred for 30 minutes. The reaction mixture was cooled down to 0 °C and methyl iodide (0.16 mL, 2.6 mmol) was added dropwise. The reaction was allowed to warm up slowly to room temperature and stirred for 16 hours. The reaction was quenched with saturated aqueous NH4Cl solution (5 mL) and then extracted with ethyl acetate (3 x 10 mL). The combined extracts were washed with brine (5 mL), dried over sodium sulfate and the solvent was removed in vacuo to afford the title compound as an oil (254 mg, 1.04 mmol, 120%).

[0367] 1H NMR (400 MHz, Chloroform-d) δ 3.55 – 3.22 (m, 2H), 3.21 – 3.12 (m, 5H), 2.32 – 2.20 (m, 1H), 1.88 – 1.68 (m, 2H), 1.41 (s, 9H), 1.14 – 1.06 (m, 6H).

[0368] UPLC MS-ELS (basic method, 2 min): Rt = 1.17 min, m / z = 244.2 [M+H]+. (3R)-3-(1-Methoxy-1-methyl-ethyl)pyrrolidine hydrochloride

[0369] To a stirred solution of tert-butyl-(3R)-3-(1-methoxy-1-methyl-ethyl)pyrrolidine-1- carboxylate (254 mg, 1.04 mmol) in 1,4-dioxane (4 mL) was added hydrogen chloride solution in dioxane (2.5 mL, 1.04 mmol). The reaction mixture was stirred for 3 hours at room temperature. The volatiles were removed under reduced pressure to afford the title compound as an oil (185 mg, 1.03 mmol, 99%).

[0370] 1H NMR (400 MHz, Chloroform-d) δ 9.51 (s, 1H), 9.35 (s, 1H), 3.38 – 3.29 (m, 2H), 3.27 – 3.14 (m, 2H), 3.15 – 3.10 (m, 3H), 2.46 – 2.32 (m, 1H), 2.03 – 1.88 (m, 2H), 1.11 (d, J = 2.0 Hz, 6H). N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[(3R)-3-(1-methoxy-1-methyl-ethyl)pyrrolidin-1- yl]pyrimidin-4-amine

[0371] To a stirred solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4- amine (180 mg, 0.764 mmol) and (3R)-3-(1-methoxy-1-methyl-ethyl)pyrrolidine;hydrochloride (165 mg, 0.917 mmol) in n-butanol (2.5 mL) was added N,N-diisopropylethylamine (0.67 mL, 3.8 mmol). The reaction mixture was heated to 120 °C and stirred for 16 hours under a nitrogen atmosphere. The volatiles were removed under reduced pressure to afford an oil which was purified by column chromatography, over silica gel, eluting with 91:9 v / v dichloromethane:methanol. The residue was dissolved in methanol (2 mL) then loaded onto an SCX-2 cartridge. The cartridge was washed with MeOH (10 mL), then the compound was eluted with 2 M NH3 in MeOH (25 mL). The eluent was concentrated to dryness under reduced pressure to afford the title compound as a solid (68 mg, 0.19 mmol, 24%).

[0372] 1H NMR (400 MHz, Chloroform-d) δ 7.86 (d, J = 5.8 Hz, 1H), 5.96 (d, J = 5.5 Hz, 2H), 3.94 – 3.67 (m, 1H), 3.70 – 3.55 (m, 1H), 3.47 – 3.29 (m, 2H), 3.19 (s, 3H), 2.48 – 2.35 (m, 1H), 1.95 – 1.86 (m, 2H), 1.87 – 1.76 (m, 1H), 1.16 (d, J = 2.7 Hz, 6H), 0.96 – 0.82 (m, 2H), 0.75 – 0.63 (m, 2H).

[0373] UPLC MS (basic method, 4 min): Rt = 1.55 min, m / z = 343.3 [M+H+]. Example 44: Synthesis of 2-[(3R)-1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2- yl]pyrrolidin-3-yl]propan-2-ol (Compound 60-1)2-[(3R)-Pyrrolidin-3-yl]propan-2-ol hydrochloride

[0374] To a stirred solution of 1-Boc-(3R)-3-(2-Hydroxypropan-2-yl)pyrrolidine (150 mg, 0.654 mmol) in 1,4-dioxane (1.5 mL) was added 4 M hydrogen chloride solution in 1,4-dioxane (1.5 mL, 6.54 mmol). The reaction mixture was stirred for 3 hours. The volatiles were removed under reduced pressure to afford 2-[(3R)-pyrrolidin-3-yl]propan-2-ol;hydrochloride (105 mg, 0.634 mmol, 97%) as an oil.

[0375] 1H NMR (400 MHz, Chloroform-d) δ 9.16 (s, 1H), 8.89 (s, 1H), 3.37 – 3.23 (m, 2H), 3.27 – 3.01 (m, 2H), 2.37 – 2.23 (m, 1H), 2.00 – 1.85 (m, 2H), 1.54 – 0.89 (m, 6H). 2-[(3R)-1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3- yl]propan-2-ol

[0376] To a stirred solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4- amine (110 mg, 0.467 mmol) and 2-[(3R)-pyrrolidin-3-yl]propan-2-ol hydrochloride (93 mg, 0.560 mmol) in n-butanol (2.5 mL) was added N,N-diisopropylethylamine (0.41 mL, 2.3 mmol) under a nitrogen atmosphere. The reaction mixture was heated to 120 °C and stirred for 16 hours. The volatiles were removed under reduced pressure. The residue was dissolved in methanol and loaded onto an SCX-2 cartridge. The cartridge was washed with methanol (10 mL) then the compound was eluted with 2 M ammonia in methanol (25 mL). The eluent was concentrated to dryness under reduced pressure. The residue was further purified by flash column chromatography, over silica gel, eluting with 9:1 v / v dichloromethane:methanol to afford the title compound as a solid (31 mg, 94 µmol, 20%).

[0377] 1H NMR (400 MHz, Chloroform-d) δ 7.98 (d, J = 5.7 Hz, 1H), 7.17 (s, 1H), 5.99 (d, J = 5.7 Hz, 1H), 5.86 (s, 1H), 3.86 – 3.70 (m, 2H), 3.52 – 3.34 (m, 2H), 2.42 – 2.29 (m, 1H), 2.17 – 1.97 (m, 1H), 1.98 – 1.86 (m, 1H), 1.92 – 1.76 (m, 1H), 1.28 (s, 6H), 0.98 – 0.85 (m, 2H), 0.76 – 0.67 (m, 2H).

[0378] UPLC MS (basic method, 4 min): rt = 1.29 min, m / z = 329.2 [M+H]+. Example 45: Synthesis of 2-[1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]- 3-piperidyl]propan-2-ol (Compound 65)tert-Butyl 3-(1-hydroxy-1-methyl-ethyl)piperidine-1-carboxylate

[0379] To a solution of methyl N-Boc-piperidine-3-carboxylate (1.00 g, 4.11 mmol) in THF ( 10 mL) at -78 °C, under nitrogen was added methylmagnesium bromide (3.0 M in Et2O, 3.0 mL, 9.04 mmol) dropwise over 10 minutes. The reaction mixture was allowed to warm to room temperature and stir for 1 hour then quenched with saturated aqueous NH4Cl solution (12 mL) and extracted with EtOAc (2 x 25 mL). The organics were washed with brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as an oil (1.01 g, 4.03 mmol, 98% yield).

[0380] 1H NMR (400 MHz, CDCl3) δ 4.24 (ddt, J = 12.9, 3.9, 2.0 Hz, 1H), 4.09 – 4.03 (m, 1H), 2.58 (td, J = 12.9, 3.0 Hz, 1H), 2.51 – 2.42 (m, 1H), 1.96 – 1.88 (m, 1H), 1.74 – 1.66 (m, 1H), 1.45 (s, 9H), 1.44 – 1.35 (m, 2H), 1.24 – 1.22 (m, 1H), 1.20 (s, 6H). 2-(3-Piperidyl)propan-2-ol;hydrochloride

[0381] To a solution of tert-butyl 3-(1-hydroxy-1-methyl-ethyl)piperidine-1-carboxylate (300 mg, 1.20 mmol) in CH2Cl2(1 mL) was added 4 N HCl in 1,4-dioxane (3.0 mL, 12.0 mmol) and the reaction mixture stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to give the title compound as an oil (270 mg, 1.23 mmol, quant. yield).

[0382] 1H NMR (400 MHz, CD3OD) δ 3.53 – 3.47 (m, 1H), 3.36 – 3.32 (m, 1H), 2.91 – 2.82 (m, 1H), 2.78 (t, J = 12.3 Hz, 1H), 2.05 – 1.92 (m, 2H), 1.79 – 1.63 (m, 2H), 1.44 – 1.32 (m, 1H), 1.22 (s, 3H), 1.18 (s, 3H). 2-[1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3-piperidyl]propan-2-ol

[0383] A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (238 mg, 1.01 mmol), 2-(3-piperidyl)propan-2-ol;hydrochloride (265 mg, 1.21 mmol) and N,N- diisopropylethylamine (0.88 mL, 5.04 mmol) in 1-butanol (10 mL) was heated at 118 °C for 20 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was dissolved in water (20 mL) and extracted with CH2Cl2 (3 x 20 mL) and the organics washed with brine (15 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with MeOH (0% to 5% v / v) in CH2Cl2 to give the title compound as a solid (141 mg, 0.412 mmol, 41% yield).

[0384] 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.31 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.56 – 5.76 (m, 2H), 4.85 (d, J = 12.4 Hz, 1H), 4.65 (d, J = 12.7 Hz, 1H), 4.19 (s, 1H), 2.58 (t, J = 12.1 Hz, 1H), 2.49 – 2.44 (m, 1H), 1.90 – 1.79 (m, 2H), 1.73 – 1.66 (m, 1H), 1.39 – 1.19 (m, 3H), 1.11 (s, 6H), 0.92 – 0.84 (m, 2H), 0.69 – 0.63 (m, 2H).

[0385] UPLC-MS (4 min, basic method): Rt: 1.41 min, m / z: 343.3 [M+H]+. Example 46: Synthesis of N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[3-(1-methoxy-1-methyl- ethyl)-1-piperidyl]pyrimidin-4-amine (Compound 66)tert-Butyl 3-(1-methoxy-1-methyl-ethyl)piperidine-1-carboxylate

[0386] To a solution of tert-butyl 3-(1-hydroxy-1-methyl-ethyl)piperidine-1-carboxylate (680 mg, 2.71 mmol) in THF (15 mL) at 0 °C under nitrogen was added sodium hydride 60% in mineral oil (325 mg, 8.13 mmol) and the reaction allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was cooled to 0 °C and methyl iodide (0.51 mL, 8.13 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stir for 2 hours, then was quenched with saturated aqueous NH4Cl solution (50 mL) and extracted with EtOAc (3 x 20 mL). The organics were washed with brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with EtOAc (0% to 10% v / v) in iso-hexane to afford the title compound as an oil (550 mg, 2.07 mmol, 76 % yield).

[0387] 1H NMR (400 MHz, CDCl3) δ 4.21 – 4.14 (m, 1H), 4.11 – 4.04 (m, 1H), 3.19 (s, 3H), 2.56 (td, J = 12.9, 2.9 Hz, 1H), 2.43 (dd, J = 13.0, 11.5 Hz, 1H), 1.86 – 1.78 (m, 1H), 1.71 – 1.65 (m, 1H), 1.63 – 1.54 (m, 1H), 1.45 (s, 9H), 1.44 – 1.35 (m, 1H), 1.23 – 1.18 (m, 1H), 1.12 (s, 6H).

[0388] UPLC-MS (basic method, 2 min): Rt: 1.23 min, m / z: 256.4 [M-H]-. 3-(1-Methoxy-1-methyl-ethyl)piperidine hydrochloride

[0389] To a solution of tert-butyl 3-(1-methoxy-1-methyl-ethyl)piperidine-1-carboxylate (300 mg, 1.13 mmol) in CH2Cl2 (1 mL) was added 4 N HCl in 1,4-dioxane (2.8 mL, 11.3 mmol) and the reaction stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to afford the title compound as a solid (220 mg,1.14 mmol, 100% yield).

[0390] 1H NMR (400 MHz, CDCl3) δ 9.63 (s, 1H), 9.30 (s, 1H), 3.48= 32.7, 12.5 Hz, 2H), 3.17 (s, 3H), 2.78 – 2.63 (m, 2H), 2.16 – 2.07 (m, 1H), 1.94 – 1.81 (m, 3H), 1.37 – 1.26 (m, 1H), 1.16 (s, 3H), 1.10 (s, 3H).

[0391] UPLC-MS (4 min, basic method): Rt: 0.69 min, m / z: 158.1 [M+H]+. N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[3-(1-methoxy-1-methyl-ethyl)-1-piperidyl]pyrimidin- 4-amine

[0392] A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (223 mg, 0.946 mmol), 3-(1-methoxy-1-methyl-ethyl)piperidine;hydrochloride (220 mg, 1.14 mmol) and N,N-diisopropylethylamine (0.82 mL, 4.73 mmol) in 1-butanol (9.5 mL) was heated to 118 °C for 20 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure, then diluted with water (20 mL) and extracted with CH2Cl2 (3 x 20 mL)and the organics washed with brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluting with a gradient of MeOH (0% to 5% v / v) in CH2Cl2to afford the title compound as a solid (125 mg, 0.351 mmol, 37 % yield).

[0393] 1H NMR (400 MHz, CD3OD) δ 7.83 (d, J = 5.9 Hz, 1H), 6.27 – 6.05 (m, 2H), 4.81 (d, J = 12.9 Hz, 1H), 4.61 (d, J = 13.1 Hz, 1H), 3.20 (s, 3H), 2.73 (t, J = 12.8 Hz, 1H), 2.62 (t, J = 12.1 Hz, 1H), 1.93 – 1.84 (m, 2H), 1.82 – 1.73 (m, 1H), 1.71 – 1.61 (m, 1H), 1.56 – 1.32 (m, 2H), 1.20 (s, 3H), 1.18 (s, 3H), 1.00 – 0.90 (m, 2H), 0.78 – 0.68 (m, 2H).

[0394] UPLC-MS (4 min, basic method): Rt: 1.74 min, m / z: 357.2 [M+H]+. Example 47: Synthesis of 1-[1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]- 3-piperidyl]cyclopropanol (Compound 67)Methyl piperidine-3-carboxylate

[0395] Methyl N-Boc-piperidine-3-carboxylate (600 mg, 2.47 mmol) was dissolved in CH2Cl2 (10 mL) and trifluoroacetic acid (0.94 mL, 12.3 mmol) was added at 0 °C and stirred for 5 min. The reaction mixture was brought to RT and stirred for 2 h, then concentrated under reduced pressure and the residue taken up in MeOH and purified by SCX-2 cartridge, washing with MeOH and eluting with 2 M NH3 in MeOH to afford the title compound as an oil (300 mg, 2.10 mmol, 85% yield) as oil.

[0396] 1H NMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 3.15 (ddt, J = 12.6, 3.8, 1.4 Hz, 1H), 2.92 (dtt, J = 12.4, 4.1, 1.0 Hz, 1H), 2.80 (dd, J = 12.4, 9.3 Hz, 1H), 2.63 (ddd, J = 12.4, 10.3, 3.1 Hz, 1H), 2.45 (ddt, J = 9.9, 9.2, 4.0 Hz, 1H), 2.03 – 1.91 (m, 1H), 1.70 – 1.61 (m, 3H), 1.52 – 1.37 (m, 1H). Methyl 1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]piperidine-3- carboxylate

[0397] 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (494 mg, 2.10 mmol), methyl piperidine-3-carboxylate (300 mg, 2.10 mmol), and N,N-diisopropylethylamine (1.1 mL, 6.29 mmol) were dissolved in 1-butanol (3 mL) and the reaction mixture was heated at 115 °C for 24 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, then ice water was added. The precipitate was filtered and purified by column chromatography over silica gel eluting with a gradient of EtOAc (0% to 100% v / v) in iso-hexane to afford the title compound as a solid (610 mg, 1.78 mmol, 85% yield).

[0398] 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 9.40 (s, 1H), 7.86 (d, J = 5.7 Hz, 1H), 6.23 (s, 1H), 6.09 (s, 1H), 4.66 (d, J = 13.0 Hz, 1H), 4.42 (d, J = 13.1 Hz, 1H), 3.63 (s, 3H), 3.05 (t, J = 11.7 Hz, 1H), 2.93 (t, J = 11.9 Hz, 1H), 2.46 (dt, J = 10.4, 3.9 Hz, 1H), 1.99 (d, J = 12.7 Hz, 1H), 1.85 (tt, J = 8.4, 5.0 Hz, 1H), 1.72 – 1.57 (m, 2H), 1.42 (t, J = 11.9 Hz, 1H), 0.96 – 0.87 (m, 2H), 0.69 – 0.60 (m, 2H).

[0399] UPLC-MS (4 min, basic): Rt: 1.50 min, m / z = 343.2 [M+H]+. 1-[1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3-piperidyl]cyclopropanol

[0400] Methyl 1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]piperidine-3- carboxylate (125 mg, 0.365 mmol) was dissolved in THF (2 mL) and cooled to 0 °C. Chlorotriisopropoxytitanium(IV) (0.52 mL, 2.19 mmol) was added and stirred for 5 min, then ethylmagnesium bromide (1 M in diethyl ether, 3.7 mL, 3.65 mmol) was added to the reaction mixture over 10 min then the reaction mixture allowed to warm to room temperature and stirred for 24 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution (5 mL) and diluted with EtOAc (15 mL). The suspension was filtered through celite and the layers separated. The organics were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel twice successively, eluting with a gradient of EtOAc (0% to 100% v / v) in iso-hexane to afford the title compound as a solid (20 mg, 0.0576 mmol, 16% yield).

[0401] 1H NMR (400 MHz, CD3OD) δ 7.80 (d, J = 5.9 Hz, 1H), 6.19 (s, 1H), 6.08 (s, 1H), 4.74 (d, J = 13.2 Hz, 1H), 4.59 (d, J = 13.2 Hz, 1H), 2.78 (dt, J = 43.2, 12.5 Hz, 2H), 1.95 – 1.82 (m, 2H), 1.80 – 1.57 (m, 2H), 1.54 – 1.39 (m, 1H), 1.12 – 1.01 (m, 1H), 0.96 (d, J = 8.1 Hz, 2H), 0.80 – 0.67 (m, 3H), 0.66 – 0.61 (m, 1H), 0.59 – 0.51 (m, 1H), 0.50 – 0.37 (m, 1H).

[0402] UPLC-MS (4 min, basic): Rt: 1.39 min, m / z = 341.2 [M+H]+. Example 48: Synthesis of 2-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-N,N- dimethyl-2-azabicyclo[2.1.1]hexane-4-carboxamide (Compound 69)

[0403] To N,N-dimethyl-2-azabicyclo[2.1.1]hexane-4-carboxamide (30 mg, 0.20 mmol) in 1- butanol (2 mL) was added N,N-diisopropylethylamine (0.10 mL, 0.58 mmol) and 2-chloro-N-(5- cyclopentyl-1H-pyrazol-3-yl)pyrimidin-4-amine (44 mg, 0.17 mmol), and the reaction mixture heated to 120 °C. After 18 hours the reaction mixture was allowed to cool to room temperature and diluted with CH2Cl2 (10 mL) and washed with water (10 mL) and saturated brine solution (10 mL). The organics were separated and dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by reversed phase basic preparative HPLC to give the title compound as a solid (22 mg, 60 µmol, 30%).

[0404] 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 9.44 (s, 1H), 7.87 (d, J = 5.7 Hz, 1H), 6.29 (s, 1H), 4.65 – 4.59 (m, 1H), 3.56 (s, 2H), 3.01 (p, J = 7.9 Hz, 1H), 2.95 (s, 3H), 2.85 (s, 3H), 2.18 – 2.08 (m, 2H), 2.02 – 1.92 (m, 2H), 1.79 – 1.70 (m, 1H), 1.74 – 1.49 (m, 7H).

[0405] UPLC-MS (basic method, 4 min): Rt: 1.37 min, m / z = 382.3 [M+H]+. Example 49: Synthesis of 2-[(3R)-1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2- yl]pyrrolidin-3-yl]propan-2-ol (Compound 71)2-[(3R)-Pyrrolidin-3-yl]propan-2-ol hydrochloride

[0406] To a stirred solution of 1-Boc-(3R)-3-(2-hydroxypropan-2-yl)pyrrolidine (150 mg, 0.654 mmol) in 1,4-dioxane (1.5 mL) was added 4 M hydrogen chloride solution in 1,4-dioxane (1.5 mL, 6.54 mmol). The reaction mixture was stirred for 3 hours. The volatiles were removed under reduced pressure to afford 2-[(3R)-pyrrolidin-3-yl]propan-2-ol;hydrochloride (105 mg, 0.634 mmol, 97%) as an oil.

