Mrgprx2 antagonists and methods of use thereof

Abstract

Disclosed are compounds, compositions, and methods useful for preventing or treating an MRGPRX2 -mediated disease or disorder.

Description

[0001] MRGPRX2 Antagonists and Methods of Use Thereof

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Provisional Patent Application Nos. 63 / 809,628, filed May 21, 2025; and 63 / 702,764, filed October 3, 2024.

[0004] BACKGROUND

[0005] Mature mammalian mast cells ordinarily reside near blood vessels or nerves, beneath or within epithelia, within airways, gastrointestinal and genitourinary tracts, and near smooth muscle and mucus-producing glands. Classically, mast cells are activated by IgE antibodies, secreting a wide range of substances with local and systemic effects, including histamine, serotonin, proteases, chemokines, and cytokines. Indeed, mast cells are implicated in the progression and / or maintenance of many diseases.

[0006] Recent work has emphasized the role of the Mas-related G protein-coupled receptor (MRGPR) family, specifically, Mrgprb2, in mast cell activation. Mrgprb2 is the mouse receptor for several cationic molecules, collectively called basic secretagogues, and the ortholog of the human receptor MRGPRX2. To date, Mrgprb2 and MRGPRX2 have been reported to be expressed only on certain populations of mast cells. This knowledge provides an opportunity to target mast cell degranulation in a very precise manner.

[0007] Natural endogenous ligands of Mrgprb2 / MRGPRX2 have been reported and are mostly neuropeptides, including substance P (SP), vasoactive intestinal polypeptide (VIP), Corti statin- 14, and pituitary adenylate cyclase activating polypeptide (PACAP). Others include P-defensin, cathelicidin (LL-37), and proadrenomedullin N-terminal 20 peptide (PAMP[9-20]). Given the close proximity between mast cells and sensory nerves in various pathological conditions, it follows that neuropeptide-activated MRGPRX2 could contribute to symptoms of neurogenic inflammation including pain, swelling and pruritus. Various observations using knock-out (KO) mice are consistent with the Mrgprb2 / MRGPRX2 receptors playing a role in mast cell-mediated neurogenic inflammation. For instance, Mrgprb2 / MRGPRX2 agonists induce various symptoms such as flushing, swelling and itch in wild type mice, but not in Mrgprb2-deficient mice. Mrgprb2-deficent mice have also demonstrated significant reductions in inflammation (leukocyte infiltration, including mast cells), swelling, pain and overall clinical score in various disease models. An important and relevant observation was the demonstration that Substance P injection could stimulate the infiltration of leukocytes in wild type and NKR1 (canonical Substance P receptor) KO mice whereas the response was substantially blunted in Mrgprb2 null mice. This observation extends the role of Mrgprb2 / MRGPRX2 as a key receptor in mediating Substance P-induced inflammatory responses, including pain. Indeed, a Substance P / Mrgprb2 sensory cluster was demonstrated to be critical in driving the clinical score of a severe preclinical model of atopic dermatitis.

[0008] In addition to the various reports using Mrgprb2-deficient mice, further evidence suggests a role for various ligands of MRGPRX2 in human disease. For example, in addition to the number of MRGPRX2-expressing mast cells being significantly increased in severe chronic urticaria, PACAP nerve fibres were demonstrated to be in close proximity to tryptase-positive mast cells, providing the morphological basis for increased mast cell - sensory interactions. In support of this, patients with urticaria exhibit enhanced wheal reactions vs healthy individuals to MRGPRX2 agonists (e.g., Substance P) when injected intradermally. In addition, PACAP and the antimicrobial peptide, LL-37, which is implicated in cutaneous inflammation, were both demonstrated to be upregulated in rosacea. Indeed, mast cell-deficient mice do not develop inflammation / flushing following LL-37 injection thus inferring a role for Mrgprb2.

[0009] In addition to skin disorders, mast cell involvement has been highlighted for inflammatory bowel disease (IBD) and arthritis as well as asthma and migraine. In patients with rheumatoid arthritis (RA), the number of degranulated mast cells is increased in synovial tissue and is correlated with disease activity, as it is for patients with IBD. A positive correlation between serum Substance P levels and chronic pain intensity has been noted in both osteoarthritic and RA patients and a recent article suggested that the SP- MRGPRX2 axis may play a role in the pathogenesis of RA, especially in the regulation of inflammation and pain. Finally, there is a growing body of evidence for a role of PACAP in migraine pathogenesis and that it is mediated via activation of mast cells.