[0407] 1H NMR (400 MHz, Chloroform-d) δ 9.16 (s, 1H), 8.89 (s, 1H), 3.37 – 3.23 (m, 2H), 3.27 – 3.01 (m, 2H), 2.37 – 2.23 (m, 1H), 2.00 – 1.85 (m, 2H), 1.54 – 0.89 (m, 6H). 2-[(3R)-1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3- yl]propan-2-ol

[0408] To a stirred solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4- amine (110 mg, 0.467 mmol) and 2-[(3R)-pyrrolidin-3-yl]propan-2-ol hydrochloride (93 mg, 0.560 mmol) in n-butanol (2.5 mL) was added N,N-diisopropylethylamine (0.41 mL, 2.3 mmol) under a nitrogen atmosphere. The reaction mixture was heated to 120 °C and stirred for 16 hours. The volatiles were removed under reduced pressure. The residue was dissolved in methanol and loaded onto an SCX-2 cartridge. The cartridge was washed with methanol (10 mL) then the compound was eluted with 2 M ammonia in methanol (25 mL). The eluent was concentrated to dryness under reduced pressure. The residue was further purified by flash column chromatography, over silica gel, eluting with 9:1 v / v dichloromethane:methanol to afford the title compound as a solid (31 mg, 94 µmol, 20%).

[0409] 1H NMR (400 MHz, Chloroform-d) δ 7.98 (d, J = 5.7 Hz, 1H), 7.17 (s, 1H), 5.99 (d, J = 5.7 Hz, 1H), 5.86 (s, 1H), 3.86 – 3.70 (m, 2H), 3.52 – 3.34 (m, 2H), 2.42 – 2.29 (m, 1H), 2.17 – 1.97 (m, 1H), 1.98 – 1.86 (m, 1H), 1.92 – 1.76 (m, 1H), 1.28 (s, 6H), 0.98 – 0.85 (m, 2H), 0.76 – 0.67 (m, 2H).

[0410] UPLC MS (basic method, 4 min): rt = 1.29 min, m / z = 329.2 [M+H]+. Example 50: Synthesis of ((1R,4R)-2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin- 2-yl)-2-azabicyclo[2.2.1]heptan-4-yl)methanol and ((1S,4S)-2-(4-((5-cyclopropyl-1H- pyrazol-3-yl)amino)pyrimidin-2-yl)-2-azabicyclo[2.2.1]heptan-4-yl)methanol (Compounds 72-1 and 72-2)

[0411] Enantiomer separation by chiral preparative SFC was carried out on Compound 28 using a Lux A2 (21.2 mm x 250 mm, 5 µm) column and the following parameters: temperature: 40 °C; flow rate: 50 mL / min; mobile phase: 30:70 EtOH:CO2(0.2% v / v NH3), to afford Compound 72-1 as a solid (37 mg, 0.11 mmol, 37%) and compound 72-2 as a solid (38 mmol, 0.12 mmol, 38%). Compound 72-1

[0412] 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.29 (s, 1H), 7.79 (d, J = 5.7 Hz, 1H), 6.37 – 5.98 (m, 2H), 4.71 – 4.62 (m, 1H), 4.53 – 4.42 (m, 1H), 3.67 – 3.56 (m, 2H), 3.31 (s, 1H), 3.17 – 3.02 (m, 1H), 1.91 – 1.80 (m, 1H), 1.80 – 1.49 (m, 4H), 1.44 – 1.28 (m, 2H), 0.97 – 0.83 (m, 2H), 0.70 – 0.57 (m, 2H).

[0413] UPLC-MS (4 min, basic method): Rt: 1.12 min, m / z = 327.2 [M+H]+.

[0414] Chiral SFC: column: Chiralpak IG (4.6 mm x 250 mm, 5 μm); mobile phase: 4:6 EtOH:CO2, flow rate: 3 mL / min; temperature: 40 °C; rt = 6.08 min (minor), 7.32 min (major), >99% e.e.

[0415] [α]25D: –111.200 °. Compound 72-2

[0416] 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.28 (s, 1H), 7.79 (d, J = 5.7 Hz, 1H), 6.40 – 5.97 (m, 2H), 4.81 – 4.61 (m, 1H), 4.59 – 4.42 (m, 1H), 3.71 – 3.54 (m, 2H), 3.31 (s, 1H), 3.17 – 3.00 (m, 1H), 1.90 – 1.79 (m, 1H), 1.79 – 1.50 (m, 4H), 1.43 – 1.28 (m, 2H), 0.96 – 0.86 (m, 2H), 0.69 – 0.59 (m, 2H).

[0417] UPLC-MS (4 min, basic method): Rt: 1.21 min, m / z = 327.2 [M+H]+.

[0418] Chiral HPLC: column: Chiralpak IG (4.6 mm x 250 mm, 5 μm); mobile phase: 4:6 EtOH:CO2, flow rate: 3 mL / min; temperature: 40 °C; rt = 6.09 min (major), 7.33 min (minor), >99% e.e.

[0419] [α]25D: +104.500 °. Example 51: Synthesis of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[4-(methoxymethyl)-2- azabicyclo[2.2.2]octan-2-yl]pyrimidin-4-amine (Compound 73)t -Butyl 4-(methoxymethyl)-2-azabicyclo[2.2.2]octane-2-carboxylate

[0420] To 2-Boc-4-(hydroxymethyl)-2-azabicyclo[2.2.2]octane (300 mg, 1.24 mmol) in THF (9 mL) at 0 °C, was added a 60% w / w suspension of sodium hydride in mineral oil (60 mg, 1.49 mmol). The mixture was allowed to warm to room temperature and was and stirred for 15 mins. Methyl iodide (77 µL, 1.24 mmol) was then added and the mixture was stirred for 28 hours. Additional methyl iodide (15 µL, 0.24 mmol) was added and the mixture was stirred for a further 3 days. The reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL) and the aqueous layer was extracted again with EtOAc (30 mL). The combined organic phases were washed with brine (30 mL), dried over MgSO4and concentrated under vacuum to afford the title compound as an oil (302 mg, 1.18 mmol, 95%).

[0421] 1H NMR (400 MHz, DMSO-d6) δ 3.91 – 3.85 (m, 0.5H), 3.84 – 3.80 (m, 0.5H), 3.28 – 3.18 (m, 3H), 3.14 – 3.06 (m, 1H), 3.05 – 3.00 (m, 3H), 1.76 – 1.51 (m, 4H), 1.50 – 1.29 (m, 13H). (Note: Two rotameric species observed in1H NMR.) 4-(Methoxymethyl)-2-azabicyclo[2.2.2]octane

[0422] To tert-butyl 4-(methoxymethyl)-2-azabicyclo[2.2.2]octane-2-carboxylate (302 mg, 1.18 mmol) in DCM (12 mL), trifluoroacetic acid (1.8 mL, 23.6 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours and the solvent was removed under reduced pressure. The crude residue was dissolved in MeOH (2 mL) and loaded onto an SCX-2 cartridge. The cartridge was washed with MeOH (20 mL), then the compound was eluted with 2 M NH3 in MeOH) (20 mL). The eluent was concentrated to dryness under reduced pressure to afford the title compound as an oil (172 mg, 1.11 mmol, 94%).

[0423] 1H NMR (400 MHz, DMSO-d6) δ 3.19 (s, 3H), 2.90 (s, 2H), 2.69 – 2.60 (m, 3H), 1.73 – 1.60 (m, 2H), 1.58 – 1.25 (m, 7H).

[0424] UPLC-MS (2 min, basic method) rt: 0.64 min, m / z = 156.1 [M+H]+. N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[4-(methoxymethyl)-2-azabicyclo[2.2.2]octan-2- yl]pyrimidin-4-amine

[0425] To 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (208 mg, 0.883 mmol) and 4-(methoxymethyl)-2-azabicyclo[2.2.2]octane (164 mg, 1.06 mmol) in butan-1-ol (10 mL), N,N-diisopropylethylamine (0.15 mL, 0.88 mmol) was added. The mixture heated to 100 °C and stirred for 30 hrs. The solvent was removed under vacuum and the residue was purified by reversed-phase column chromatography, over C18-modified silica gel, eluting with a 5% – 70% gradient of MeCN (0.1 v / v NH3) in water (0.1% v / v NH3) to afford the title compound as a solid (167 mg, 0.466 mmol, 53%).

[0426] 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 9.48 – 9.11 (m, 1H), 7.91 – 7.63 (m, 1H), 6.46 – 5.81 (m, 2H), 4.62 (s, 1H), 3.34 (s, 2H) 3.32 – 3.21 (m, 3H), 3.18 - 3.13 (m, 2H), 1.93 – 1.59 (m, 5H), 1.59 – 1.34 (m, 4H), 0.92 (d, J = 8.1 Hz, 2H), 0.71 – 0.54 (m, 2H).

[0427] UPLC-MS (4 min, basic method) rt: 1.69 min, m / z = 355.2 [M+H]+. Example 52: Synthesis of 2-[4-[(5-Cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.1.1]hexane-4-carboxamide (Compound 19)

[0428] To ethyl 2-[4-[(5-cyclopentyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.1.1]hexane-4-carboxylate (20 mg, 52 µmol) was added 7 M NH3 in MeOH (12 mL) and the reaction stirred at room temperature for 42 hours. The reaction mixture was concentrated to dryness to afford the title compound as a solid (18 mg, 48 µmol, 92%).

[0429] 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.41 (s, 1H), 7.86 (d, J = 5.7 Hz, 1H), 7.41 (s, 1H), 7.12 (s, 1H), 6.30 (s, 2H), 4.65 (t, J = 1.8 Hz, 1H), 3.54 (s, 2H), 3.00 (p, J = 7.9 Hz, 1H), 2.13 – 2.07 (m, 2H), 2.03 – 1.93 (m, 2H), 1.77 – 1.53 (m, 8H).

[0430] UPLC-MS (basic method, 4 min): Rt: 1.24 min, m / z = 354.2 [M+H]+. Example 53: Synthesis of 1-[2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]- 2-azabicyclo[2.2.1]heptan-4-yl]cyclopropanol (Compound 32)O2-tert-Butyl O4-Methyl 2-Azabicyclo[2.2.1]heptane-2,4-dicarboxylate

[0431] To a solution of 2-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptane-4-carboxylic acid (2.00 g, 8.29 mmol) in DMF (40 mL) was added potassium carbonate (2.29 g, 16.6 mmol). The mixture was stirred for 15 min before methyl iodide (2.6 mL, 41 mmol) was added. The mixture was heated to 35 °C and stirred for 5 days. The volatiles were removed under reduced pressure and the residue was partitioned between EtOAc (70 mL) and water (70 mL). The aqueous layer was extracted with EtOAc (50 mL). The organics were combined and washed with brine (70 mL), then dried over Na2SO4. The volatiles were removed under reduced pressure to afford the title compound as an oil (1.98 g, 7.75 mmol, 94%).

[0432] 1H NMR (400 MHz, DMSO-d6) δ 4.15 – 4.06 (m, 1H), 3.65 (s, 3H), 3.42 – 3.33 (m, 1H), 3.17 – 3.09 (m, 1H), 2.01 – 1.88 (m, 1H), 1.87 – 1.52 (m, 5H), 1.38 (s, 9H). tert-Butyl 4-(1-Hydroxycyclopropyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0433] To a stirred solution of O2-tert-butyl O4-methyl 2-azabicyclo[2.2.1]heptane-2,4- dicarboxylate (680 mg, 2.53 mmol) in anhydrous THF (20 mL) at 0 °C under a nitrogen atmosphere was added chlorotriisopropoxytitanium(IV) (3.96 g, 15.2 mmol), followed by the dropwise addition of 1 M solution of ethylmagnesium bromide in THF (25 mL, 25 mmol). The reaction was stirred for 2 days whilst kept in the dark. The reaction mixture was cooled to 0 °C and quenched with saturated aqueous NH4Cl solution (5 mL). DCM (30 mL) was added, and the mixture was filtered through celite, the solid washed with DCM (100 mL) and water (50 mL) then the phases separated. The aqueous phase was extracted with DCM (50 mL), and the combined organic phases washed with brine (50 mL), dried over Na2SO4, filtered and the volatiles removed under reduced pressure to afford the title compound as an oil (316 mg, 1.25 mmol, 49%).

[0434] 1H NMR (400 MHz, DMSO-d6) δ 5.20 (s, 1H), 3.99 (d, J = 11.1 Hz, 1H), 3.23 – 3.08 (m, 1H), 3.06 – 2.96 (m, 1H), 1.70 – 1.41 (m, 5H), 1.38 (s, 9H), 1.34 – 1.24 (m, 1H), 0.59 – 0.45 (m, 4H).

[0435] UPLC-MS (basic method, 2 min, ELS Detector): rt = 1.57 min, m / z = 252.3 [M-H]-. 1-(2-azabicyclo[2.2.1]heptan-4-yl)cyclopropanol

[0436] To a stirred solution of tert-butyl 4-(1-hydroxycyclopropyl)-2- azabicyclo[2.2.1]heptane-2-carboxylate (390 mg, 1.46 mmol) in DCM (14 mL) cooled to 0 °C was added trifluoroacetic acid (1.1 mL, 15 mmol) dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min. The reaction mixture was concentrated under reduced pressure, and the crude residue was dissolved in methanol (3 mL) and loaded onto an SCX cartridge (10 g), washed with methanol (50 mL) and eluted with 2 M NH3 in methanol (20 mL). The eluent was then concentrated under reduced pressure to afford the title compound as a solid (224 mg, 1.46 mmol, 100%).

[0437] 1H NMR (400 MHz, DMSO-d6) δ 4.98 (s, 1H), 3.20 – 3.17 (m, 1H), 2.74 – 2.66 (m, 1H), 2.56 (dd, J = 8.8, 1.2 Hz, 1H), 1.66 – 1.36 (m, 5H), 1.20 – 1.10 (m, 1H), 1.08 – 1.00 (m, 1H), 0.56 – 0.39 (m, 4H).1-[2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptan- 4-yl]cyclopropanol

[0438] To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (335 mg, 1.42 mmol) and 1-(2-azabicyclo[2.2.1]heptan-4-yl)cyclopropanol (224 mg, 1.46 mmol) in n- butanol (20 mL) was added N,N-diisopropylethylamine (1.2 mL, 7.1 mmol). The reaction mixture was heated to 100 °C and allowed to stir for 16 hours. The reaction mixture was concentrated under reduced pressure and diluted with water (60 mL). The mixture was then extracted with DCM (3 × 50 mL), and the combined organic fractions were washed with saturated brine solution (40 mL), dried over Na2SO4and concentrated to dryness to afford an oil, which was purified by column chromatography over silica gel, eluting with a gradient of 2 M NH3 in MeOH (5% to 80%; v / v) in DCM. The residue was further purified by reversed-phase basic preparative HPLC to afford the title compound as a powder (140 mg, 0.378 mmol, 27%).

[0439] 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.29 (s, 1H), 7.80 (s, 1H), 6.18 (s, 2H), 5.21 (s, 1H), 4.47 (d, J = 9.2 Hz, 1H), 3.22 (d, J = 9.1 Hz, 1H), 1.90 – 1.38 (m, 6H), 1.32 – 1.24 (m, 1H), 0.94 – 0.88 (m, 2H), 0.66 – 0.61 (m, 3H), 0.60 – 0.55 (m, 4H).

[0440] UPLC-MS (basic method, 4 min): rt = 1.36 min, m / z = 353.2 [M+H]+. Example 54: Synthesis of 2-[2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]- 2-azabicyclo[2.2.1]heptan-4-yl]propan-2-ol (Compound 33)tert-Butyl 4-(1-Hydroxy-1-methyl-ethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0441] O2-tert-butyl O4-methyl 2-azabicyclo[2.2.1]heptane-2,4-dicarboxylate (1.92 g, 7.52 mmol) was dissolved in THF (20 mL) at 0 °C and 3.4 M solution of methylmagnesium bromidein 2-Me-THF (7.5 mL, 23 mmol) was added to it slowly over a period of 10 min and the reaction mixture was stirred for 24 hours. The reaction mixture was then cooled, and quenched with saturated aqueous ammonium chloride solution (10 mL) and stirred for 15 minutes. Ethyl acetate (50 mL) was added to it then the organic phase was washed with water (20 mL), saturated aqueous brine solution (20 mL) and dried over sodium sulfate. The organic phase was concentrated to dryness under reduced pressure to afford the title compound as an oil (1.91 g, 7.48 mmol, 99%).

[0442] 1H NMR (400 MHz, Chloroform-d) δ 4.17 (s, 1H), 3.37 (dd, J = 9.3, 3.3 Hz, 1H), 3.07 – 2.88 (m, 1H), 2.03 (s, 1H), 1.88 – 1.51 (m, 6H), 1.44 (d, J = 0.7 Hz, 9H), 1.30 – 1.24 (m, 6H). 2-(2-Azabicyclo[2.2.1]heptan-4-yl)propan-2-ol

[0443] tert-butyl 4-(1-hydroxy-1-methyl-ethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (0.80 g, 3.1 mmol) was dissolved in DCM (10 mL) at 0 °C and trifluoroacetic acid (1.2 mL, 15.7 mmol) was added to it and the reaction mixture was stirred for 12 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in methanol (10 mL) and loaded onto an SCX-2 cartridge. The cartridge was washed with MeOH, then the compound was eluted with 0.7 M NH3in MeOH. The eluent was concentrated to dryness under reduced pressure to afford the title compound as an oil (270 mg, 1.74 mmol, 56%).

[0444] 1H NMR (400 MHz, Chloroform-d) δ 3.47 (s, 1H), 3.46 – 3.41 (m, 1H), 3.07 – 3.00 (m, 1H), 2.63 (dd, J = 9.3, 1.2 Hz, 1H), 1.78 – 1.74 (m, 2H), 1.58 – 1.50 (m, 2H), 1.41 – 1.32 (m, 2H), 1.26 – 1.23 (m, 6H).

[0445] UPLC-MS analysis: (2 min, basic): rt = 0.43 min, m / z = 156.1 [M+H]+. 2-[2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptan- 4-yl]propan-2-ol

[0446] 2-(2-azabicyclo[2.2.1]heptan-4-yl)propan-2-ol (270 mg, 1.74 mmol) and 2-chloro-N- (5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (410 mg, 1.74 mmol) were dissolved in n- butanol (5 mL) and N,N-diisopropylethylamine (0.91 mL, 5.2 mmol) was added to it and the reaction mixture was stirred for 10 minutes. Then, the reaction mixture was heated to reflux and stirred for 12 hours. The reaction mixture was then concentrated to dryness under reduced pressure, then the residue was purified by flash column chromatography, over silica gel, eluting with a gradient of ethyl acetate (0% - 100% v / v) in iso-hexane followed by a gradient of MeOH(0% - 20%) in DCM. The residue was then suspended in water (10 mL) and stirred for 16 hours then the product was collected by filtration. The precipitate was then suspended in ethyl acetate (10 mL) and stirred for 6 hours then the product was collected by filtration to afford the title compound as a solid (250 mg, 0.705 mmol, 41%).

[0447] 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 9.47 (s, 1H), 7.75 (d, J = 5.8 Hz, 1H), 6.16 (s, 2H), 4.45 (s, 1H), 4.35 (d, J = 11.1 Hz, 1H), 3.49 (dd, J = 23.7, 7.0 Hz, 1H), 3.03 (dd, J = 16.5, 9.5 Hz, 1H), 1.89 – 1.50 (m, 5H), 1.48 – 1.36 (m, 1H), 1.34 – 1.21 (m, 1H), 1.14 (d, J = 5.9 Hz, 6H), 0.95 – 0.80 (m, 2H), 0.71 – 0.51 (m, 2H).

[0448] UPLC-MS analysis: (4 min, basic): rt = 1.36 min, m / z = 355.4 [M+H]+. Example 55: Synthesis of 2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-N- methyl-2-azabicyclo[2.2.1]heptane-4-carboxamide (Compound 34)N-Methyl-2-azabicyclo[2.2.1]heptane-4-carboxamide

[0449] To a solution of 2-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptane-4-carboxylic acid (1.00 g, 4.14 mmol) in THF (40 mL) was added N,N'-carbonyldiimidazole (806 mg, 4.97 mmol) and the reaction mixture was stirred at room temperature for 3 hours.2.0 M solution of methylamine in MeOH (4.1 mL, 8.3 mmol) was added and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, giving an oil that was diluted with EtOAc (20 mL). The organic layer was washed with water (3 × 20 mL) and saturated aqueous brine solution (20 mL), dried over Na2SO4, and concentrated under reduced pressure to dryness to afford an oil. To the residue was added 4 M HCl in 1,4- dioxane (1.4 mL, 41 mmol), and the resulting mixture stirred for 1 hour. The volatiles were removed under reduced pressure, and the residue was dissolved in MeOH, loaded onto an SCX-2 cartridge. The cartridge was washed with MeOH and the compound was eluted with 2M NH3inMeOH. The volatiles were removed from the eluent under reduced pressure to afford the title compound as an oil (280 mg, 1.82 mmol, 44%).

[0450] 1H NMR (400 MHz, DMSO-d6) δ 3.30 – 3.26 (m, 1H), 2.83 (dd, J = 9.0, 3.2 Hz, 1H), 2.69 – 2.62 (m, 1H), 2.56 (d, J = 4.5 Hz, 3H), 1.76 – 1.30 (m, 7H). 2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-N-methyl-2- azabicyclo[2.2.1]heptane-4-carboxamide

[0451] To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (260 mg, 1.10 mmol) and N-methyl-2-azabicyclo[2.2.1]heptane-4-carboxamide (276 mg, 1.43 mmol) in n-butanol (12 mL) was added N,N-diisopropylethylamine (0.77 mL, 4.4 mmol). The reaction mixture was heated to 100 °C and allowed to stir for 18 h. The reaction mixture was concentrated under reduced pressure and diluted with water (30 mL). The mixture was then extracted with DCM (3 × 30 mL). The combined organic fractions were washed with saturated brine solution (30 mL), dried over Na2SO4and concentrated to dryness to afford an oil. The crude material was purified by column chromatography over silica gel, eluting with a gradient of 2 M NH3 in MeOH (5% to 10%; v / v) in DCM to afford a powder, which was purified further by reversed-phase basic preparative HPLC to afford the title compound as a solid (89 mg, 0.25 mmol, 23%).

[0452] 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.33 (s, 1H), 7.97 – 7.65 (m, 2H), 6.19 (s, 2H), 4.54 (s, 1H), 3.57 – 3.44 (m, 1H), 3.37 (s, 1H), 2.63 (d, J = 4.2 Hz, 3H), 1.95 – 1.71 (m, 5H), 1.71 – 1.56 (m, 2H), 0.91 (d, J = 8.3 Hz, 2H), 0.65 (t, J = 5.8 Hz, 2H).

[0453] UPLC-MS (basic method, 4 min): rt = 1.13 min, m / z: 354.3 [M+H]+. Example 56: Synthesis of 2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.2.1]heptane-4-carboxamide Synthesis of (Compound 35)2-Azabicyclo[2.2.1]heptane-4-carboxamide

[0454] To a solution of 2-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptane-4-carboxylic acid (203 mg, 0.841 mmol) in anhydrous THF (8 mL) was added N,N'-carbonyldiimidazole (205 mg, 1.26 mmol) and the reaction mixture was stirred at ambient temperature for 1 h.7 M solution of NH3 in MeOH (0.24 mL, 1.7 mmol) was added, and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was concentrated under reduced pressure, giving an oil which was diluted with EtOAc (20 mL) and water (20 mL). The layers were separated, and the organic layer washed with water (2 × 20 mL) and saturated brine solution (20 mL), dried over Na2SO4 and concentrated under reduced pressure to dryness to afford a solid.4 M solution of HCl in 1,4-dioxane (2.1 mL, 8.4 mmol) was added, and the resulting mixture stirred for 1 h. The volatiles were removed under reduced pressure to give a residue, which was dissolved in MeOH, loaded onto an SCX cartridge. The cartridge was washed with MeOH then the compound eluted with 2 M NH3 in MeOH. The volatiles were removed from the eluent under reduced pressure to afford the title compound as a solid (105 mg, 0.487 mmol, 58%).

[0455] 1H NMR (400 MHz, DMSO-d6) δ 4.11 (s, 1H), 3.27 (t, J = 2.1 Hz, 1H), 2.85 (dd, J = 9.0, 3.4 Hz, 1H), 2.65 (dd, J = 9.0, 1.2 Hz, 1H), 1.79 – 1.40 (m, 6H). 2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptane-4- carboxamide

[0456] To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (91 mg, 0.39 mmol) and 2-azabicyclo[2.2.1]heptane-4-carboxamide (104 mg, 0.444 mmol) in n- butanol (4 mL) was added N,N-diisopropylethylamine (0.20 mL, 1.2 mmol). The reaction mixture was heated to 90 °C and stirred for 3 days. The reaction mixture was concentrated under reduced pressure and diluted with water (30 mL). The mixture was then extracted with 3:1 CHCl3:IPA (3 × 20 mL), and the combined organic fractions were washed with saturated brine solution (20 mL), dried over Na2SO4 and concentrated to dryness to afford a solid. The crude material was purified by column chromatography over C18-modified silica gel, eluting with a gradient of MeCN (0.1% NH3) (5% to 40%; v / v) in water (0.1% NH3), the volatiles removed under reduced pressure to afford the title compound as a solid (65 mg, 0.19 mmol, 50%).

[0457] 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 9.36 (s, 1H), 7.81 (s, 1H), 7.34 (d, J = 11.1 Hz, 1H), 7.06 (s, 1H), 6.19 (s, 2H), 4.56 – 4.50 (m, 1H), 3.61 – 3.44 (m, 1H), 3.40 – 3.34 (m, 1H), 1.98 – 1.54 (m, 7H), 0.91 (d, J = 8.3 Hz, 2H), 0.65 (t, J = 3.9 Hz, 2H).

[0458] UPLC-MS (basic method, 4 min): rt = 1.06 min, m / z: 340.3 [M+H]+.Example 57: Synthesis of N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[3-(1- methoxycyclopropyl)pyrrolidin-1-yl]pyrimidin-4-amine (Compound 58)tert-Butyl 3-(1-hydroxycyclopropyl)pyrrolidine-1-carboxylate

[0459] To a stirred solution of methyl-1-Boc-pyrrolidine-3-carboxylate (500 mg, 2.18 mmol) in THF (10 mL) was added chlorotriisopropoxytitanium(IV) (3.41 g, 13.1 mmol) at 0 °C. After 15 minutes of stirring, 1.0 M solution of ethylmagnesium bromide in THF (22 mL, 22 mmol) was added dropwise under a nitrogen atmosphere at 0 °C in the dark. The reaction mixture was stirred for 16 hours, after which the reaction was quenched with saturated ammonium chloride solution (5 mL) and diluted with ethyl acetate (20 mL). After 15 minutes of stirring, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic extracts were washed with brine (10 mL), and concentrated under reduced pressure to afford the title compound as an oil (472 mg, 2.08 mmol, 95%).

[0460] 1H NMR (400 MHz, Chloroform-d) δ 3.52 – 3.37 (m, 2H), 3.25 – 3.08 (m, 2H), 2.10 – 1.96 (m, 1H), 1.85 – 1.63 (m, 2H), 1.39 (s, 9H), 0.78 – 0.67 (m, 2H), 0.52 – 0.39 (m, 2H). tert-Butyl 3-(1-methoxycyclopropyl)pyrrolidine-1-carboxylate

[0461] To a stirring solution of tert-butyl 3-(1-hydroxycyclopropyl)pyrrolidine-1-carboxylate (472 mg, 2.08 mmol) in THF (8 mL) was added 60% w / w suspension of sodium hydride in mineral oil (249 mg, 6.23 mmol) portion wise at 0 °C under a nitrogen atmosphere. The reaction mixture was allowed to warm up to room temperature and stirred for 30 minutes. Afterwards, it was cooled back down to 0 °C and then methyl iodide (0.39 mL, 6.2 mmol) was added dropwise.Reaction was warmed to room temperature. And stirred for 16 hours at room temperature. The reaction was then quenched with saturated ammonium chloride solution (5 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound as an oil (470 mg, 1.95 mmol, 94%).

[0462] 1H NMR (400 MHz, Chloroform-d) δ 3.56 – 3.39 (m, 2H), 3.38 – 3.14 (m, 5H), 1.88 – 1.77 (m, 1H), 1.50 – 1.40 (m, 11H), 0.79 – 0.68 (m, 2H), 0.54 – 0.45 (m, 2H). 3-(1-Methoxycyclopropyl)pyrrolidine hydrochloride

[0463] To a round bottom flask was added tert-butyl 3-(1-methoxycyclopropyl)pyrrolidine- 1-carboxylate (470 mg, 1.95 mmol) in 1,4-dioxane (4.7 mL) and the reaction mixture was cooled to 0 °C.4 M hydrogen chloride solution in 1,4-dioxane (4.9 mL, 19.5 mmol) was added dropwise and reaction was stirred for 3 hours at room temperature. The volatiles were removed under reduced pressure and the residue was triturated in diethyl ether to afford the title compound as a gum (313 mg, 1.76 mmol, 90%).

[0464] 1H NMR (400 MHz, Chloroform-d) δ 9.53 (s, 2H), 3.27 – 3.18 (m, 2H), 3.20 – 3.03 (m, 5H), 2.01 – 1.86 (m, 1H), 1.68 – 1.48 (m, 2H), 1.00 – 0.59 (m, 2H), 0.54 – 0.37 (m, 2H). N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[3-(1-methoxycyclopropyl)pyrrolidin-1-yl]pyrimidin- 4-amine

[0465] To a stirred solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4- amine (290 mg, 1.23 mmol) and 3-(1-methoxycyclopropyl)pyrrolidine hydrochloride (306 mg, 1.72 mmol) in 1-butanol (3 mL) was added N,N-diisopropylethylamine (1.1 mL, 6.2 mmol). The reaction mixture was heated to 120 °C and stirred for 16 hours. The volatiles were removed under reduced pressure. The crude residue was diluted with water (10 mL) and extracted into dichloromethane (2 × 25 mL). The organic layers were combined, washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by reversed-phase preparative HPLC to afford the title compound as a solid (81 mg, 0.24 mmol, 19%).

[0466] 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.30 (s, 1H), 7.78 (d, J = 5.7 Hz, 1H), 6.44 – 5.83 (m, 2H), 3.68 – 3.55 (m, 2H), 3.37 – 3.31 (m, 1H), 3.29 (s, 3H), 3.02 – 2.98 (m, 1H), 2.88 – 2.76 (m, 1H), 1.92 – 1.87 (m, 1H), 1.86 – 1.74 (m, 1H), 1.58 – 1.48 (m, 1H), 0.90 – 0.84 (m, 2H), 0.67 – 0.62 (m, 2H), 0.61 – 0.56 (m, 2H), 0.56 – 0.46 (m, 2H).

[0467] UPLC MS (Basic method, 6 min) rt = 2.50 min, m / z = 341.1 [M+H]+. Example 58: Synthesis of 1-[1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2- yl]pyrrolidin-3-yl]cyclopropanol (Compound 61)Methyl 1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidine-3- carboxylate

[0468] To a stirred solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4- amine (300 mg, 1.27 mmol) and methyl 3-pyrrolidinecarboxylate hydrochloride (253 mg, 1.53 mmol) in 1-butanol (6 mL) was added N,N-diisopropylethylamine (1.1 mL, 6.4 mmol). The reaction mixture was heated to reflux and stirred for 16 hours. The volatiles were then removed under reduced pressure. The crude residue was diluted water (5 mL) the extracted with DCM (2 × 20 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography, over silica gel, eluting with 92:8 DCM;MeOH to afford the title compound as an oil (290 mg, 0.883 mmol, 69%).

[0469] 1H NMR (400 MHz, Chloroform-d) δ 7.93 (d, J = 5.8 Hz, 1H), 6.02 (d, J = 5.8 Hz, 1H), 5.91 (s, 1H), 3.91 – 3.82 (m, 1H), 3.80 – 3.67 (m, 5H), 3.65 – 3.50 (m, 1H), 3.22 – 3.10 (m, 1H), 2.32 – 2.17 (m, 2H), 1.92 – 1.80 (m, 1H), 1.00 – 0.85 (m, 2H), 0.77 – 0.68 (m, 2H).

[0470] UPLC MS (Basic method, 2 min) rt = 0.90 min, m / z = 329.3 [M+H]+. 1-[1-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]pyrrolidin-3- yl]cyclopropanol

[0471] To a stirred solution of methyl 1-[4-[(5-cyclopropyl-1H-pyrazol-3- yl)amino]pyrimidin-2-yl]pyrrolidine-3-carboxylate (160 mg, 0.487 mmol) in THF (8 mL) was added chlorotriisopropoxytitanium(IV) (762 mg, 2.92 mmol). The reaction mixture was cooled to 0 °C and stirred for 20 minutes then 1.0 M solution of ethylmageniusm bromide in THF (4.9 mL, 4.9 mmol) was added dropwise at 0 °C in the dark. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction was quenched with saturated ammonium chloride solution (5 mL) and extracted with dichloromethane (2 × 30 mL). The combined organic extracts were dried over Na2SO4 then concentrated to dryness under reduced pressure. The crude residue was purified by flash column purification, over silica gel, eluting with 96:4 DCM:MeOH. The residue was dissolved in methanol (2 mL) and loaded onto an SCX-2 cartridge. The cartridge was washed with MeOH (10 mL), then the compound was eluted with 2 M ammonia in MeOH (20 mL). The eluent was concentrated to dryness under reduced pressure. The residue was recrystallized from refluxing methanol to afford the title compound as a solid (40 mg, 0.12 mmol, 25%).

[0472] 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.26 (s, 1H), 7.78 (d, J = 5.7 Hz, 1H), 6.51 – 5.97 (m, 2H), 5.18 (s, 1H), 3.66 – 3.54 (m, 2H), 3.40 – 3.27 (m, 1H), 3.25 – 3.15 (m, 1H), 2.17 – 2.04 (m, 1H), 1.96 – 1.85 (m, 1H), 1.85 – 1.74 (m, 2H), 0.94 – 0.84 (m, 2H), 0.65 – 0.57 (m, 2H), 0.57 – 0.50 (m, 2H), 0.44 – 0.37 (m, 2H).

[0473] UPLC-MS (Basic method, 2 min) rt = 1.25 min, m / z = 327.3 [M+H+]. Example 59: Synthesis of 1-[2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]- 2-azabicyclo[2.2.2]octan-4-yl]cyclopropanol (Compound 74)O2-tert-Butyl O4-Methyl 2-Azabicyclo[2.2.2]octane-2,4-dicarboxylate

[0474] To a stirring solution of 2-tert-butoxycarbonyl-2-azabicyclo[2.2.2]octane-4- carboxylic acid (200 mg, 0.783 mmol) in DMF (10 mL) was added potassium carbonate (119 mg, 0.862 mmol) and the reaction mixture was stirred at room temperature for 15 minutes. Methyl iodide (59 µL, 0.940 mmol) was added then the reaction mixture was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated to dryness under reduced pressure and the residual material was partitioned between EtOAc (20 mL) and water (20 mL). The combined organic portion was washed with water (10 mL), brine (10 mL) and then dried over anhydrous MgSO4. The solvent was removed under reduced pressure to afford the title compound as a solid (183 mg, 0.656 mmol, 84%).

[0475] 1H NMR (400 MHz, DMSO-d6) δ 3.94 - 3.88 (m, 1H), 3.88 - 3.83 (m, 1H) 3.62 (d, J = 1.1 Hz, 3H), 3.34 (m, 1H), 1.87 – 1.53 (m, 8H), 1.39 (d, J = 5.4 Hz, 9H). tert-Butyl 4-(1-Hydroxycyclopropyl)-2-azabicyclo[2.2.2]octane-2-carboxylate

[0476] To a 0 °C cooled stirring solution of O2-tert-butyl O4-methyl 2- azabicyclo[2.2.2]octane-2,4-dicarboxylate (168 mg, 0.624 mmol) in THF (4 mL) was added ClTi(i-OPr)3(163 mg, 0.624 mmol) and the reaction mixture was warmed to room temperature and stirred for 5 minutes.1 M solution of EtMgBr in Et2O (3.7 mL, 3.7 mmol) was added dropwise at 0 °C and the reaction mixture was stirred at room temperature for 22.5 hours. The reaction mixture was cooled to 0 °C and quenched with saturated aqueous NH4Cl solution (0.5 mL) then diluted with EtOAc (10 mL) and passed through a pad of celite. The organic layer wasseparated from the aqueous layer formed in the filtrate, dried over anhydrous MgSO4 and concentrated to dryness to afford the crude compound. The residue was purified by flash column chromatography, over silica gel, eluting with a gradient of 40-50% of EtOAc in iso-hexane to afford the title compound as a solid (123 mg, 0.460 mmol, 74%).

[0477] 1H NMR (400 MHz, DMSO-d6) δ 5.06 (d, J = 2.1 Hz, 1H), 3.92 – 3.84 (m, 0.5H), 3.84 – 3.77 (m, 0.5H), 3.23 – 3.14 (m, 1H), 3.15 – 3.05 (m, 1H), 1.74 – 1.60 (m, 2H), 1.60 - 1.50 (m, 2H) 1.49 - 1.21 (m, 13H), 0.56 – 0.47 (m, 2H), 0.41 – 0.34 (m, 2H). 1-(2-Azabicyclo[2.2.2]octan-4-yl)cyclopropanol;2,2,2-trifluoroacetic acid

[0478] To a solution of tert-butyl 4-(1-hydroxycyclopropyl)-2-azabicyclo[2.2.2]octane-2- carboxylate (123 mg, 0.460 mmol) in DCM (5.0 mL) was added trifluoroacetic acid (0.70 mL, 9.2 mmol) dropwise and the resultant reaction mixture was stirred at room temperature for 2.25 hours. The solvent was removed under reduced pressure to yield the title compound as an oil (129 mg, 0.443 mmol, 96%).

[0479] 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 2H), 3.39 (s, 1H), 2.98 (t, J = 5.8 Hz, 2H), 1.93 – 1.78 (m, 2H), 1.73-1.59 (m, 2H), 1.55 – 1.42 (m, 2H), 1.41-1.48 (m, 2H), 0.58 – 0.49 (m, 2H), 0.47 – 0.37 (m, 2H). 1-[2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.2.2]octan-4- yl]cyclopropanol

[0480] To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (86 mg, 0.365 mmol) and 1-(2-azabicyclo[2.2.2]octan-4-yl)cyclopropanol;2,2,2-trifluoroacetic acid (123 mg, 0.438 mmol) in n-BuOH (4.5 mL) was added N,N-diisopropylethylamine (0.64 mL, 3.7 mmol) and the reaction mixture was stirred at 100 °C for 41 hours. The reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The crude residue was purified by reversed-phase flash column chromatography, over C18-modified silica gel, eluting with a gradient of 25-55% of acetonitrile (0.1% v / v NH3) in water (0.1% v / v NH3). The residue was further purified by column chromatography, over silica gel, eluting with a gradient of 5-10% of MeOH in EtOAc to afford the title compound as a solid (18 mg, 47 µmol, 13%).

[0481] 1H NMR (400 MHz, DMSO-d6): δ 11.92 (s, 1H), 9.38 – 9.19 (m, 1H), 7.89 – 7.73 (m, 1H), 6.22 (s, 1H), 6.12 (s, 1H), 5.12 – 4.95 (m, 1H), 4.63 – 4.52 (m, 1H), 3.35 (s, 2H), 1.87 –1.78 (m, 1H), 1.80 – 1.58 (m, 4H), 1.56 – 1.39 (m, 4H), 0.98 – 0.86 (m, 2H), 0.72 – 0.50 (m, 4H), 0.52 – 0.37 (m, 2H).

[0482] UPLC-MS (basic method, 4 min): rt = 1.48 min, m / z: 367.4 [M+H]+. Example 60: Synthesis of 2-[2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]- 2-azabicyclo[2.2.2]octan-4-yl]propan-2-ol (Compound 76)tert-Butyl 4-(1-Hydroxy-1-methyl-ethyl)-2-azabicyclo[2.2.2]octane-2-carboxylate

[0483] To a solution of O2-tert-butyl O4-methyl 2-azabicyclo[2.2.2]octane-2,4-dicarboxylate (0.45 g, 1.64 mmol) in anhydrous THF (4.0 mL) at -78 °C and under nitrogen atmosphere was added 3.4 M solution of methylmagnesium bromide in 2-Me-THF (1.06 mL, 3.61 mmol) drop- wise and the reaction mixture was stirred for 1 hour. The reaction mixture was then warmed to room temperature and stirred further for 19 hours. The reaction mixture was cooled to 0 °C then quenched with saturated aqueous NH4Cl solution (3.0 mL). The compound was extracted with EtOAc (2 × 30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous MgSO4and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography, over silica gel, eluting with a gradient of ethyl acetate in iso- hexane (5% to 50% v / v) to afford the title compound as a solid (0.39 g, 1.5 mmol, 88%).

[0484] 1H NMR (400 MHz, DMSO-d6) δ 4.19 – 4.10 (m, 1H), 3.89 – 3.73 (m, 1H), 3.16 (d, J = 16.5 Hz, 2H), 1.74 – 1.59 (m, 2H), 1.59 – 1.42 (m, 6H), 1.39 (d, J = 6.0 Hz, 9H), 1.01 (s, 6H). 2-(2-Azabicyclo[2.2.2]octan-4-yl)propan-2-ol;2,2,2-trifluoroacetic acid

[0485] To a solution of tert-butyl 4-(1-hydroxy-1-methyl-ethyl)-2-azabicyclo[2.2.2]octane-2- carboxylate (190 mg, 0.700 mmol) in DCM (6.0 mL) was added trifluoroacetic acid (1.10 mL, 14.1 mmol) dropwise and the reaction mixture was stirred at room temperature for 4.5 hours. The solvent was removed under reduced pressure to afford the title compound as an oil (200 mg, 0.92 mmol, 100%).

[0486] 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 2H), 3.44 – 3.26 (m, 1H), 3.04 – 2.91 (m, 2H), 1.88 – 1.76 (m, 2H), 1.71 – 1.44 (m, 6H), 1.01 (s, 6H). 2-[2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.2.2]octan-4- yl]propan-2-ol

[0487] To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (139 mg, 0.59 mmol) and 2-(2-azabicyclo[2.2.2]octan-4-yl)propan-2-ol;2,2,2-trifluoroacetic acid (200 mg, 0.71 mmol) in n-BuOH (7.0 mL) was added N,N-diisopropylethylamine (1.0 mL, 5.9 mmol) and the reaction mixture was stirred at 100 °C for 29.5 hours, then the solvent was removed under reduced pressure. The residue was purified by reversed-phase column chromatography, over C18-modified silica gel, eluting with a gradient of 25-55% of acetonitrile (0.1% v / v NH3) in water (0.1% v / v NH3). The residue was dissolved in MeOH (2 mL) then loaded onto an SCX-2 cartridge. The cartridge was washed with MeOH (20 mL), then the compound was eluted with 2 M NH3 in MeOH (20 mL). The eluent was concentrated to dryness under reduced pressure. The residue was further purified by reversed-phase basic preparative HPLC to afford the title compound as a solid (36 mg, 0.10 mmol, 16%).