[0010] Accordingly, there is a need for small-molecule agonists of MRGPRX2 that block IgE-independent mast cell de-granulation, which are expected to provide therapeutic benefit in mast-cell driven pathologies including skin disorders such as urticaria, atopic dermatitis and rosacea as well as additional indications like inflammatory bowel disease, arthritis and migraine. Accordingly, there is a need in the art to provide small molecule therapeutics that modulate MRGPRX2. SUMMARY

[0011] One aspect of the invention provides compounds that are antagonists of MRGPRX2, compositions comprising them, and methods useful for preventing or treating MRGPRX2- mediated diseases or disorders.

[0012] In some aspects, the invention comprises a compound according to Formula (I): or a pharmaceutically acceptable salt thereof; wherein:

[0013] Y is (C3-C8)cycloalkyl, or 4- to 7-membered heterocycloalkyl; wherein each (C3-C8)cycloalkyl, or 4- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents selected from halo, (C1-C6)alkyl, and (C1-C6)haloalkyl;

[0014] A1is 6-membered aryl or 5- 6-membered heteroaryl; wherein the 6-membered aryl or 5- to 6-membered heteroaryl is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, and (C3- C8)cycloalkyl;

[0015] A2is hydrogen, 6- to 10-membered aryl, 4- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein each 6- to 10-membered aryl, 4- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, C(O)R1a, C(0)2R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, S(O)(NH)R1a, NR1aR1b, S(O)2R1a, carb oximi dami de, (C1- C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, and 4- to 7-membered heterocycloalkyl; wherein (C1-C6)alkyl, 4- to 7-membered heterocycloalkyl, (C3-C8)cycloalkyl, and (C1-C6)alkoxy are optionally substituted with one or more substituents selected from halo, cyano, hydroxy, C(O)2R1a, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, S(O)(NH)R1a, NR1aR1b, S(O)2R1a, NR1aSO2R1b, carboximidamide, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1- C6)haloalkoxy, 6- to 10-membered aryl, 5- to 6-membered heteroaryl, (C3-C8)cycloalkyl, and 4- to 7- heterocyclyloalkyl;

[0016] R1aand R1bare each independently hydrogen, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C3- C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, (C3-C8)cycloalkylalkyl, 4- to 7-membered heterocycloalkylalkyl, or (C1-C6)alkylNRaNRb, NRaNRb, wherein (C3-C8)cycloalkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more halo, cyano, hydroxy, C(O)Ra, C(O)2Ra, C(O)NRaRb, S(O)NRaRb, S(O)2NRaRb, S(O)(NH)Ra, NRaRb, S(O)2Ra, carboximidamide, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, or 4- to 7- membered heterocycloalkyl, wherein (C3-C8)cycloalkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more halo, cyano, hydroxy, C(O)Ra, C(O)2Ra, C(O)NRaRb, S(O)NRaRb, S(O)2NRaRb, S(O)(NH)Ra, NRaRb, S(O)2Ra, carboximidamide, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, or 4- to 7-membered heterocycloalkylor R1aand R1btaken together with the nitrogen to which they are attached form a 3- to 7-membered heterocycloalkyl ring;

[0017] Raand Rbare each independently hydrogen, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C3- C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, (C3-C8)cycloalkylalkyl, or 4- to 7- membered heterocycloalkylalkyl, or Raand Rbtaken together with the nitrogen to which they are attached form a 3- to 7-membered heterocycloalkyl ring; and m is 1 and n is 1; or m is 2 and n is 0.

[0018] In some embodiments, the compound of Formula (I) has the structure of Formula la: or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the compound of Formula (I) has the structure of Formula lb: or a pharmaceutically acceptable salt thereof.

[0020] In other aspects, provided herein is a pharmaceutical composition, comprising a compound provided herein and at least one pharmaceutically acceptable excipient.

[0021] In some aspects, provided herein is a method of preventing or treating an MRGPRX2- mediated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein.

[0022] Also provided herein are pharmaceutical compositions comprising a compound of Formula (la) or (lb); and at least one pharmaceutically acceptable excipient.

[0023] Additionally, methods of preventing or treating an MRGPRX2-mediated disease or disorder, comprise administering to a subject in need thereof a therapeutically effective amount of the compound of Formula (I), Formula (la) or (lb). For example, an MRGPRX2- mediated disease or disorder may be chronic spontaneous urticaria, prurigo nodularis, irritable bowel syndrome, chronic inducible urticaria, atopic dermatitis, osteoarthritis, rosacea, migraine, pseudo-analphylaxis, mast cell activation syndrome, mastocytosis, pruritus, neurodermatitis, contact urticaria, allergic rhinitis, asthma, acute contact dermatitis, ulcerative colitis, crohns disease, idiopathic chronic cough, rheumatoid arthritis, multiple sclerosis, geographic atrophy, endometriosis, seborrheic dermatitis, psoriasis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, neuropathic itch, periodontitis, autism, abdominal aortic aneurysms, deep vein thrombosis, amyotrophic lateral sclerosis, interstitial cystitis, coronary artery disease, cancer, sickle cell disease, obesity, or ulcers.