[0488] 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.45 – 9.11 (m, 1H), 7.90 – 7.71 (m, 1H), 6.52 – 5.90 (m, 2H), 4.60 – 4.48 (m, 1H), 4.16 (s, 1H), 3.48 – 3.36 (m, 2H), 1.89 – 1.47 (m, 9H), 1.13 – 1.00 (m, 6H), 0.95 – 0.85 (m, 2H), 0.70 – 0.57 (m, 2H).

[0489] UPLC-MS (basic method, 4 min): rt = 1.50 min, m / z: 369.4 [M+H]+. Example 61: Synthesis of N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[4-(methylsulfonylmethyl)- 2-azabicyclo[2.1.1]hexan-2-yl]pyrimidin-4-amine (Compound 80)tert-Butyl 4-(Methylsulfanylmethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

[0490] Sodium thiomethoxide (72 mg, 1.03 mmol) was dissolved in THF (2 mL) and the reaction mixture was stirred at room temperature for 5 minutes. Then 2-methyl-2-propanyl 4- {[(methylsulfonyl)oxy]methyl}-2-azabicyclo[2.1.1]hexane-2-carboxylate (100 mg, 0.343 mmol) was added to the reaction mixture and stirred. The reaction mixture was stirred for a further 24 hours. Saturated aqueous ammonium chloride solution (10 mL) was added, and the organics were extracted with ethyl acetate (3 × 30 mL). The combined organic extracts were washed with water (20 mL), saturated aqueous brine solution (20 mL), dried over Na2SO4, then concentrated to dryness under reduced pressure to afford the title compound as an oil (70 mg, 0.29 mmol, 84% yield).

[0491] 1H NMR (400 MHz, Chloroform-d): δ 4.33 (t, J = 1.8 Hz, 1H), 3.26 (s, 2H), 2.80 (s, 2H), 2.14 (s, 3H), 1.79 (dt, J = 4.1, 1.9 Hz, 2H), 1.52 (dd, J = 4.5, 1.9 Hz, 2H), 1.47 (s, 9H). tert-Butyl 4-(Methylsulfonylmethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate

[0492] tert-Butyl 4-(methylsulfanylmethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (70 mg, 0.288 mmol) was dissolved in methanol (2 mL) and water (1 mL). Oxone (219 mg, 1.44 mmol) was added, and the reaction mixture was stirred for 6 hours. DCM (10 mL) was added to the reaction mixture and organic solvent was decanted off. Residual solid was washed with DCM (10 mL). The combined organic solutions were dried over Na2SO4 and concentrated to dryness under reduced pressure to afford the title compound as a solid (45 mg, 0.16 mmol, 57%).

[0493] 1H NMR (400 MHz, Chloroform-d) δ 4.41 (t, J = 1.9 Hz, 1H), 3.46 (s, 2H), 3.41 (s, 2H), 2.95 (s, 2H), 2.05 (dt, J = 4.4, 1.9 Hz, 2H), 1.71 (dd, J = 4.7, 1.9 Hz, 2H), 1.47 (s, 9H). 4-(Methylsulfonylmethyl)-2-azabicyclo[2.1.1]hexane;2,2,2-trifluoroacetic acid

[0494] tert-Butyl 4-(methylsulfonylmethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (45 mg, 0.163 mmol) was dissolved in DCM (3 mL) at 0 °C and trifluoroacetic acid (63 µL, 0.817 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure to afford the title compound as an oil (47 mg, 0.16 mmol, 100%).

[0495] 1H NMR (400 MHz, Chloroform-d) δ 3.46 (s, 2H), 3.41 (s, 2H), 3.04 – 3.00 (m, 1H), 2.94 (d, J = 0.6 Hz, 2H), 2.90 (s, 3H). N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[4-(methylsulfonylmethyl)-2-azabicyclo[2.1.1]hexan- 2-yl]pyrimidin-4-amine

[0496] 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (39 mg, 0.16 mmol) was dissolved in n-butanol (5 mL) and 4-(methylsulfonylmethyl)-2- azabicyclo[2.1.1]hexane;2,2,2-trifluoroacetic acid (47 mg, 0.16 mmol) and N,N- diisopropylethylamine (0.14 mL, 0.82 mmol) was added. The reaction mixture was heated to reflux and stirred for 24 hours. The solvent was evaporated under reduced pressure and the crude material was diluted with water (20 mL) extracted with 1:4 v / v MeOH / DCM (2 × 20 mL). The combined organic extracts were washed with water (20 mL), saturated aqueous brine solution (20 mL), dried over Na2SO4then concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography, over silica gel, eluting with a gradient of 0-100% ethyl acetate in iso-hexane gradient followed by a gradient of 0-20% MeOH in DCM MeOH / DCM. The residue was further purified by basic reversed-phase preparative HPLC to afford the title compound as a solid (8.0 mg, 21 µmol, 13%).

[0497] 1H NMR (400 MHz, DMSO-D6) δ 11.93 (s, 1H), 9.39 (s, 1H), 7.85 (d, J = 5.7 Hz, 1H), 6.29 (s, 1H), 6.15 (s, 1H), 4.83 – 4.56 (m, 1H), 3.69 (s, 2H), 3.54 (s, 2H), 3.01 (s, 3H), 2.01 (s, 2H), 1.90 – 1.78 (m, 1H), 1.62 – 1.48 (m, 2H), 1.01 – 0.79 (m, 2H), 0.73 – 0.60 (m, 2H).

[0498] UPLC-MS analysis: (4 min, basic): rt = 1.14 min, m / z = 375.3 [M+H]+. Example 62: Synthesis of 3-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3- azabicyclo[3.1.1]heptan-1-ol (Compound 81)3-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3-azabicyclo[3.1.1]heptan-1-ol

[0499] To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (130 mg, 0.552 mmol) and 3-azabicyclo[3.1.1]heptan-1-ol hydrochloride (99 mg, 0.66 mmol) in n- butanol (6 mL) was added N,N-diisopropylethylamine (0.48 mL, 2.8 mmol). The reaction mixture was heated to 100 °C and allowed to stir for 16 h. The reaction mixture was concentrated to dryness under reduced pressure and diluted with water (40 mL). The mixture was then extracted with DCM (3 × 30 mL). The combined organic fractions were washed with saturated aqueous brine solution (30 mL), dried over Na2SO4and concentrated to dryness to afford a solid. The residue was purified by basic reversed-phase preparative HPLC to afford the title compound as a solid (20 mg, 64 µmol, 12%).

[0500] 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.37 (s, 1H), 7.86 (d, J = 5.7 Hz, 1H), 6.25 (s, 2H), 5.59 (s, 1H), 3.49 (d, J = 14.4 Hz, 4H), 2.40 (s, 1H), 1.98 (t, J = 7.0 Hz, 2H), 1.84 (td, J = 8.5, 4.4 Hz, 1H), 1.66 – 1.57 (m, 2H), 0.95 – 0.86 (m, 2H), 0.67 – 0.63 (m, 2H).

[0501] UPLC-MS (basic method, 4 min): rt = 1.19 min, m / z: 313.1 [M+H]+. Example 63: Synthesis of 2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.1.1]hexane-4-carbonitrile (Compound 82)tert-Butyl 4-Carbamoyl-2-azabicyclo[2.1.1]hexane-2-carboxylate

[0502] 2-tert-Butoxycarbonyl-2-azabicyclo[2.1.1]hexane-4-carboxylic acid (4.32 g, 19.0 mmol) and N,N'-carbonyldiimidazole (4.62 g, 28.5 mmol) were dissolved in THF (50 mL) and the reaction mixture was stirred at room temperature for 4 hours. Then, 0.5 M solution of ammonia in THF (76 mL, 38.0 mmol) was added. The reaction mixture was stirred at room temperature for further 24 hours. The solvent was evaporated, and ice water was added to the crude material, resulting in a precipitation. The precipitated solid was collected by filtration, and the filter cake was washed with water (50 mL), then dried under suction to afford the title compound as a solid (2.70 g, 11.9 mmol, 63%).

[0503] 1H NMR (400 MHz, DMSO-d6) δ 7.36 (s, 1H), 7.11 (s, 1H), 4.09 (t, J = 1.8 Hz, 1H), 3.27 (s, 2H), 2.06 – 1.96 (m, 2H), 1.54 – 1.44 (m, 2H), 1.36 (s, 9H).

[0504] UPLC-MS analysis: (2 min, basic): rt = 0.84 min, m / z = 225.2 [M-H]+. tert-Butyl 4-Cyano-2-azabicyclo[2.1.1]hexane-2-carboxylate

[0505] tert-Butyl 4-carbamoyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (2.40 g, 10.6 mmol) was dissolved in pyridine (2.6 mL) at 0 °C and trifluoroacetic anhydride (2.2 mL, 16 mmol) was added slowly to the reaction mixture. Reaction mixture was warmed to room temperature and stirred for 24 h. The reaction mixture was quenched by adding 1 M aqueous solution of HCl (20 mL) then extracted with DCM (2 × 20 mL). The combined organic extracts were separated, then washed with water, brine and dried over sodium sulfate. The solvent was evaporated and crude material was purified by column chromatography, over silica gel, to afford the title compound as a solid (1.92 g, 9.22 mmol, 87%).

[0506] 1H NMR (400 MHz, Chloroform-d) δ 4.34 (s, 1H), 3.56 (s, 2H), 2.31 (dt, J = 4.7, 1.9 Hz, 2H), 1.84 (dd, J = 4.7, 1.9 Hz, 2H), 1.46 (s, 9H). 2-Azabicyclo[2.1.1]hexane-4-carbonitrile;2,2,2-trifluoroacetic acid

[0507] tert-Butyl 4-cyano-2-azabicyclo[2.1.1]hexane-2-carboxylate (1.90 g, 9.12 mmol) was dissolved in DCM (10 mL). Then, trifluoroacetic acid (3.5 mL, 46 mmol) was added to the solution at 0 °C and the reaction mixture was stirred for 5 min. The reaction mixture was brought to room temperature and stirred for further 4 hours. The reaction mixture was then concentrated to dryness under reduced pressure to afford the title compound as an oil (2.02 g, 9.09 mmol, 99%).

[0508] 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 2H), 4.15 (t, J = 1.9 Hz, 1H), 3.53 (t, J = 3.9 Hz, 2H), 2.52 (dtd, J = 5.5, 2.1, 1.1 Hz, 2H), 1.85 (dd, J = 5.6, 2.2 Hz, 2H). 2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexane-4- carbonitrile

[0509] 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (145 mg, 0.615 mmol), 2-azabicyclo[2.1.1]hexane-4-carbonitrile;2,2,2-trifluoroacetic acid (137 mg, 0.615 mmol), and N,N-diisopropylethylamine (1.1 mL, 6.2 mmol) were dissolved in n-butanol (10 mL) and the reaction mixture was heated to reflux and stirred for 24 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography, over silica gel, eluting with 4:1 v / v DCM:MeOH to afford the title compound as a solid (55 mg, 0.18 mmol, 29%).

[0510] 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 9.48 (s, 1H), 7.88 (d, J = 5.7 Hz, 1H), 6.35 (s, 1H), 6.13 (s, 1H), 4.68 (t, J = 1.9 Hz, 1H), 3.74 (s, 2H), 2.47 – 2.39 (m, 2H), 1.88 (ddd, J = 13.5, 8.5, 5.0 Hz, 1H), 1.83 (dd, J = 4.4, 1.8 Hz, 2H), 0.96 – 0.87 (m, 2H), 0.72 – 0.63 (m, 2H).

[0511] UPLC-MS analysis: (4 min, basic): rt = 0.95 min, m / z = 308.1 [M+H]+. Example 64: Synthesis of N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[1-(1-methoxyethyl)-3- azabicyclo[3.1.1]heptan-3-yl]pyrimidin-4-amine (Compound 53)tert-Butyl 1-(1-Hydroxyethyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate

[0512] Sodium borohydride (33 mg, 0.88 mmol) was added to a stirred solution of tert-butyl 1-acetyl-3-azabicyclo[3.1.1]heptane-3-carboxylate (70 mg, 0.29 mmol) in methanol (2.25 mL). The solution was stirred at room temperature for 18 hours, under nitrogen. The reaction mixture was diluted with ethyl acetate (15 mL) and then washed separately with water (5 mL), saturated aqueous brine solution (5 mL) and dried over Na2SO4. The solvent was removed under reduced pressure afford the title compound as an oil (90 mg, 0.373 mmol).

[0513] 1H NMR (400 MHz, DMSO-d6) δ 4.55 – 4.50 (m, 1H), 3.48 – 3.38 (m, 2H), 3.37 – 3.34 (m, 1H), 3.32 – 3.30 (m, 1H), 3.30 – 3.22 (m, 1H), 2.34 – 2.23 (m, 1H), 1.92 – 1.85 (m, 1H), 1.83 – 1.77 (m, 1H), 1.41 (d, J = 2.2 Hz, 9H), 1.26 – 1.20 (m, 1H), 1.14 – 1.05 (m, 1H), 0.92 (d, J = 6.4 Hz, 3H).

[0514] UPLC-MS (2 minute, basic metho, ELSD): rt = 1.02 min, m / z = 242.2 [M+H]+. tert-butyl 1-(1-methoxyethyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate

[0515] A 60% w / w suspension of sodium hydride in mineral oil (22 mg, 0.56 mmol) was added to a stirred solution of tert-butyl 1-(1-hydroxyethyl)-3-azabicyclo[3.1.1]heptane-3- carboxylate (90 mg, 0.37 mmol) in THF (1.8 mL) at 0 °C, under nitrogen. The mixture wasallowed to warm up to room temperature and stirred for 30 minutes. The mixture was cooled back down to 0 °C and then methyl iodide (70 µL, 1.1 mmol) was added. The reaction mixture was allowed to warm up slowly to room temperature and stirred for 3 days. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (4.0 mL) and extracted with ethyl acetate (3 x 5 mL). The combined extracts were washed with saturated aqueous brine solution (5 mL) and dried over Na2SO4. The solvent was removed in vacuo to afford the title compound as an oil (100 mg, 0.372 mmol, 99%).

[0516] 1H NMR (400 MHz, Chloroform-d) δ 3.52 – 3.45 (m, 2H), 3.45 – 3.38 (m, 2H), 3.32 (s, 3H), 3.19 – 3.06 (m, 1H), 2.43 – 2.28 (m, 1H), 2.01 – 1.86 (m, 2H), 1.48 (s, 9H), 1.28 – 1.23 (m, 2H), 1.02 (d, J = 6.4 Hz, 3H).

[0517] UPLC-MS (2 minute, basic method, ELSD): rt = 1.18 min, m / z = 256.2 [M+H]+. 1-(1-methoxyethyl)-3-azabicyclo[3.1.1]heptane; hydrochloride

[0518] 4 M hydrogen chloride in 1,4-dioxane (0.93 mL, 3.7 mmol) was added to a stirred solution of tert-butyl 1-(1-methoxyethyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate (100 mg, 0.372 mmol) in DCM (1 mL). The solution was stirred at room temperature for 2 hours and then the solvents were removed in vacuo afford the title compound as a gum (70 mg, 0.365 mmol, 98%).

[0519] 1H NMR (400 MHz, Methanol-d4) δ 3.44 – 3.40 (m, 2H), 3.40 – 3.37 (m, 2H), 3.32 (s, 3H), 3.25 (q, J = 6.4 Hz, 1H), 2.50 – 2.44 (m, 1H), 2.20 – 2.13 (m, 2H), 1.76 – 1.70 (m, 1H), 1.58 – 1.52 (m, 1H), 1.03 (d, J = 6.4 Hz, 3H). N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[1-(1-methoxyethyl)-3-azabicyclo[3.1.1]heptan-3- yl]pyrimidin-4-amine

[0520] A stirred solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (72 mg, 0.30 mmol), 1-(1-methoxyethyl)-3-azabicyclo[3.1.1]heptane; hydrochloride (70 mg, 0.365 mmol) and N,N-diisopropylethylamine (0.27 mL, 1.5 mmol) in n-butanol (3 mL) was heated at reflux under nitrogen and stirred for 17 hours. The reaction mixture was allowed to cool to room temperature and then the solvent was removed under reduced pressure. The residue was diluted with water (5 mL) then extracted with chloroform / propan-2-ol 3:1 (3 x 5 mL). The combined extracts were dried (Na2SO4), filtered and the solvent was removed under reduced pressure. The crude material was purified by column chromatography over silica gel, elutingwith a gradient of methanol (0% to 10%; v / v) in DCM to afford the title compound as a solid (49 mg, 0.13 mmol, 43%).

[0521] 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 9.43 (s, 1H), 7.86 (d, J = 5.6 Hz, 1H), 6.45 – 6.06 (m, 2H), 3.75 – 3.50 (m, 4H), 3.31 – 3.18 (m, 4H), 2.48 – 2.40 (m, 1H), 2.00 – 1.88 (m, 2H), 1.88 – 1.75 (m, 1H), 1.49 – 1.38 (m, 1H), 1.34 – 1.26 (m, 1H), 1.04 (d, J = 6.3 Hz, 3H), 0.95 – 0.86 (m, 2H), 0.68 – 0.60 (m, 2H).

[0522] UPLC-MS (4 minute, basic method): rt = 1.68 min, m / z = 355.2 [M+H]+. Example 65: Synthesis of 1-[3-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]- 3-azabicyclo[3.1.1]heptan-1-yl]ethanol (Compound 52)tert-Butyl 1-[Methoxy(methyl)carbamoyl]-3-azabicyclo[3.1.1]heptane-3-carboxylate

[0523] N,N'-carbonyldiimidazole (1.01 g, 6.22 mmol) was added to a solution of 3-[(2- methylpropan-2-yl)oxycarbonyl]-3-3.1.1] heptane-1-carboxylic acid (1.00 g, 4.14 mmol) in THF (38 mL). The solution was stirred at room temperature under nitrogen for 3 hours. N-O-dimethyl hydroxylamine hydrochloride (0.61 g, 6.2 mmol) was then added, followed by N,N- diisopropylethylamine (2.2 mL, 12 mmol) and the reaction mixture was stirred for 18 hour. The reaction mixture was diluted with ethyl acetate (200 mL) and then washed separately with water (150 mL), saturated aqueous brine solution (150 mL), dried over Na2SO4 then the solvent was removed in vacuo. The crude material was purified by column chromatography over silica gel,eluting with a gradient of methanol (0% to 20%; v / v) in DCM to afford the title compound as a solid (690 mg, 2.31 mmol, 56%).

[0524] 1H NMR (400 MHz, Chloroform-d) δ 3.70 – 3.59 (m, 5H), 3.54 – 3.47 (m, 2H), 3.17 (s, 3H), 2.41 – 2.25 (m, 3H), 1.75 – 1.68 (m, 2H), 1.47 (s, 9H). tert-Butyl 1-Acetyl-3-azabicyclo[3.1.1]heptane-3-carboxylate

[0525] 2.0 M solution of methylmagnesium bromide in diethyl ether (1.6 mL, 4.9 mmol) was added dropwise to a stirred solution of tert-butyl 1-[methoxy(methyl)carbamoyl]-3- azabicyclo[3.1.1]heptane-3-carboxylate (490 mg, 1.64 mmol) in THF (16 mL) at –78°C, under nitrogen. The reaction mixture was stirred at this temperature for 30 minutes and then allowed to warm up to room temperature and stirred for another 2 hours. The reaction mixture was cooled to 0 °C and then quenched with saturated aqueous solution of ammonium chloride (3.3 mL). The mixture was partitioned between saturated aqueous solution of ammonium chloride (8.3 mL) and ethyl acetate (2 x 35 mL). The combined extracts were washed with brine (17 mL) and dried over Na2SO4 then the solvent was removed in vacuo to afford the title compound as an oil (410 mg, 1.63 mmol, 99%).

[0526] 1H NMR (400 MHz, Chloroform-d) δ 3.62 (d, J = 21.2 Hz, 2H), 3.56 – 3.50 (m, 2H), 2.48 – 2.32 (m, 1H), 2.32 – 2.22 (m, 2H), 2.12 (d, J = 13.6 Hz, 3H), 1.61 – 1.53 (m, 2H), 1.48 (s, 9H). 1-(3-Azabicyclo[3.1.1]heptan-1-yl)ethanone; hydrochloride

[0527] 4 M hydrogen chloride solution in 1,4-dioxane (2.0 mL, 7.9 mmol) was added to a stirred solution of tert-butyl 1-acetyl-3-azabicyclo[3.1.1]heptane-3-carboxylate (200 mg, 0.794 mmol) in DCM (1 mL) under a nitrogen atmosphere. The solution was stirred at room temperature for 2 hours. The solvents were then removed in vacuo to afford the title compound as a solid (147 mg, 0.794 mmol, 100%).

[0528] 1H NMR (400 MHz, Methanol-d4) δ 3.60 – 3.57 (m, 2H), 3.48 (d, J = 2.5 Hz, 2H), 2.68 – 2.60 (m, 2H), 2.58 – 2.52 (m, 1H), 2.20 (s, 3H), 1.88 – 1.79 (m, 2H). 1-[3-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3-azabicyclo[3.1.1]heptan- 1-yl]ethanone

[0529] A stirred solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (156 mg, 0.662 mmol), 1-(3-azabicyclo[3.1.1]heptan-1-yl)ethanone; hydrochloride (147 mg, 0.794 mmol) and N,N-diisopropylethylamine (0.58 mL, 3.3 mmol) in n-butanol (6.6 mL) washeated at reflux, under nitrogen for 18 hours. The reaction mixture was allowed to cool to room temperature and then the solvent was removed in vacuo. The residue was suspended in water (10 mL) and extracted with 3:1 chloroform / propan-2-ol (3 x 10 mL). The combined organic extracts were dried (Na2SO4), filtered and then the solvents were removed in vacuo. The residue was purified by column chromatography over silica gel, eluting with a gradient of methanol (0% to 10%; v / v) in DCM to afford the title compound as a foam (160 mg, 0.44 mmol, 66%).

[0530] 1H NMR (400 MHz, Chloroform-d) δ 8.02 (d, J = 6.0 Hz, 1H), 6.40 – 5.90 (m, 2H), 3.93 – 3.87 (m, 2H), 3.85 – 3.78 (m, 2H), 2.65 – 2.51 (m, 1H), 2.45 – 2.31 (m, 2H), 2.19 (s, 3H), 1.94 – 1.85 (m, 1H), 1.71 – 1.60 (m, 2H), 1.01 – 0.91 (m, 2H), 0.84 – 0.68 (m, 2H).

[0531] UPLC-MS (2 minute, basic method): rt = 0.94 min, m / z = 339.1 [M+H]+. 1-[3-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3-azabicyclo[3.1.1]heptan- 1-yl]ethanol

[0532] Sodium borohydride (17 mg, 0.443 mmol) was added to a stirred solution of 1-[3-[4- [(5-cyclopropyl-1H-pyrazol-3-yl) amino]pyrimidin-2-yl]-3-azabicyclo[3.1.1]heptan-1- yl]ethanone (50 mg, 0.148 mmol) in methanol (2 mL). The reaction mixture was stirred at room temperature under nitrogen for 15 hours. The reaction mixture was diluted with ethyl acetate (15 mL) and then washed separately with water (5 mL) then saturated aqueous brine solution (5 mL) and dried over Na2SO4 then the solvent was removed in vacuo to afford the title compound as a solid (51 mg, 0.14 mmol, 97%).

[0533] 1H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.41 (s, 1H), 7.87 (d, J = 5.7 Hz, 1H), 6.57 – 5.90 (m, 2H), 4.63 – 4.50 (m, 1H), 3.73 – 3.57 (m, 3H), 3.57 – 3.49 (m, 2H), 2.48 – 2.38 (m, 1H), 2.01 – 1.96 (m, 1H), 1.92 – 1.87 (m, 1H), 1.87 – 1.77 (m, 1H), 1.35 – 1.28 (m, 1H), 1.24 – 1.18 (m, 1H), 1.05 – 0.96 (m, 3H), 0.93 – 0.87 (m, 2H), 0.68 – 0.61 (m, 2H).

[0534] UPLC-MS (4 minute, basic method): rt = 1.36 min, m / z = 341.1 [M+H]+. Example 66: Synthesis of 2-[3-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]- 3-azabicyclo[3.1.1]heptan-1-yl]propan-2-ol (Compound 54)3-tert-Butoxycarbonyl-3-azabicyclo[3.1.1]heptane-1-carboxylic acid

[0535] To a stirred solution of tert-butyl 1-(hydroxymethyl)-3-azabicyclo[3.1.1]heptane-3- carboxylate (3.00 g, 13.2 mmol) in a mixture of chloroform (30 mL), acetonitrile (30 mL) and water (30 mL) were added ruthenium (IV) oxide (176 mg, 1.32 mmol) and sodium (meta)periodate (16.94 g, 79.2 mmol). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was then diluted with to 1:9 v / v methanol:DCM (300 mL) and water (100 mL) and stirred for 30 minutes. The mixture was filtered through celite and then the organic layer was separated. The organic phase was washed with saturated aqueous brine solution (100 mL) and dried over Na2SO4then the solvent was removed in vacuo to afford the title compound as a solid (3.12 g, 12.3 mmol, 93%).

[0536] 1H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 3.51 (d, J = 18.8 Hz, 2H), 3.40 (d, J = 20.8 Hz, 2H), 2.42 – 2.22 (m, 3H), 1.50 – 1.46 (m, 2H), 1.42 (s, 9H).

[0537] UPLC-MS (2 minute, basic method) rt = 0.73 min, m / z = 240.1 [M–H]–. O3-tert-Butyl O1-Methyl 3-azabicyclo[3.1.1]heptane-1,3-dicarboxylate

[0538] To a stirred solution of 3-tert-butoxycarbonyl-3-azabicyclo[3.1.1]heptane-1- carboxylic acid (3.12 g, 12.3 mmol) in methanol (30 mL), under nitrogen, was added 2 M solution of (trimethylsilyl)diazomethane in diethyl ether (12 mL, 25 mmol) dropwise, over 20 minutes. The solution was stirred at room temperature for 2 hours. Additional 2 M solution of (trimethylsilyl)diazomethane in diethyl ether (12 mL, 24.6 mmol) was added and the reaction mixture was stirred for 18 hours. The reaction mixture was quenched with acetic acid (6.0 mL), followed by 2 M aqueous citric acid solution (60 mL) and stirred for 20 minutes. The mixturewas then poured into saturated aqueous sodium bicarbonate solution (500 mL) and extracted with ethyl acetate (2 x 300 mL). The combined extracts were washed with more saturated aqueous sodium bicarbonate solution (250 mL), saturated aqueous brine solution (300 mL) and dried over Na2SO4. The solvent was removed in vacuo, then the crude material was purified by column chromatography over silica gel, eluting with a gradient of ethyl acetate (0% to 10%; v / v) in iso-hexane to afford the title compound as an oil (2.00 g, 7.44 mmol, 61%).

[0539] 1H NMR (400 MHz, Chloroform-d) δ 3.74 – 3.63 (m, 5H), 3.54 – 3.49 (m, 2H), 2.49 – 2.36 (m, 3H), 1.60 – 1.56 (m, 2H), 1.49 (s, 9H).

[0540] UPLC-MS (2 minute, basic method) rt = 1.12 min, m / z = 156.1 [M–Boc+H]+. tert-butyl 1-(1-hydroxy-1-methyl-ethyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate

[0541] A solution of 3 M methylmagnesium bromide in Et2O (1.8 mL, 5.26 mmol) was added dropwise, over 10 minutes, to a stirred solution of O3-tert-butyl O1-methyl 3- azabicyclo[3.1.1]heptane-1,3-dicarboxylate (610 mg, 2.39 mmol) in THF (6.0 mL) at -78 °C, under a nitrogen atmosphere. The reaction mixture was stirred at this temperature for 30 minutes and then allowed to warm up to room temperature and the resulting solution was stirred for 1 hour. The solution was cooled in an ice-water bath and then the reaction mixture was quenched with saturated aqueous ammonium chloride solution (4.0 mL). The reaction mixture was partitioned between saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (2 x 20 mL). The combined extracts were washed with saturated aqueous brine solution (20 mL) and dried over Na2SO4then the solvents were removed in vacuo.

[0542] In a separate flask a solution of 3 M methylmagnesium bromide in Et2O (0.88 mL, 2.6 mmol) was added dropwise, over 10 minutes, to a stirred solution of O3-tert-butyl O1-methyl 3-azabicyclo[3.1.1]heptane-1,3-dicarboxylate (305 mg, 1.19 mmol) in THF (3.0 mL) at -78 °C, under nitrogen. The reaction mixture was stirred at this temperature for 30 minutes and then allowed to warm up to room temperature and the resulting solution was stirred for 1 hour. The solution was cooled in an ice-water bath and then the reaction was quenched with saturated aqueous NH4Cl solution (2.0 mL). The residue was partitioned between aqueous NH4Cl solution (5 mL) and ethyl acetate (2 x 10 mL). The combined organic extracts were washed with saturated aqueous brine solution (10 mL) and dried over Na2SO4then the solvents were removed in vacuo. The crude material from both reactions were combined and purified by columnchromatography over silica gel, eluting with a gradient of ethyl acetate (0% to 40%; v / v) in iso- hexane to afford the title compound as a solid (750 mg, 2.20 mmol, 82%).

[0543] 1H NMR (400 MHz, Chloroform-d) δ 3.51 – 3.40 (m, 4H), 2.41 – 2.25 (m, 1H), 2.18 – 2.08 (m, 2H), 1.48 (s, 9H), 1.24 – 1.20 (m, 2H), 1.11 (s, 6H).

[0544] UPLC-MS :(basic, 2 min): rt = 1.06 min, m / z = 254.4 [M–H]–. 2-(3-azabicyclo[3.1.1]heptan-1-yl)propan-2-ol;hydrochloride

[0545] 4 M hydrogen chloride solution in 1,4-dioxane (3.2 mL, 13 mmol) was added to a stirred solution of tert-butyl 1-(1-hydroxy-1-methyl-ethyl)-3-azabicyclo[3.1.1]heptane-3- carboxylate (350 mg, 1.27 mmol) in DCM (1.1 mL) at room temperature, under a nitrogen atmosphere. The reaction mixture was stirred for 2 hours. The solvents were removed in vacuo to afford the title compound as a solid (250 mg, 1.24 mmol, 98%).

[0546] 1H NMR (400 MHz, Methanol-d4) δ 3.46 – 3.40 (m, 4H), 2.48 – 2.43 (m, 1H), 2.43 – 2.34 (m, 2H), 1.57 – 1.50 (m, 2H), 1.13 (s, 6H).

[0547] UPLC-MS (2 minute, basic method, ELSD): rt = 0.37 min, m / z = 156.1 [M+H]+. 2-[3-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3-azabicyclo[3.1.1]heptan- 1-yl]propan-2-ol

[0548] A stirred solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (243 mg, 1.03 mmol), 2-(3-azabicyclo[3.1.1]heptan-1-yl)propan-2-ol;hydrochloride (250 mg, 1.24 mmol) and N,N-diisopropylethylamine (0.90 mL, 5.2 mmol) in n-butanol (10.3 mL) was heated at reflux under nitrogen for 18 hours. The reaction mixture was cooled to room temperature and then the solvent was removed in vacuo. The residue was suspended in water (20 mL) and extracted with DCM (3 x 20 mL). The combined extracts were washed with saturated aqueous brine solution and dried over Na2SO4then the solvent was removed in vacuo. The crude material was purified by column chromatography over silica gel, eluting with a gradient of methanol (0% to 10%; v / v) in DCM to afford the title compound as a solid (151 mg, 0.420 mmol, 40%).

[0549] 1H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 9.56 (s, 1H), 7.86 (d, J = 6.4 Hz, 1H), 6.47 – 5.97 (m, 2H), 4.42 – 4.28 (m, 1H), 3.77 – 3.54 (m, 4H), 2.46 – 2.34 (m, 1H), 2.25 – 2.14 (m, 2H), 1.91 – 1.77 (m, 1H), 1.21 – 1.15 (m, 2H), 1.11 – 1.00 (m, 6H), 0.94 – 0.86 (m, 2H), 0.67 – 0.61 (m, 2H).

[0550] UPLC-MS (4 minute, basic method): rt = 1.37 min, m / z = 355.3 [M+H]+.Example 67: Synthesis of N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[1-(1-methoxy-1-methyl- ethyl)-3-azabicyclo[3.1.1]heptan-3-yl]pyrimidin-4-amine (Compound 55)tert-Butyl 1-(1-Methoxy-1-methyl-ethyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate

[0551] 60% w / w suspension of sodium hydride in mineral oil (152 mg, 3.80 mmol) was added portion wise to a stirred solution of tert-butyl 1-(1-hydroxy-1-methyl-ethyl)-3- azabicyclo[3.1.1]heptane-3-carboxylate (350 mg, 1.27 mmol) in THF (7.0 mL) at 0 °C, under a nitrogen atmosphere. The mixture was then allowed to warm up to room temperature and stirred for another 1 hour and 30 minutes. The mixture was cooled back down to 0 °C and then methyl iodide (0.24 mL, 3.80 mmol) was added dropwise, over 10 minutes. The reaction mixture was allowed to warm up slowly to room temperature and then stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (25 mL) and then extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine (20 mL) and dried over Na2SO4 then the solvent was removed. The crude material was purified by column chromatography over silica gel, eluting with a gradient of ethyl acetate (0% to 20%; v / v) in iso-hexane to afford the title compound as an oil (300 mg, 1.11 mmol, 88%).

[0552] 1H NMR (400 MHz, Chloroform-d) δ 3.49 (s, 2H), 3.45 (d, J = 2.6 Hz, 2H), 3.17 (s, 3H), 2.33 – 2.25 (m, 1H), 2.17 – 2.10 (m, 2H), 1.48 (s, 9H), 1.26 – 1.20 (m, 2H), 1.04 (s, 6H).1-(1-methoxy-1-methyl-ethyl)-3-azabicyclo[3.1.1]heptane;hydrochloride

[0553] Hydrogen chloride solution in 1,4-dioxane (2.8 mL, 11.1 mmol) was added to a stirred solution of tert-butyl 1-(1-methoxy-1-methyl-ethyl)-3-azabicyclo[3.1.1] heptane-3- carboxylate (300 mg, 1.11 mmol) in DCM (1.0 mL) at room temperature, under a nitrogen atmosphere. The solution was stirred for 2 hours. The solvents were removed in vacuo to afford the title compound as a solid (220 mg, 1.07 mmol, 96%).

[0554] 1H NMR (400 MHz, Methanol-d4) δ 3.45 (s, 2H), 3.39 (d, J = 2.5 Hz, 2H), 3.19 (s, 3H), 2.45 – 2.32 (m, 3H), 1.56 – 1.49 (m, 2H), 1.09 (s, 6H). N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[1-(1-methoxy-1-methyl-ethyl)-3- azabicyclo[3.1.1]heptan-3-yl]pyrimidin-4-amine

[0555] A stirred solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (219 mg, 0.93 mmol), 1-(1-methoxy-1-methyl-ethyl)-3-azabicyclo [3.1.1]heptane;hydrochloride (229 mg, 1.11 mmol) and N,N-diisopropylethylamine (0.81 mL, 4.6 mmol) in n-butanol (9.3 mL) was heated at reflux under nitrogen for 18 hours. The reaction mixture was cooled to room temperature and then the solvent was removed in vacuo to reveal an oil. The oil was diluted with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic extracts were washed with saturated aqueous brine solution (10 mL) and dried over Na2SO4then the solvent was removed in vacuo. The crude material was purified by column chromatography over silica gel, eluting with a gradient of methanol (0% to 10%; v / v) in DCM to afford the title compound as a solid (185 mg, 0.487 mmol, 52%).

[0556] 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 9.45 (s, 1H), 7.86 (d, J = 5.6 Hz, 1H), 6.51 – 5.94 (m, 2H), 3.79 – 3.52 (m, 4H), 3.15 (s, 3H), 2.47 – 2.36 (m, 1H), 2.20 – 2.08 (m, 2H), 1.89 – 1.73 (m, 1H), 1.30 – 1.21 (m, 2H), 1.15 – 1.01 (m, 6H), 0.95 – 0.86 (m, 2H), 0.67 – 0.60 (m, 2H).

[0557] UPLC-MS (4 minute, basic method): rt = 1.77 min, m / z = 369.2 [M+H]+. Example 68: Synthesis of 1-[3-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]- 3-azabicyclo[3.1.1]heptan-1-yl]cyclopropanol (Compound 56)tert-Butyl 1-(1-Hydroxycyclopropyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate

[0558] 1 M solution of ethylmagnesium bromide in THF (22.3 mL, 22.3 mmol) was added dropwise, over 10 minutes, to a stirred solution of O3-tert-butyl O1-methyl 3- azabicyclo[3.1.1]heptane-1,3-dicarboxylate (600 mg, 2.23 mmol) and chlorotriisopropoxytitanium(IV) (3.49 g, 13.40 mmol) in THF (15.0 mL) at 0 °C, under nitrogen. The reaction mixture was allowed to warm up slowly to room temperature and stirred for 18 hours. The reaction mixture was cooled to 0 °C and then quenched with saturated aqueous ammonium chloride solution (12.0 mL). Ethyl acetate (120 mL) was added, and the mixture was stirred for 15 minutes. The organic layer was separated then the aqueous was further extracted with ethyl acetate (120 mL). The combined organic extracts were washed with saturated aqueous brine solution (60 mL) and dried over Na2SO4. The solvents were removed in vacuo.

[0559] In a separate reaction flask, 1 M solution of ethylmagnesium bromide in THF (13.0 mL, 13 mmol) was added dropwise, over 10 minutes, to a stirred solution of O3-tert-butyl O1- methyl 3-azabicyclo[3.1.1]heptane-1,3-dicarboxylate (350 mg, 1.30 mmol) and chlorotriisopropoxytitanium(IV) (2.0 g, 7.8 mmol) in THF (8.5 mL) at 0 °C, under a nitrogen atmosphere. The reaction mixture was allowed to warm up slowly to room temperature and stirred for 18 hours. The reaction mixture was cooled to 0 °C and then quenched with saturated aqueous NH4Cl solution (7.0 mL). Ethyl acetate (70 mL) was added and the mixture was stirred for 15 minutes. The organic layer was separated and the aqueous was extracted with ethyl acetate (70 mL). The combined organic extracts were washed with brine (40 mL) and dried over Na2SO4then the solvents were removed in vacuo to leave a viscous oil. The crude material from both reactions were combined and purified by column chromatography over silica gel, eluting with a gradient of ethyl acetate (0% to 40%; v / v) in iso-hexane to afford the title compound as a solid (500 mg, 2.00 mmol, 57%).

[0560] 1H NMR (400 MHz, Chloroform-d) δ 3.60 (s, 2H), 3.52 – 3.45 (m, 2H), 2.48 – 2.25 (m, 1H), 1.83 – 1.71 (m, 3H), 1.49 (s, 9H), 1.38 – 1.31 (m, 2H), 0.74 – 0.66 (m, 2H), 0.62 – 0.55 (m, 2H).

[0561] UPLC-MS (2 minute, basic method, ELSD): rt = 1.06 min, m / z = 254.1 [M+H]+. 1-(3-azabicyclo[3.1.1]heptan-1-yl)cyclopropanol;hydrochloride

[0562] 4 M hydrogen chloride in 1,4-dioxane (2.5 mL, 9.9 mmol) was added to a stirred solution of tert-butyl 1-(1-hydroxycyclopropyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate (250 mg, 0.987 mmol) in DCM (1 mL) at room temperature, under a nitrogen atmosphere. The solution was stirred for 2 hours. The solvent was removed in vacuo to afford the title compound as a solid (180 mg, 0.949 mmol, 96%).

[0563] 1H NMR (400 MHz, Methanol-d4) δ 3.55 - 3.51 (m, 2H), 3.42 (d, J = 2.6 Hz, 2H), 2.47 – 2.42 (m, 1H), 2.04 – 1.96 (m, 2H), 1.62 – 1.56 (m, 2H), 0.66 – 0.59 (m, 4H). 1-[3-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3-azabicyclo[3.1.1]heptan- 1-yl]cyclopropanol

[0564] A stirred solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (186 mg, 0.791 mmol), 1-(3-azabicyclo[3.1.1]heptan-1-yl)cyclopropanol;hydrochloride (180 mg, 0.949 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.79 mmol) in n-butanol (7.9 mL) was heated at reflux under nitrogen for 18 hours. The reaction mixture was allowed to cool to room temperature and then the solvent was removed in vacuo. Water (10 mL) was added and then the mixture was extracted with 3:1 v / v chloroform / propan-2-ol 3:1 (3 x 10 mL). The combined extracts were dried over Na2SO4 then the solvent was removed in vacuo. The crude material was purified by preparative HPLC to afford the title compound as a solid (29 mg, 82 mmol, 10%).

[0565] 1H NMR (400 MHz, DMSO-D6) δ 11.93 (s, 1H), 9.38 (s, 1H), 7.87 (d, J = 5.6 Hz, 1H), 6.34 – 6.15 (m, 2H), 5.19 – 5.02 (m, 1H), 3.76 – 3.56 (m, 4H), 2.48 – 2.37 (m, 1H), 1.89 – 1.73 (m, 3H), 1.33 – 1.26 (m, 2H), 0.94 – 0.85 (m, 2H), 0.72 – 0.61 (m, 2H), 0.56 – 0.46 (m, 4H).

[0566] UPLC-MS:(acidic, 4 min): rt = 1.10 min, m / z = 353.2 [M+H]+.Example 69: Synthesis of 2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.2.2]octane-4-carboxamide (Compound 78)t -Butyl 4-Carbamoyl-2-azabicyclo[2.2.2]octane-2-carboxylate

[0567] To 2-tert-butoxycarbonyl-2-azabicyclo[2.2.2]octane-4-carboxylic acid (200 mg, 0.783 mmol) in THF (7 mL), N,N'-carbonyldiimidazole (127 mg, 0.783 mmol) was added. The mixture was stirred at room temperature for 4.5 hours then 7 M solution of ammonia in methanol (0.22 mL, 1.57 mmol) was added. The mixture was stirred for further 17.5 hours. The solid that had formed was removed by vacuum filtration and the filtrate was concentrated to dryness under reduced pressure. The residue was partitioned between water (25 mL) and a 4:1 DCM / MeOH (25 mL). The organic layer was separated, then aqueous layer was extracted once more with 4:1 DCM / MeOH (25 mL). The combined organic extracts were washed with saturated aqueous NaHCO3solution (25 mL), dried over MgSO4and concentrated to dryness under reduced pressure to afford the title compound as a solid (94 mg, 0.37 mmol, 47%).

[0568] 1H NMR (400 MHz, DMSO-d6) δ 7.15 (s, 1H), 6.95 (d, J = 11.8 Hz, 1H), 4.00 – 3.77 (m, 1H), 3.31 – 3.20 (m, 2H), 1.88 – 1.50 (m, 9H), 1.39 (d, J = 5.3Hz, 8H).

[0569] UPLC-MS (2 minute, basic method) Rt = 0.90, m / z = 253.1 [M–H]-. 2-azabicyclo[2.2.2]octane-4-carboxamide;2,2,2-trifluoroacetic acid

[0570] To tert-butyl 4-carbamoyl-2-azabicyclo[2.2.2]octane-2-carboxylate (69 mg, 0.27 mmol) in DCM (3 mL), trifluoroacetic acid (0.41 mL, 5.4 mmol) was added dropwise. Themixture was stirred at room temperature for 2.5 hours then the solvent was removed under reduced pressure to afford the title compound as an oil (73 mg, 0.27 mmol, 99%).

[0571] 1(400 MHz, DMSO-d6) δ 8.60 (s, 2H), 7.40 – 6.99 (m, 2H), 3.49 – 3.30 (m, 1H), 3.10 (t, J = 6.0 Hz, 2H), 1.96 – 1.79 (m, 4H), 1.79 – 1.59 (m, 4H). 2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.2.2]octane-4- carboxamide

[0572] To 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (51 mg, 0.22 mmol) and 2-azabicyclo[2.2.2]octane-4-carboxamide;2,2,2-trifluoroacetic acid (70 mg, 0.26 mmol) in n-butanol (2.5 mL) in was added N,N-diisopropylethylamine (0.38 mL, 2.2 mmol) was added. The mixture was heated at 100 °C for 25 hours and the solvent was removed under reduced pressure. The residue was purified by basic reversed-phase preparative HPLC. The residue was then dissolved in MeOH (2 mL), then loaded onto an SCX-2 cartridge. The cartridge was washed with MeOH (10 mL), then the compound was eluted with 2 M NH3in MeOH (10 mL). The eluent was concentrated to dryness under reduced pressure to afford the title compound as a solid (32 mg, 89 µmol, 41%).

[0573] 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 9.52 – 9.11 (m, 1H), 7.98 – 7.65 (m, 1H), 7.19 (s, 1H), 7.06 – 6.79 (m, 1H), 6.49 – 5.77 (m, 2H), 4.62 (s, 1H), 3.66 – 3.39 (m, 2H), 1.94 – 1.54 (m, 9H), 0.89 (s, 2H), 0.78 – 0.55 (m, 2H).

[0574] UPLC-MS (4 minute, basic method) Rt = 1.17, m / z = 354.3 [M+H]+. Example 70: Synthesis of 1-(3-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-3- azabicyclo[3.1.1]heptan-1-yl)ethan-1-ol (Compounds 83-1 and 83-2)

[0575] Enantiomer separation by chiral preparative SFC was carried out on Compound 56 using a Chiralpak lG (21 mm × 250 mm, 5 μm) column and the following parameters: temperature: 40 °C, mobile phase: 1:1 MeOH:CO2(0.2% v / v NH3), flow rate: 50 mL / min), toafford compound 83-1 as a solid (6 mg, 18 µmol, 20%) and compound 83-2 as a solid (7 mg, 20 µmol, 22%). Compound 83-1

[0576] 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 9.38 (s, 1H), 7.87 (d, J = 5.7 Hz, 1H), 6.33 – 6.16 (m, 2H), 4.60 – 4.51 (m, 1H), 3.70 – 3.48 (m, 5H), 2.47 – 2.38 (m, 1H), 2.02 – 1.96 (m, 1H), 1.92 – 1.87 (m, 1H), 1.86 – 1.78 (m, 1H), 1.33 – 1.28 (m, 1H), 1.24 – 1.19 (m, 1H), 1.06 – 0.96 (m, 3H), 0.93 – 0.87 (m, 2H), 0.68 – 0.60 (m, 2H).

[0577] UPLC-MS (4 min, basic method): Rt: 1.35 min, m / z = 341.1 [M+H]+.

[0578] Chiral SFC: column: Chiralpak IG (4.6 mm x 250 mm, 5 μm); mobile phase: 1:1 MeOH:CO2(0.1% v / v NH3), flow rate: 3 mL / min; temperature: 40 °C; rt = 4.74 min (major), 6.37 min (minor), 99% e.e. Compound 83-2

[0579] 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 9.36 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.32 – 6.06 (m, 2H), 4.60 – 4.42 (m, 1H), 3.65 – 3.44 (m, 5H), 2.43 – 2.36 (m, 1H), 1.99 – 1.91 (m, 1H), 1.89 – 1.83 (m, 1H), 1.83 – 1.74 (m, 1H), 1.30 – 1.24 (m, 1H), 1.20 – 1.14 (m, 1H), 1.02 – 0.92 (m, 3H), 0.90 – 0.83 (m, 2H), 0.64 – 0.57 (m, 2H).

[0580] UPLC-MS (4 min, basic method): Rt: 1.35 min, m / z = 341.1 [M+H]+.

[0581] Chiral SFC: column: Chiralpak IG (4.6 mm x 250 mm, 5 μm); mobile phase: 1:1 MeOH:CO2(0.1% v / v NH3), flow rate: 3 mL / min; temperature: 40 °C; rt = 4.74 min (minor), 6.29 min (major), 98% e.e. Example 71: Synthesis of 2-(2-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)-2- azabicyclo[2.2.1]heptan-4-yl)propan-2-ol (Compounds 84-1 and 84-2)

[0582] Enantiomer separation by chiral preparative SFC was carried out on 230 mg of Compound 35 using a Lux C1 (21.2 mm x 250 mm, 5 µm) column and the following parameters:temperature: 40 °C; flow rate: 50 mL / min; mobile phase: 30:70 MeOH:CO2 (0.2% v / v NH3), to afford compound 84-1 as a solid (67 mg, 0.19 mmol, 29%) and compound 84-2 as a solid (68 mmol, 0.19 mmol, 30%). Compound 84-1

[0583] 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.32 (s, 1H), 7.79 (d, J = 5.7 Hz, 1H), 6.16 (s, 2H), 4.48 (s, 1H), 4.35 (d, J = 14.5 Hz, 1H), 3.54 (s, 1H), 3.07 (d, J = 10.6 Hz, 1H), 1.95 – 1.36 (m, 6H), 1.29 (s, 1H), 1.18 (s, 6H), 1.01 – 0.77 (m, 2H), 0.63 (s, 2H).

[0584] UPLC-MS (4 min, basic method): Rt: 1.36 min, m / z = 355.2 [M+H]+.

[0585] Chiral SFC: column: Lux C1 (4.6 mm x 250 mm, 5 μm); mobile phase: 3:7 EtOH:CO2, flow rate: 3 mL / min; temperature: 40 °C; rt = 5.28 min (major), 5.95 min (minor), 97.5% e.e. Compound 84-2

[0586] 1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 10.22 (s, 1H), 7.78 (d, J = 6.4 Hz, 1H), 6.27 (s, 2H), 4.53 (d, J = 13.6 Hz, 1H), 4.47 (s, 1H), 3.66 – 3.53 (m, 1H), 3.20 – 3.00 (m, 1H), 1.95 – 1.60 (m, 5H), 1.55 – 1.48 (m, 1H), 1.44 – 1.31 (m, 1H), 1.18 (s, 6H), 0.99 – 0.88 (m, 2H).

[0587] UPLC-MS (4 min, basic method): Rt: 1.36 min, m / z = 355.2 [M+H]+.

[0588] Chiral SFC: column: Lux C1 (4.6 mm x 250 mm, 5 μm); mobile phase: 3:7 EtOH:CO2, flow rate: 3 mL / min; temperature: 40 °C; rt = 5.41 min (minor), 6.01 min (major), >99% e.e. Example 72: Synthesis of [6-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-6- azabicyclo[3.2.1]octan-1-yl]methanol (Compound 85)[6-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-6-azabicyclo[3.2.1]octan-1- yl]methanol

[0589] A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (160 mg, 0.679 mmol), {6-azabicyclo[3.2.1]octan-1-yl}methanol hydrochloride (241 mg, 1.36 mmol) and N,N-diisopropylethylamine (0.59 mL, 3.4 mmol) in n-butanol (10 mL) was degassed with nitrogen gas for 5 minutes and the reaction mixture was stirred at 100 °C for 18 hours. The reaction mixture was cooled to room temperature, diluted with water (10 mL), then extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with saturated aqueous brine solution (10 mL), dried over Na2SO4and concentrated to dryness under reduced pressure. The residue was purified by flash column chromatography, over silica gel, eluting with 1:9 v / v MeOH:EtOAc to afford the title compound as a solid (175 mg, 0.514 mmol, 76%).

[0590] 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 9.29 (s, 1H), 7.85 – 7.75 (m, 1H), 6.40 – 6.02 (m, 2H), 4.72 – 4.60 (m, 1H), 4.40 – 4.33 (m, 1H), 3.43 – 3.33 (m, 2H), 3.31 – 3.18 (m, 2H), 2.07 – 1.89 (m, 1H), 1.88 – 1.74 (m, 2H), 1.64 – 1.49 (m, 2H), 1.46 – 1.25 (m, 4H), 0.98 – 0.82 (m, 2H), 0.71 – 0.53 (m, 2H).

[0591] UPLC-MS (Basic method, 4 min): rt = 1.31 min, m / z = 341.1 [M+H]+. Example 73: Synthesis of [3-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3- azabicyclo[3.2.1]octan-1-yl]methanol (Compound 86)[3-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-3-azabicyclo[3.2.1]octan-1- yl]methanol

[0592] A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (160 mg, 0.679 mmol), {3-azabicyclo[3.2.1]octan-1-yl}methanol hydrochloride (241 mg, 1.36 mmol) and N,N-diisopropylethylamine (0.59 mL, 3.4 mmol) in n-butanol (10 mL) was degassed with nitrogen gas for 5 minutes and the reaction mixture was heated to 100 °C and stirred for 18 hours. The reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was purified by column chromatography over silica gel, elutingwith a gradient of EtOAc (95% to 100%; v / v) in iso-hexane to afford the title compound as a solid (154 mg, 0.452 mmol, 67%).

[0593] 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 9.29 (s, 1H), 7.84 (d, J = 5.7 Hz, 1H), 6.33 – 6.04 (m, 2H), 4.64 - 4.58 (m, 1H), 4.37 – 4.27 (m, 2H), 3.46 – 3.35 (m, 2H), 2.84 – 2.77 (m, 1H), 2.73 – 2.65 (m, 1H), 2.31 – 2.26 (m, 1H), 1.90 – 1.79 (m, 1H), 1.71 – 1.59 (m, 1H), 1.51– 1.45 (m, 1H), 1.44 – 1.32 (m, 3H), 0.95 – 0.86 (m, 2H), 0.70 – 0.61 (m, 2H).

[0594] UPLC-MS (Basic method, 4 min): rt = 1.37 min, m / z = 341.1 [M+H]+. Example 74: Synthesis of 2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.1.1]hexan-4-ol (Compound 87)2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexan-4-ol

[0595] A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (100 mg, 0.424 mmol), 2-azabicyclo[2.1.1]hexan-4-ol hydrochloride (86 mg, 0.64 mmol) and N,N- diisopropylethylamine (0.37 mL, 2.1 mmol) in n-butanol (2.5 mL) was degassed with nitrogen gas and then heated to 100 °C and stirred for 18 hours. The reaction mixture was cooled to room temperature diluted with water (10 mL) then extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with saturated aqueous brine solution (10 mL), dried over Na2SO4 then concentrated to dryness under reduced pressure. The crude residue was purified by reversed-phase flash column chromatography over C18-modified silica gel, eluting with a gradient of MeCN (0.1% NH3) (20% to 40%; v / v) in water (0.1% NH3). The residue was further purified by reversed-phase preparative HPLC to afford the title compound as a solid (20 mg, 66 µmol, 16%).

[0596] 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.37 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.54 – 5.97 (m, 3H), 4.53 – 4.48 (m, 1H), 3.23 (s, 2H), 1.90 – 1.84 (m, 1H), 1.84 – 1.78 (m, 2H), 1.69 – 1.59 (m, 2H), 0.96 – 0.87 (m, 2H), 0.69 – 0.61 (m, 2H).

[0597] UPLC-MS (Basic method, 4 min): rt = 1.07 min, m / z = 299.1 [M+H]+.Example 75: Synthesis of [2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.2.2]octan-4-yl]methanol (Compound 88)2-azabicyclo[2.2.2]octan-4-ylmethanol

[0598] To a solution of 2-Boc-4-(hydroxymethyl)-2-azabicyclo[2.2.2]octane (200 mg, 0.829 mmol) in DCM (7 mL), trifluoroacetic acid (1.3 mL, 17 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2.5 hours and then the solvent was removed under reduced pressure. The residue was dissolved in MeOH and then loaded onto an SCX-2 cartridge. The cartridge was washed with MeOH (10 mL), then the compound was eluted with 0.7 M NH3 in MeOH (10 mL). The eluent was concentrated to dryness under reduced pressure to afford the title compound as an oil (76 mg, 0.54 mmol, 65%).

[0599] 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 4.71 (s, 1H), 3.21 (q, J = 1.4 Hz, 1H), 3.12 (s, 2H), 2.86 (t, J = 1.5 Hz, 2H), 1.92 – 1.59 (m, 4H), 1.57 – 1.30 (m, 4H). [2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.2.2]octan-4- yl]methanol

[0600] To 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (95 mg, 0.402 mmol) and 2-azabicyclo[2.2.2]octan-4-ylmethanol (68 mg, 0.48 mmol) in n-butanol (4.5 mL), N,N-diisopropylethylamine (70 µL, 0.40 mmol) was added. The mixture was stirred at 100 °C for 4 days. Additional N,N-diisopropylethylamine (35 µL, 0.20 mmol) was added and the reaction mixture was stirred for a further 3 days. The reaction mixture was then concentrated to dryness. The residue was purified by reversed-phase basic preparative HPLC to afford the title compound as a solid (6.9 mg, 20 µmol, 5%).

[0601] 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 9.40 – 9.09 (m, 1H), 7.98 – 7.67 (m, 1H), 6.44 – 5.88 (m, 2H), 4.73 – 4.40 (m, 2H), 3.31 – 3.24 (m, 2H), 1.90 – 1.58 (m, 5H), 1.45 (t, J = 7.1 Hz, 4H), 1.23 (s, 1H), 0.91 (d, J = 6.7 Hz, 2H), 0.64 (s, 2H).

[0602] UPLC-MS analysis (4 min, basic method) Rt = 1.33, m / z = 341.3 [M+H]+. Example 76: Synthesis of [2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.2.1]heptan-4-yl]methanol (Compound 28)[2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptan-4- yl]methanol

[0603] A second batch of Compound 28 was synthesized through the following protocol. A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (1.70 g, 7.21 mmol), 2-azabicyclo[2.2.1]heptan-4-ylmethanol (1.10 g, 8.66 mmol) and N,N-diisopropylethylamine (3.1 mL, 18.0 mmol) in n-butanol (20 mL) was heated to 100 °C and stirred for 24 hours. The reaction mixture was concentrated to dryness under reduced pressure. The residue was diluted with water (100 mL) then extracted with 3:1 CHCl3:IPA (3 × 100 mL). The combined organic extracts were dried over Na2SO4, then concentrated to dryness under reduced pressure. The crude material was purified by column chromatography over silica gel, eluting with a gradient of MeOH (0% to 20%; v / v) in DCM. The residue was purified by reversed-phase preparative HPLC to afford the title compound as a solid (1.27 g, 3.89 mmol, 54%).

[0604] 1H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 9.28 (s, 1H), 7.80 (d, J = 5.7 Hz, 1H), 6.42 – 5.90 (m, 2H), 4.73 – 4.60 (m, 1H), 4.54 – 4.44 (m, 1H), 3.72 – 3.54 (m, 2H), 3.40 –3.26 (m, 1H), 3.19 – 3.01 (m, 1H), 1.90 – 1.79 (m, 1H), 1.79 – 1.50 (m, 4H), 1.43 – 1.29 (m, 2H), 0.96 – 0.84 (m, 2H), 0.69 – 0.57 (m, 2H).

[0605] UPLC-MS (4 min, basic method): Rt: 1.21 min, m / z = 327.3 [M+H]+. Example 77: Synthesis of 1-[2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]- 2-azabicyclo[2.1.1]hexan-4-yl]ethanol (Compound 89)tert-Butyl 4-[methoxy(methyl)carbamoyl]-2-azabicyclo[2.1.1]hexane-2-carboxylate

[0606] To 2-tert-Butoxycarbonyl-2-azabicyclo[2.1.1]hexane-4-carboxylic acid (500 mg, 2.20 mmol) in anhydrous THF (12 mL) was added N,N'-carbonyldiimidazole (535 mg, 3.30 mmol) and the reaction mixture stirred at room temperature for 4 hours. After this time was added N,N- diisopropylethylamine (1.1 mL, 6.6 mmol) and N,O-dimethyl hydroxylamine hydrochloride (322 mg, 3.30 mmol) and the reaction mixture stirred for 16 hours at room temperature. The reaction mixture was diluted with EtOAc (25 mL) and washed with water (25 mL) then saturated aqueous brine solution (25 mL). The organics were separated, dried (Na2SO4), and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel,eluting with MeOH (0% to 5%) in CH2Cl2 to give the title compound as an oil (375 mg, 1.39 mmol, 63%).

[0607] 1H NMR (400 MHz, DMSO-d6) δ 4.14 (t, J = 1.9 Hz, 1H), 3.64 (s, 3H), 3.11 (s, 3H), 2.14 – 2.09 (m, 2H), 1.63 – 1.59 (m, 2H), 1.40 (s, 9H). tert-Butyl 4-acetyl-2-azabicyclo[2.1.1]hexane-2-carboxylate

[0608] To tert-butyl 4-[methoxy(methyl)carbamoyl]-2-azabicyclo[2.1.1]hexane-2- carboxylate (375 mg, 1.39 mmol) in anhydrous THF (8 mL) at -20 °C was added methylmagnesium bromide (3 M in THF, 1.4 mL, 4.16 mmol) and the reaction mixture allowed to stir for 1 hour, then the reaction was warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with water (5 mL), diluted with EtOAc (10 mL) and the organic phase was washed with water (15 mL) then saturated aqueous brine solution (15 mL). The organics were separated, dried (Na2SO4) and concentrated under reduced pressure to the title compound as an oil (264 mg, 1.17 mmol, 84%).

[0609] 1H NMR (400 MHz, DMSO-d6) δ 4.18 (t, J = 1.8 Hz, 1H), 3.36 (s, 2H), 2.18 (s, 3H), 2.14 – 2.11 (m, 2H), 1.58 (dd, J = 4.6, 1.9 Hz, 2H), 1.40 (s, 9H). 1-(2-Azabicyclo[2.1.1]hexan-4-yl)ethanone

[0610] To tert-butyl 4-acetyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (264 mg, 1.17 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (0.90 mL, 11.7 mmol) and the reaction mixture stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue taken up in MeOH and loaded onto an SCX-2 cartridge. The cartridge was washed with MeOH (20 mL) and the compound was eluted with 2 M NH3 in MeOH (20 mL). The solvent was removed under reduced pressure to afford the title compound as an oil (139 mg, 1.11 mmol, 95%).

[0611] 1H NMR (400 MHz, DMSO-d6) δ 3.11 – 3.07 (m, 1H), 2.50 (s, 2H), 1.76 (s, 3H), 1.48 – 1.45 (m, 2H), 1.07 – 1.04 (m, 2H). 1-[2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexan-4- yl]ethanone

[0612] To a solution of 1-(2-azabicyclo[2.1.1]hexan-4-yl)ethanone (139 mg, 1.11 mmol) in n-butanol (6 mL) was added N,N-diisopropylethylamine (0.58 mL, 3.3 mmol) and 2-chloro-N-(5- cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (222 mg, 0.944 mmol) and the reaction mixture heated at 120 °C for 18 hours. The reaction mixture was allowed to cool to room temperature anddiluted with EtOAc (15 mL) and washed with water (15 mL) and brine (15 mL). The organics were separated, dried (Na2SO4), concentrated under reduced pressure. The crude residue was purified by flash column chromatography over silica gel, eluting with MeOH (0% to 10%) in CH2Cl2 to afford the title compound as a solid (117 mg, 0.361 mmol, 32%).

[0613] 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 9.41 (s, 1H), 7.86 (d, J = 5.8 Hz, 1H), 4.72 – 4.67 (m, 1H), 3.59 (s, 2H), 2.22 (s, 3H), 2.21 – 2.18 (m, 2H), 1.93 – 1.81 (m, 2H), 1.71 – 1.60 (m, 2H), 0.95 – 0.85 (m, 3H), 0.70 – 0.62 (m, 2H).

[0614] UPLC-MS (basic method, 2 min), rt = 0.87 min, m / z = 325.1 [M+H+]. 1-[2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexan-4- yl]ethanol

[0615] To 1-[2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.1.1]hexan-4-yl]ethanone (58 mg, 0.18 mmol) in MeOH (2 mL) was added sodium borohydride (20 mg, 0.54 mmol) and the reaction mixture stirred for 18 hours. The reaction mixture was diluted with EtOAc (10 mL) and washed with water (10 mL) then saturated aqueous brine solution (10 mL) and the organics separated, dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a solid (40 mg, 0.12 mmol, 69%).

[0616] 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.34 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.29 – 6.09 (m, 1H), 4.69 – 4.65 (m, 1H), 4.63 (s, 1H), 3.89 – 3.83 (m, 1H), 3.37 – 3.26 (m, 2H), 1.92 – 1.79 (m, 2H), 1.76 – 1.70 (m, 1H), 1.40 – 1.26 (m, 2H), 1.10 (d, J = 6.4 Hz, 3H), 0.96 – 0.83 (m, 2H), 0.69 – 0.61 (m, 2H).

[0617] UPLC-MS (basic method, 4 min), rt = 1.20 min, m / z = 327.2 [M+H+]. Example 78: Synthesis of [2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.1.1]hexan-4-yl]methanol (Compound 5)2-azabicyclo[2.1.1]hexan-4-ylmethanol;hydrochloride

[0618] Another batch of Compound 5 was synthesis through the following synthetic route. To a solution of tert-butyl 4-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (2.50 g, 11.7 mmol) in DCM (10 mL) was added a 4 M hydrogen chloride solution in 1,4-dioxane (29.3 mL, 117 mmol) and the reaction mixture was stirred at room temperature, under nitrogen, for 2 hours. The solvent was removed in vacuo to afford the title compound as an oil (2.17 g, 12.5 mmol, quantitative yield).

[0619] 1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 2H), 4.97 (s, 1H), 4.07 (s, 1H), 3.60 (s, 2H), 3.07 – 3.01 (m, 2H), 1.85 – 1.77 (m, 2H), 1.51 – 1.43 (m, 2H). [2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexan-4- yl]methanol

[0620] A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (2.20 g, 9.33 mmol), 2-azabicyclo[2.1.1]hexan-4-ylmethanol;hydrochloride (1.68 g, 11.2 mmol) and Ndiisopropylethylamine (6.5 mL, 37 mmol) in n-butanol (22 mL) was heated to reflux and stirred for 17 hours. The reaction mixture was then concentrated to dryness under reduced pressure. The residue was diluted with water (100 mL) then extracted with 3:1 CHCl3 / IPA (3 × 100 mL). The combined organic extracts were dried (Na2SO4), filtered and the solvent was removed in vacuo. The residue was purified by flash column chromatography over silica gel, eluting with a gradient of MeOH (10% to 20% v / v) in DCM. The residue was dissolved in MeOH (5 mL), then loaded onto an SCX-2 cartridge. The cartridge was washed with MeOH (100 mL) then the compound was eluted with 2M NH3 in MeOH (100 mL). The eluent was concentrated to dryness under reduced pressure to afford the title compound as a solid (1.72 g, 5.44 mmol, 58%).

[0621] 1H NMR (400 MHz, Methanol-d4) δ 7.83 (d, J = 6.0 Hz, 1H), 6.30 – 5.96 (m, 2H), 4.82 – 4.77 (m, 1H), 3.85 – 3.77 (m, 2H), 3.50 – 3.37 (m, 2H), 1.99 – 1.84 (m, 3H), 1.56 – 1.45 (m, 2H), 1.06 – 0.86 (m, 2H), 0.78 – 0.65 (m, 2H).

[0622] 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.32 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.34 – 6.09 (m, 2H), 4.73 – 4.64 (m, 2H), 3.64 (d, J = 5.4 Hz, 2H), 3.31 (s, 2H), 1.91 – 1.83 (m, 1H), 1.83 – 1.74 (m, 2H), 1.38 – 1.30 (m, 2H), 0.97 – 0.86 (m, 2H), 0.69 – 0.63 (m, 2H).

[0623] UPLC-MS (basic method, 4 min): Rt: 1.13 min, m / z = 313.1 [M+H]+. Example 79: Synthesis of [2-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2- azabicyclo[2.1.1]hexan-4-yl]methanol (Compound 5)2-Azabicyclo[2.1.1]hexan-4-ylmethanol;hydrochloride

[0624] Another batch of Compound 5 was synthesis through the following synthetic route. To a solution of tert-butyl 4-(hydroxymethyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (2.50 g, 11.7 mmol) in DCM (10 mL) was added a 4 M hydrogen chloride solution in 1,4-dioxane (29.3 mL, 117 mmol) and the reaction mixture was stirred at room temperature, under nitrogen, for 2 hours. The solvent was removed in vacuo to afford the title compound as an oil (2.11 g, 12.0 mmol, quantitative yield).

[0625] 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 2H), 4.60 (s, 1H), 4.13 – 4.02 (m, 1H), 3.60 (s, 2H), 3.07 – 3.02 (m, 2H), 1.86 – 1.77 (m, 2H), 1.52 – 1.43 (m, 2H). [2-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-2-azabicyclo[2.1.1]hexan-4- yl]methanol

[0626] A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (2.20 g, 9.33 mmol), 2-azabicyclo[2.1.1]hexan-4-ylmethanol;hydrochloride (1.68 g, 11.2 mmol) and NN diisopropylethylamine (6.5 mL, 37 mmol) in n-butanol (22 mL) was heated to reflux and stirred for 17 hours. The reaction mixture was then concentrated to dryness under reduced pressure. The residue was diluted with water (100 mL) then extracted with 3:1 chloroform / propan-2-ol (3 × 100 mL). The combined organic extracts were dried (Na2SO4), filtered and the solvent was removed in vacuo. The residue was purified by flash column chromatography over silica gel, eluting with a gradient of methanol (10% to 20% v / v) in DCM. The residue was dissolved in methanol, then loaded onto an SCX-2 cartridge. The cartridge was washed with methanol (100 mL) then the compound was eluted with 2 M ammonia in methanol solution (100 mL). The eluent was concentrated to dryness under reduced pressure to afford the title compound as a solid (1.74 g, 5.57 mmol, 60%).

[0627] 1H NMR (400 MHz, Methanol-d4) δ 7.83 (d, J = 5.9 Hz, 1H), 6.26 – 6.09 (m, 2H), 4.81 – 4.77 (m, 1H), 3.82 – 3.79 (m, 2H), 3.49 – 3.39 (m, 2H), 1.95 – 1.86 (m, 3H), 1.54 – 1.47 (m, 2H), 1.03 – 0.89 (m, 2H), 0.76 – 0.69 (m, 2H).

[0628] 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.32 (s, 1H), 7.83 (d, J = 5.7 Hz, 1H), 6.34 – 6.10 (m, 2H), 4.72 – 4.65 (m, 2H), 3.64 (d, J = 5.4 Hz, 2H), 3.31 (s, 2H), 1.91 – 1.82 (m, 1H), 1.82 – 1.74 (m, 2H), 1.38 – 1.31 (m, 2H), 0.96 – 0.85 (m, 2H), 0.70 – 0.63 (m, 2H).

[0629] UPLC-MS (basic method, 4 min): Rt: 1.12 min, m / z = 313.3 [M+H]+. Example 80: Synthesis of N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-(1-methoxy-3- azabicyclo[3.1.1]heptan-3-yl)pyrimidin-4-amine (Compound 90)N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-(1-methoxy-3-azabicyclo[3.1.1]heptan-3- yl)pyrimidin-4-amine

[0630] To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (150 mg, 0.636 mmol) and 1-methoxy-3-azabicyclo[3.1.1]heptane (97 mg, 0.76 mmol) in n-butanol (7 mL) was added N,N-diisopropylethylamine (0.55 mL, 3.2 mmol). The reaction mixture was heated to 100 °C and allowed to stir for 16 hours. The reaction mixture was concentrated under reduced pressure and diluted with water (40 mL). The mixture was then extracted with DCM (3 × 30 mL). The combined organic fractions were washed with saturated brine solution (30 mL), dried over Na2SO4and concentrated to dryness under reduced pressure. The residue was purified by reversed-phase preparative HPLC to afford the title compound as a powder (93 mg, 0.29 mmol, 45%).

[0631] 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 9.43 (s, 1H), 7.88 (d, J = 5.7 Hz, 1H), 6.25 (s, 2H), 3.63 – 3.47 (m, 4H), 3.24 (s, 3H), 2.47 (s, 1H), 2.17 (s, 2H), 1.84 (m, 1H), 1.55 (dd, J = 6.6, 2.5 Hz, 2H), 0.95 – 0.87 (m, 2H), 0.68 – 0.59 (m, 2H).

[0632] UPLC-MS (basic method, 4 min): rt = 1.45 min, m / z: 327.2 [M+H]+.Example 81: Synthesis of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-(methoxymethyl)-2- azabicyclo[2.2.1]heptan-2-yl)pyrimidin-4-amine (Compounds 91-1 and 91-2)

[0633] Enantiomer separation by chiral preparative SFC was carried out on Compound 29 using a Lux iC5(20 mm x 250 mm, 5 µm) column and the following parameters: temperature: 40 °C, mobile phase: 1:3 EtOH:CO2(0.2% v / v NH3), flow rate: 50 mL / min to afford compound 91-1 as a solid (9.2 mg, 27 µmol, 23%) and compound 91-2 as a solid (11 mg, 33 µmol, 28%). Compound 91-1

[0634] 1H NMR (400 MHz, Chloroform-d) δ 7.98 (d, J = 5.6 Hz, 1H), 6.82 (s, 1H), 5.99 – 5.95 (m, 2H), 4.69 – 4.65 (m, 1H), 3.58 (s, 2H), 3.40 (s, 3H), 3.30 – 3.20 (m, 1H), 1.92 – 1.79 (m, 3H), 1.73 – 1.67 (m, 3H), 1.56 – 1.45 (m, 3H), 0.99 – 0.86 (m, 2H), 0.77 – 0.69 (m, 2H).

[0635] UPLC-MS (basic method, 4 min): rt = 1.48 min, m / z = 341.3 [M+H]+.

[0636] Chiral SFC: column: Lux iC5(4.6 mm x 250 mm, 5 μm); mobile phase: 1:3 EtOH:CO2 (0.1% v / v NH3), flow rate: 3 mL / min; temperature: 40 °C; rt = 7.81 min (major), 8.98 min (minor), >99% e.e. Compound 91-2

[0637] 1H NMR (400 MHz, Chloroform-d) δ 7.98 (d, J = 5.5 Hz, 1H), 6.89 (s, 1H), 5.99 – 5.95 (m, 2H), 4.69 – 4.63 (m, 1H), 3.57 (s, 2H), 3.40 (s, 3H), 3.30 – 3.23 (m, 1H), 1.92 – 1.79 (m, 3H), 1.73 – 1.67 (m, 3H), 1.55 – 1.45 (m, 3H), 0.98 – 0.91 (m, 2H), 0.77 – 0.69 (m, 2H).

[0638] UPLC-MS analysis (basic method, 4 min): rt = 1.48 min, m / z = 341.3 [M+H]+.

[0639] Chiral SFC: column: Lux iC5(4.6 mm x 250 mm, 5 μm); mobile phase: 1:3 EtOH:CO2(0.1% v / v NH3), flow rate: 3 mL / min; temperature: 40 °C; rt = 8.01 min (minor), 9.00 min (major), 98% e.e. Example 82: Synthesis of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[4-(1-methoxycyclopropyl)- 2-azabicyclo[2.2.1]heptan-2-yl]pyrimidin-4-amine (Compound 92)tert-Butyl 4-(1-Methoxycyclopropyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0640] To a solution of tert-butyl 4-(1-hydroxycyclopropyl)-2-azabicyclo[2.2.1]heptane-2- carboxylate (927 mg, 2.74 mmol) in THF (20 mL) at 0 °C was added a 60% w / w suspension of sodium hydride in mineral oil (220 mg, 5.49 mmol). After stirring for 30 min, methyl iodide (1.7 mL, 27 mmol) was added at 0 °C, then the reaction mixture was allowed to warm to ambient temperature and stirred for 2 days. The mixture was quenched by the addition of saturated aqueous ammonium chloride (10 mL) and was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with saturated aqueous brine solution (50 mL) and concentrated to afford the title compound as an oil (805 mg, 2.86 mmol, quantitative yield).

[0641] 1H NMR (400 MHz, DMSO-d6) δ 3.98 (d, J = 13.2 Hz, 1H), 3.20 – 3.18 (m, 3H), 3.17 – 3.06 (m, 2H), 1.73 – 1.51 (m, 5H), 1.38 (s, 9H), 1.34 – 1.26 (m, 1H), 0.75 – 0.69 (m, 2H), 0.65 – 0.55 (m, 2H). 4-(1-Methoxycyclopropyl)-2-azabicyclo[2.2.1]heptane

[0642] To a stirred solution of tert-butyl 4-(1-methoxycyclopropyl)-2- azabicyclo[2.2.1]heptane-2-carboxylate (800 mg, 2.84 mmol) in DCM (20 mL) was added trifluoroacetic acid (2.2 mL, 28.4 mmol) dropwise, and the reaction mixture was stirred for 30min. The reaction mixture was concentrated under reduced pressure. The crude residue was dissolved in methanol (3 mL) and loaded onto an SCX-2 cartridge (10 g). The cartridge was washed with methanol (50 mL), then the compound was eluted with 2 M NH3in methanol (20 mL). The eluent was concentrated to afford the title compound as an oil (259 mg, 1.47 mmol, 51.74%).

[0643] 1H NMR (400 MHz, DMSO-d6) δ 3.22 – 3.20 (m, 1H), 3.16 (s, 3H), 2.77 – 2.72 (m, 1H), 2.69 – 2.64 (m, 1H), 1.74 – 1.39 (m, 4H), 1.20 – 1.13 (m, 1H), 1.10 – 1.05 (m, 1H), 0.73 – 0.66 (m, 2H), 0.57 – 0.51 (m, 2H). N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[4-(1-methoxycyclopropyl)-2-azabicyclo[2.2.1]heptan- 2-yl]pyrimidin-4-amine

[0644] To a solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (286 mg, 1.21 mmol) and 4-(1-methoxycyclopropyl)-2-azabicyclo[2.2.1]heptane (256 mg, 1.46 mmol) in n-butanol (12 mL) was added N,N-diisopropylethylamine (1.1 mL, 6.1 mmol). The reaction mixture was heated to 100 °C and allowed to stir for 16 hours. The reaction mixture was concentrated under reduced pressure and diluted with water (60 mL). The mixture was then extracted with DCM (3 × 50 mL). The combined organic fractions were washed with saturated brine solution (40 mL), dried over Na2SO4and concentrated to dryness. The residue was purified by reversed-phase basic preparative HPLC. The residue was then dissolved in methanol (3 mL) and loaded onto an SCX-2 cartridge (10 g). The cartridge was washed with methanol (50 mL), then the compound was eluted with 2 M NH3in methanol (20 mL). The eluent was concentrated to dryness and the residue was freeze dried to afford the title compound as a powder (145 mg, 0.396 mmol, 33%).

[0645] 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 9.34 (s, 1H), 7.80 (s, 1H), 6.19 (s, 2H), 4.45 (s, 1H), 3.46 – 3.35 (m, 2H), 3.30 – 3.21 (m, 3H), 1.92 – 1.55 (m, 5H), 1.44 – 1.39 (m, 1H), 1.30 – 1.26 (m, 1H), 0.93 – 0.89 (m, 2H), 0.84 – 0.57 (m, 6H).

[0646] UPLC-MS (basic method, 4 min): rt = 1.61 min, m / z = 367.2 [M+H]+. Example 83: Synthesis of N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[4-(methoxymethyl)-2- azabicyclo[2.2.1]heptan-2-yl]pyrimidin-4-amine (Compound 29)tert-Butyl 4-(methoxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

[0647] Another batch of Compound 29 was synthesized according to the following protocol. To a suspension of tert-butyl 4-(bromomethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.50 g, 5.17 mmol) and sodium iodide (813 mg, 5.43 mmol) in methanol (15 mL) was added 5.4 M solution of sodium methoxide in methanol (15 mL, 81.0 mmol). The reaction mixture was heated to reflux and stirred for 20 hours. The reaction mixture was concentrated to dryness under reduced pressure. The residue was suspended in water (50 mL) then extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over Na2SO4, then concentrated to dryness under reduced pressure to afford the title compound as a gum (1.20 g, 4.97 mmol, 96%).

[0648] 1H NMR (400 MHz, DMSO-d6) δ 4.06 – 3.99 (m, 1H), 3.49 – 3.42 (m, 2H), 3.28 – 3.24 (m, 3H), 3.14 – 3.03 (m, 1H), 2.93 – 2.85 (m, 1H), 1.75 – 1.60 (m, 1H), 1.60 – 1.50 (m, 2H), 1.50 – 1.34 (m, 11H), 1.34 – 1.25 (m, 1H).

[0649] UPLC-MS (2 min, basic method, ELS detector), rt = 1.13 min, m / z = 242.2 [M+H]+. 4-(Methoxymethyl)-2-azabicyclo[2.2.1]heptane hydrochloride

[0650] To a solution of tert-butyl 4-(methoxymethyl)-2-azabicyclo[2.2.1]heptane-2- carboxylate (1.20 g, 4.97 mmol) in DCM (10 mL) was added 4 M hydrogen chloride in 1,4- dioxane (10 mL, 40.0 mmol) and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then concentrated to dryness under reduced pressure to afford the title compound as a solid (880 mg, 4.95 mmol, 99%).

[0651] 1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.89 (s, 1H), 3.95 – 3.91 (m, 1H), 3.50 (s, 2H), 3.28 (s, 3H), 2.98 – 2.82 (m, 2H), 1.95 – 1.85 (m, 1H), 1.79 – 1.67 (m, 1H), 1.65 – 1.41 (m, 4H).

[0652] UPLC MS (2 min, basic method,), rt = 0.69 min, m / z = 142.1 [M+H]+. N-(5-Cyclopropyl-1H-pyrazol-3-yl)-2-[4-(methoxymethyl)-2-azabicyclo[2.2.1]heptan-2- yl]pyrimidin-4-amine

[0653] A solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (0.97 g, 4.11 mmol), 4-(methoxymethyl)-2-azabicyclo[2.2.1]heptane;hydrochloride (876 mg, 4.93 mmol) and N,N-diisopropylethylamine (2.5 mL, 14 mmol) in n-butanol (15 mL) was heated to 100 °C and stirred for 20 hours. The reaction mixture was diluted with water (50 mL), then extracted with 3:1 CHCl3:IPA (3 × 50 mL). The combined organic extracts were dried over Na2SO4, then concentrated to dryness under reduced pressure. The crude material was purified by column chromatography over silica gel, eluting with a gradient of MeOH (0% to 15%; v / v) in DCM. The residue was then further purified by reversed-phase basic preparative HPLC to afford the title compound as a solid (501 mg, 1.47 mmol, 36%).

[0654] 1H NMR (400 MHz, Methanol-d4) δ 7.89 – 7.70 (m, 1H), 6.35 – 6.18 (m, 1H), 6.15 – 5.93 (m, 1H), 4.66 – 4.38 (m, 1H), 3.62 (s, 2H), 3.53 – 3.37 (m, 4H), 3.27 – 3.13 (m, 1H), 1.92 – 1.65 (m, 5H), 1.60 – 1.46 (m, 2H), 1.07 – 0.87 (m, 2H), 0.77 – 0.62 (m, 2H).

[0655] UPLC MS (4 min, basic method,) rt = 1.50 min, m / z = 341.3 [M+H]+.Example 84: Synthesis of N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[1-(1-methoxycyclopropyl)- 3-azabicyclo[3.1.1]heptan-3-yl]pyrimidin-4-amine (Compound 93)tert-Butyl 1-(1-Methoxycyclopropyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate

[0656] 60% w / w suspension of sodium hydride in mineral oil (31 mg, 0.77 mmol) was added portion-wise to a stirred solution of tert-butyl 1-(1-hydroxycyclopropyl)-3- azabicyclo[3.1.1]heptane-3-carboxylate (130 mg, 0.513 mmol) in THF (2.5 mL), at 0 °C, under nitrogen. The mixture was allowed to warm to room temperature and then stirred for another 20 minutes. The mixture was cooled back down to 0 °C and then methyl iodide (0.10 mL, 1.5 mmol) was added, and the reaction mixture was allowed to warm up slowly to room temperature and stirred for another 4 hours. The reaction mixture was quenched with water (6 mL) and then extracted with ethyl acetate (3 x 10 mL). The combined extracts were washed with saturated aqueous brine solution (7 mL) and dried over Na2SO4. The solvent was removed in vacuo to afford the title compound as an oil (130 mg, 0.486 mmol, 95%).

[0657] 1H NMR (400 MHz, Chloroform-d) δ 3.69 – 3.62 (m, 2H), 3.49 (d, J = 5.3 Hz, 2H), 3.23 (s, 3H), 2.42 – 2.27 (m, 1H), 1.80 – 1.71 (m, 2H), 1.50 (s, 9H), 1.41 – 1.37 (m, 2H), 0.72 – 0.66 (m, 2H), 0.58 – 0.50 (m, 2H). 1-(1-Methoxycyclopropyl)-3-azabicyclo[3.1.1]heptane; hydrochloride

[0658] 4 M solution of hydrogen chloride in 1,4-dioxane (1.2 mL, 4.86 mmol) was added to a stirred solution of tert-butyl 1-(1-methoxycyclopropyl)-3-azabicyclo[3.1.1]heptane-3- carboxylate (130 mg, 0.486 mmol) in DCM (1.3 mL), under nitrogen. The solution was stirred at room temperature for 2 hours and then the solvents were removed in vacuo afford the title compound as a solid (120 mg, 0.530 mmol, 100%).

[0659] 1H NMR (400 MHz, Methanol-d4) δ 3.58 – 3.55 (m, 2H), 3.44 (d, J = 2.5 Hz, 2H), 3.26 (s, 3H), 2.50 – 2.44 (m, 1H), 2.09 – 2.01 (m, 2H), 1.71 – 1.64 (m, 2H), 0.76 – 0.70 (m, 2H), 0.69 – 0.63 (m, 2H). N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[1-(1-methoxycyclopropyl)-3-azabicyclo[3.1.1]heptan- 3-yl]pyrimidin-4-amine

[0660] A stirred solution of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (104 mg, 0.442 mmol), 1-(1-methoxycyclopropyl)-3-azabicyclo[3.1.1]heptane; hydrochloride (120 mg, 0.530 mmol) and N,N-diisopropylethylamine (0.31 mL, 1.8 mmol) in n-butanol (4.4 mL) was heated at reflux, under nitrogen, for 20 hours. The reaction mixture was allowed to cool to room temperature and then the solvent was removed in vacuo to leave a viscous oil. Water (6 mL) was added and then the mixture was extracted with 3:1 chloroform / propan-2-ol (3 x 6 mL). The combined organic extracts were dried (Na2SO4), filtered and the solvents were removed in vacuo to leave a solid. The crude material was purified by basic preparative HPLC to afford the title compound as a solid (47 mg, 0.13 mmol, 29%).

[0661] 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 9.42 (s, 1H), 7.88 (d, J = 5.7 Hz, 1H), 6.40 – 6.09 (m, 2H), 3.85 – 3.71 (m, 2H), 3.71 – 3.57 (m, 2H), 3.19 (s, 3H), 2.48 – 2.39 (m, 1H), 1.88 – 1.74 (m, 3H), 1.45 – 1.37 (m, 2H), 0.93 – 0.82 (m, 2H), 0.69 – 0.57 (m, 6H).

[0662] UPLC-MS analysis: (basic, 4 min): rt = 1.72 min, m / z = 367.2 [M+H]+. Example 85: Synthesis of 3-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-N- methyl-3-azabicyclo[3.1.1]heptan-1-amine (Compound 94)3-[4-[(5-Cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-N-methyl-3- azabicyclo[3.1.1]heptan-1-amine

[0663] To a solution of tert-butyl N-[3-[4-[(5-cyclopropyl-1H-pyrazol-3- yl)amino]pyrimidin-2-yl]-3-azabicyclo[3.1.1]heptan-1-yl]carbamate (175 mg, 0.425 mmol) in anhydrous THF (5 mL) under a nitrogen atmosphere was added 2.4 M solution of lithium aluminum hydride in THF (1.8 mL, 4.3 mmol) and the reaction mixture heated to reflux and stirred for 4 hours. The reaction mixture was then cooled to room temperature and quenched with water (2 mL) then a 10% w / v aqueous NaOH solution (2 mL) then water (2 mL). The reaction mixture was allowed to stir for 10 minutes then filtered through celite. The filter cake was washe...

Claims

AMENDED CLAIMS received by the International Bureau on 23 October 2024 (23.10.2024)1. A comp ound of F ormul a I- A :(Formula I- A) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein:W is selected from the group consisting of N, C-H, and C-F;Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2, CH(CH3), ('(Ci hh, C(CI FCH •■).. CFH, CHCF3, CHCF?.H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); ring Z is a 4-10 membered N-bound heterocyclic, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted by one, two or three halogens), oxo, C1-C4 alkoxy, and cyano;L1is selected from the group consisting of bond, Ci-Ce alkylene (optionally substituted by one, two or three R4), and -C(=O)-; when L1is bond or Ci-Ce alkylene (optionally substituted by one, two or three R4), R3is OR”, -CN, S(O)2Ci.4alkyl, or P(O)(Ci-4alkyl)2; when L1is -C(=O)-, R3is NR’R’ or OR”;R4is each independently selected from the group consisting of halogen and Ci-Ce alkyl (optionally substituted by one, two or three halogens), or two R4together with the carbon to which the R4are attached form a C3-C5 carbocyclyl;R’ and R” for each occurrence are each independently selected from the group consisting of H and Ci-Ce alkyl (optionally substituted by one, two or three halogens);RHis selected from the group consisting of H, Ci-C4alkyl, -C(O)-Ci-C3alkyl, and C(O)-O-Ci-C3alkyl;R1is selected from the group consisting of C3-Cio cycloalkyl, spiro C5-C10 bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; wherein C3-Cio cycloalkyl, spiro C5-C10AMENDED SHEET (ARTICLE 19)bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents each independently selected from halo and Ci-C4alkyl (optionally substituted by one, two or three halogens);R2is selected from the group consisting of H, F, methyl, CF3, -C(O)-O-methyl, - C(O)OH, -O-methyl, -O-ethyl, C3-C7 cycloalkyl, and heterocyclyl optionally substituted by one, two, or three substituents each independently selected from the group consisting of halogen and Ci-4alkyl; andR5is selected from the group consisting of H, F, methyl, and CF3, or R2and R5together with the contiguous carbon atoms to which R2and R5are attached to form a phenylene ring.

2. A compound of Formula I-I A:(Formula I-I A) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein:W is selected from the group consisting of N, C-H, and C-F;Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2, CH(CH 3 ), C(CH3)2, C(CH2CH2), CFH, CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH 3)01 i, and CH(OCi h): ring Z is a 4-10 membered N-bound heterocyclic, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted by one, two or three halogens), oxo, C1-C4 alkoxy, and cyano;L1is selected from the group consisting of bond, Ci-Ce alkylene (optionally substituted by one, two or three R4), and -C(=O)-; when L1is bond or Ci-Ce alkylene (optionally substituted by one, two or three R4), R3is OR”, -CN, S(O)2Ci.4alkyl, or P(O)(Ci-4alkyl)2; when L1is -C(=O)-, R3is NR’R’ or OR”;AMENDED SHEET (ARTICLE 19)R4is each independently selected from the group consisting of halogen and Ci-Ce alkyl (optionally substituted by one, two or three halogens), or two R4together with the carbon to which the R4are attached form a C3-C5 carbocyclyl;R’ and R” for each occurrence are each independently selected from the group consisting of H and Ci-Ce alkyl (optionally substituted by one, two or three halogens);RHis selected from the group consisting of H, Ci-C4alkyl, -C(O)-Ci-C3alkyl, and C(O)-O-Ci-C3alkyl;R1is selected from the group consisting of C3-C10 cycloalkyl, spiro C5-C10 bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; wherein C3-C10 cycloalkyl, spiro C5-C10 bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents each independently selected from halo and Ci-C4alkyl (optionally substituted by one, two or three halogens); andR2is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O-methyl, -O-ethyl, C3-C7 cycloalkyl, and heterocyclyl.

3. The compound of claim 2, wherein W is N, Y is NH, RHis H, and having the Formula laa:(Formula laa) or a pharmaceutically acceptable salt, stereoisomer and / or N-oxide thereof.

4. The compound of any one of claims 1-3, wherein R1is a 5-6 membered heterocyclyl or C3-C6 cycloalkyl.

5. The compound of any one of claims 1-4, wherein R1is a C3-C6 cycloalkyl.

6. The compound of any one of claims 1-5, wherein R1is cyclopropyl.

7. The compound of any one of claims 1-5, wherein R1is cyclopentyl.

8. The compound of any one of claims 1-7, wherein ring Z is selected from the group consisting of 4-6 membered monocyclic heterocycle, 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged heterocycle.AMENDED SHEET (ARTICLE 19)9. The compound of any one of claims 1-7, wherein ring Z is selected from the group consisting of 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocyclyl, and 6-10 membered bridged heterocycle.

10. The compound of any one of claims 1-7, wherein ring Z is selected from the group consisting of 4-6 membered monocyclic heterocycle and 6-10 membered bridged heterocycle.

11. The compound of any one of claims 1-7, wherein ring Z is selected from the group consisting of:

12. The compound of any one of claims 1-7, wherein ring Z is selected from the group consisting of:

13. The compound of any one of claims 1-7, wherein ring Z is selected from the group consisting of:

14. The compound of any one of claims 2-7, represented by Formula Ibb:(Formula Ibb) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

15. The compound of any one of claims 2-7, represented by Formula Icc:AMENDED SHEET (ARTICLE 19)(Formula Icc) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

16. The compound of any one of claims 2-7, represented by Formula Idd:(Formula Idd) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

17. The compound of any one of claims 2-7, represented by Formula lee:(Formula lee) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein m is 0, 1, or 2.

18. The compound of any one of claims 1-17, wherein L1is Ci-Ce alkylene substituted by one or two R4.

19. The compound of any one of claims 1-18, wherein L1is methylene substituted by one or two R4.

20. The compound of claim 18 or 19, wherein R4is C1-C4 alkyl (optionally substituted by one, two or three halogens).

21. The compound of claim 18 or 19, wherein two R4s together with the carbon to which the R4are attached form a C3-C4 carbocyclyl.

22. The compound of any one of claims 1-17, wherein L1is Ci-Ce alkylene.

23. The compound of claim 22, wherein L1is methylene.AMENDED SHEET (ARTICLE 19)24. The compound of any one of claims 1-23, wherein R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, O-tert-butyl, P(O)(CH3)2, and S(O)2(CH3).

25. The compound of any one of claims 1-23, wherein R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, and O-tert- butyl.

26. The compound of any one of claims 1-17, wherein L1is -C(=O)-.

27. The compound of any one of claims 1-17 and 26, wherein R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, and O-tert- butyl.

28. The compound of any one of claims 1-17 and 26, wherein R3is selected from the group consisting of NH2, NHMe, N(Me)2.

29. The compound of any one of claims 1-28, wherein R2is H or F.

30. The compound of any one of claims 1-29, wherein R2is H.

31. A compound selected from the group consisting of:AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)AMENDED SHEET (ARTICLE 19)or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof.

32. A compound of Formula II- A:(Formula II- A) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein:W is selected from the group consisting of N, C-H, and C-F;Y is selected from the group consisting of NH, N-CH O, S, CH2, CF2, CH(CH 3 ), C(CH3)2, C(CH2CH2), CFH, CHCF '3, CHCF2H, CHfOCF2I 1), CHOH, C(CH3)OH, and CH(0CH-3); ring Z is selected from the group consisting of 4, 5, or 7-10-membered N-bound monocyclic heterocyclyl, 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged heterocycle, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted by one, two or three halogens), oxo, C1-C4 alkoxy, and cyano;AMENDED SHEET (ARTICLE 19)L1is selected from the group consisting of bond, Ci-Ce alkylene (optionally substituted by one, two or three R4), and -C(=O)-; when L1is bond or Ci-Ce alkylene (optionally substituted by one, two or three R4), R3is OR”, -CN, S(O)Ci-4alkyl, or P(O)(Ci-4alkyl)2; when L is -C(=O)-, R3is NR’R’ or OR”;R4is each independently selected from the group consisting of halogen and Ci-Ce alkyl (optionally substituted by one, two or three halogens), or two R4together with the carbon to which the R4are attached form a C3-C5 carbocyclyl;R’ and R” for each occurrence are each independently selected from the group consisting of H and Ci-Ce alkyl (optionally substituted by one, two or three halogens);RHis selected from the group consisting of H, Ci-C4alkyl, -C(O)-Ci-C3alkyl, and C(O)-O-Ci-C3alkyl;R1is selected from the group consisting of C3-C10 cycloalkyl, spiro C5-C10 bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; wherein C3-C10 cycloalkyl, spiro C5-C10 bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents each independently selected from halo and Ci-C4alkyl (optionally substituted by one, two or three halogens);R2is selected from the group consisting of H, F, methyl, CF3, -C(O)-O-methyl, - C(O)OH, -O-methyl, -O-ethyl, C3-C7 cycloalkyl, and heterocyclyl optionally substituted by one, two, or three substituents each independently selected from the group consisting of halogen and Ci-4alkyl; andR5is selected from the group consisting of H, F, methyl, and CF3, or R2and R5together with the contiguous carbon atoms to which R2and R5are attached to form a phenylene ring.

33. A compound of Formula II-I A:(Formula II-I A) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein:AMENDED SHEET (ARTICLE 19)W is selected from the group consisting of N, C-H, and C-F;Y is selected from the group consisting of NH, N-CH3, O, S, CH2, CF2, CH(CH3), ('(Cl h) 2, C(CH2CH2), CFH, CHCF3, CHCF2H, CH(OCF2H), CHOH, C(CH3)OH, and CH(OCH3); ring Z is selected from the group consisting of 4, 5, or 7-10-membered N-bound monocyclic heterocyclyl, 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged heterocycle, wherein Z may optionally be substituted by one or two substituents each independently selected from the group consisting of halo, hydroxyl, C1-C4 alkyl (optionally substituted by one, two or three halogens), oxo, C1-C4 alkoxy, and cyano;L1is selected from the group consisting of bond, Ci-Ce alkylene (optionally substituted by one, two or three R4), and -C(=O)-; when L1is bond or Ci-Ce alkylene (optionally substituted by one, two or three R4), R3is OR”, -CN, S(O)Ci-4alkyl, or P(O)(Ci-4alkyl)2; when L1is -C(=O)-, R3is NR’R’ or OR”;R4is each independently selected from the group consisting of halogen and Ci-Ce alkyl (optionally substituted by one, two or three halogens), or two R4together with the carbon to which the R4are attached form a C3-C5 carbocyclyl;R’ and R” for each occurrence are each independently selected from the group consisting of H and Ci-Ce alkyl (optionally substituted by one, two or three halogens);RHis selected from the group consisting of H, Ci-C4alkyl, -C(O)-Ci-C3alkyl, and C(O)-O-Ci-C3alkyl;R1is selected from the group consisting of C3-C10 cycloalkyl, spiro C5-C10 bicycloalkyl, heterocyclyl, cyano, halo, and heteroaryl; wherein C3-C10 cycloalkyl, spiro C5-C10 bicycloalkyl, heterocyclyl, or heteroaryl may be substituted by one, two or three substituents each independently selected from halo and Ci-C4alkyl (optionally substituted by one, two or three halogens); andR2is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O-methyl, -O-ethyl, C3-C7 cycloalkyl, and heterocyclyl.

34. The compound of claim 33, wherein W is N, Y is NH, RHis H, and having the Formula Ilaa:AMENDED SHEET (ARTICLE 19)(Formula Ilaa) or a pharmaceutically acceptable salt, stereoisomer and / or N-oxide thereof.

35. The compound of any one of claims 32-34, wherein R1is a 5-6 membered heterocyclyl or C3-C6 cycloalkyl.

36. The compound of any one of claims 32-35, wherein R1is a C3-C6 cycloalkyl.

37. The compound of any one of claims 32-36, wherein R1is cyclopropyl.

38. The compound of any one of claims 32-36, wherein R1is cyclopentyl.

39. The compound of any one of claims 32-38, wherein ring Z is selected from the group consisting of 4 or 5 membered monocyclic heterocycle, 6-10 membered spiroheterocycle, 6-10 membered fused bicyclic heterocycle, and 6-10 membered bridged heterocycle.

40. The compound of any one of claims 32-38, wherein ring Z is selected from the group consisting of 4 or 5 membered monocyclic heterocycle and 6-10 membered bridged heterocycle.

41. The compound of any one of claims 32-38, wherein ring Z is selected from the group consisting of:

42. The compound of any one of claims 32-41, wherein L1is Ci-Ce alkylene substituted by one or two R4.

43. The compound of any one of claims 32-42, wherein L1is methylene substituted by one or two R4.

44. The compound of claim 42 or 43, wherein R4is C1-C4 alkyl (optionally substituted by one, two or three halogens).

45. The compound of claim 42 or 43, wherein two R4s together with the carbon to which the R4are attached form a C3-C4 carbocyclyl.

46. The compound of any one of claims 32-41, wherein L1is Ci-Ce alkylene.AMENDED SHEET (ARTICLE 19)47. The compound of claim 46, wherein L1is methylene.

48. The compound of any one of claims 32-47, wherein R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, O-tert-butyl, P(O)(CH3)2, and S(O)2(CH3).

49. The compound of any one of claims 32-47, wherein R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, and O-tert- butyl.

50. The compound of any one of claims 32-41, wherein L1is -C(=O)-.

51. The compound of any one of claims 32-41 and 50, wherein R3is selected from the group consisting of OH, O-methyl, O-ethyl, O-isopropyl, O-n-propyl, O-n-butyl, and O-tert- butyl.

52. The compound of any one of claims 32-41 and 50, wherein R3is selected from the group consisting of NH2, NHMe, N(Me)2.

53. The compound of any one of claims 32-52, wherein R2is H or F.

54. The compound of any one of claims 32-53, wherein R2is H.

55. A compound Formula III-I:(Formula III-I) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein:R11is H or CH3;L1is methylene or ethylene;R3is OR”;R” is H or Ci-Ce alkyl (optionally substituted by one, two or three halogens);RHis selected from the group consisting of H, Ci-C3alkyl, -C(O)-Ci-C3alkyl, and C(O)- O-Ci-C3alkyl; andR2is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O-methyl, -O-ethyl, C3-C? cycloalkyl, and heterocyclyl.

56. A compound of Formula I V-I:AMENDED SHEET (ARTICLE 19)(Formula IV-I) or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, wherein:R11is H or CH3;L1is methylene or ethylene;R3is OR”;R” is H or Ci-Ce alkyl (optionally substituted by one, two or three halogens);RHis selected from the group consisting of H, Ci-C3alkyl, -C(O)-Ci-C3alkyl, and C(O)- O-Ci-C3alkyl; andR2is selected from the group consisting of H, F, CF3, -C(O)-O-methyl, -C(O)OH, -O-methyl, -O-ethyl, C3-C? cycloalkyl, and heterocyclyl.

57. A pharmaceutical composition comprising a compound according to any one of claims 1-56, or a pharmaceutically acceptable salt, stereoisomer, and / or N-oxide thereof, and at least one pharmaceutically acceptable carrier or diluent.

58. The pharmaceutical composition of claim 57, wherein the composition is formulated for parenteral administration.

59. The pharmaceutical composition of claim 57, wherein the composition is formulated for intravenous administration.

60. The pharmaceutical composition of claim 57, wherein the composition is formulated for subcutaneous administration.

61. A method of treating a proliferative disease, comprising: administering to a subject with a proliferative disease a therapeutically effective amount of a compound according to any one of claims 1-56, or a pharmaceutically acceptable salt, stereoisomer and / or N-oxide thereof, or a therapeutically effective amount of the pharmaceutical composition of any one of claims 57-60.

62. The method of claim 61, wherein the proliferative disease is cancer.

63. The method of claim 62, wherein the cancer is selected from the group consisting of head and neck cancer, nervous system cancer, brain cancer, neuroblastoma, lung / mediastinum cancer, breast cancer, esophageal cancer, stomach cancer, liver cancer, biliary tract cancer, pancreatic cancer, small bowel cancer, large bowel cancer, colorectalAMENDED SHEET (ARTICLE 19)cancer, gynecological cancer, genito-urinary cancer, ovarian cancer, thyroid gland cancer, adrenal gland cancer, skin cancer, melanoma, bone sarcoma, soft tissue sarcoma, pediatric malignancy, Hodgkin's disease, non-Hodgkin's lymphoma, myeloma, leukemia, and metastasis from an unknown primary site.

64. A method of modulating MycN in cells of a subject in need thereof, comprising: administering to a subject in need thereof an amount of a compound according to any one of claims 1-56, or a pharmaceutically acceptable salt, stereoisomer and / or N-oxide thereof, or a pharmaceutical composition according to any one of claims 57-60, that is effective to cause MycN modulation in cells of the subject.

65. The method of any one of claims 61-64, further comprising administering to the subject a second therapy.

66. The method of claim 65, wherein the second therapy is an antineoplastic therapy.

67. The method of claim 66, wherein the antineoplastic therapy is administration of one or more agents selected from a DNA topoisomerase I or II inhibitor, a DNA damaging agent, an immunotherapeutic agent, an antimetabolite or a thymidylate synthase (TS) inhibitor, a microtubule targeted agent, ionising radiation, an inhibitor of a mitosis regulator or a mitotic checkpoint regulator, an inhibitor of a DNA damage signal transducer, and an inhibitor of a DNA damage repair enzyme.

68. The method of claim 66, wherein the antineoplastic therapy is selected from the group consisting of immunotherapy, radiation therapy, photodynamic therapy, gene-directed enzyme prodrug therapy (GDEPT), antibody-directed enzyme prodrug therapy (ADEPT), gene therapy, and controlled diets.AMENDED SHEET (ARTICLE 19)STATEMENT UNDER ARTICLE 19 (1 )The above amendments to the Claims are being submitted in accordance with the Patent Cooperation Treaty Article 19.The differences between the claims as filed and the claims as amended are provided herein.Claims 1-30 and 32-68 are unchanged.Claim 31 is replaced by amended claim bearing the same number.The above-described amendment does not go beyond the disclosure of the international application as filed, and entry of these amendments is respectfully requested.Replacement claim set effecting the above-described amendments are being transmitted herewith.

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