[0024] Unless otherwise defined, 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 invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0025] Other features, objects, and advantages of the invention will be apparent from the detailed description, and from the claims. DETAILED DESCRIPTION

[0026] Definitions

[0027] For convenience, before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.

[0028] In order for the present invention to be more readily understood, certain terms and phrases are defined below and throughout the specification.

[0029] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0030] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0031] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity such as “either ” “one of ” “only one of ” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0032] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0033] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

[0034] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0035] Certain compounds of the present invention may exist in particular geometric, tautomeric, or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-i somers, R- and 5-enantiomers, diastereomers, (D)-isomers, (L)- isomers, tautomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention. “Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. "R," "S," "S*," "R*," "E," "Z," "cis," and "trans," indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in “atropisomeric” forms or as “atropisomers.” Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from a mixture of isomers. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.

[0036] If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

[0037] Percent purity by mole fraction is the ratio of the moles of the enantiomer (or diastereomer) or over the moles of the enantiomer (or diastereomer) plus the moles of its optical isomer. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure.

[0038] When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s) or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms.

[0039] Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a13C- or14C- enriched carbon are within the scope of this invention.

[0040] The term “prodrug” as used herein encompasses compounds that, under physiological conditions, are converted into therapeutically active agents. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal.

[0041] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient.

[0042] The term “pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulphonate salts, and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19.)

[0043] In other cases, the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, di ethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra).

[0044] The term “pharmaceutically acceptable cocrystals” refers to solid coformers that do not form formal ionic interactions with the small molecule A “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment, refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment.

[0045] The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[0046] The term “patient” or “subject” refers to a mammal in need of a particular treatment. In certain embodiments, a patient is a primate, canine, feline, or equine. In certain embodiments, a patient is a human.

[0047] An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below. A straight aliphatic chain is limited to unbranched carbon chain moieties. As used herein, the term “aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group.

[0048] “Alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or up to 30 carbon atoms if no specification is made. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties. Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl. In certain embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30for straight chains, C3-C30for branched chains), and more preferably 20 or fewer. Alkyl goups may be substituted or unsubstituted.

[0049] As used herein, the term “heteroalkyl” refers to an alkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. As used herein, the term “haloalkyl” refers to an alkyl group as hereinbefore defined substituted with at least one halogen.

[0050] As used herein, the term “haloalkoxy” refers to an alkoxy group as defined herein substituted with at least one halogen atom. For example, haloalkoxy groups include fluoroalkoxy groups, such as trifluoromethoxy, difluoromethoxy, and the like.

[0051] As used herein, the term “hydroxyalkyl” refers to an alkyl group as defined above and substituted with at least one hydroxyl.

[0052] As used herein, the term “aminoalkyl” refers to an alkyl group as defined above and substituted with at least one amino moiety.

[0053] As used herein, the term “alkylene” refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene -(CH2)-, ethylene -(CH2CH2)-, n-propylene - (CH2CH2CH2)-, isopropylene -(CH2CH(CH3))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents.

[0054] "Cycloalkyl" means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted.

[0055] “1,2-Di substituted cyclohexyl” as used herein refers to a cyclohexane ring that contains points of attachment at the 1 and 2 positions of the cyclohexane ring to the rest of the compound. Similarly, “1,2-di substituted cyclopentyl” as used herein refers to a cyclopentane ring that contains points of attachment at the 1 and 2 positions of the cyclopentane ring to the rest of the compound. 1,2-Disubstituted cyclohexyl and 1,2- disubstituted cyclopentyl can also be referred to as 1,2-cyclohexylene and 1,2- cyclopentylene, respectively.

[0056] As used herein, the term “halocycloalkyl” refers to a cycloalkyl group as hereinbefore defined substituted with at least one halogen.

[0057] "Cycloheteroalkyl" refers to an cycloalkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. Preferred cycloheteroalkyls have from 4-8 carbon atoms and heteroatoms in their ring structure, and more preferably have 4-6 carbons and heteroatoms in the ring structure. Cycloheteroalkyl groups may be substituted or unsubstituted. Unless the number of carbons is otherwise specified, “lower alkyl,” as used herein, means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent designated herein as alkyl is a lower alkyl.

[0058] “Alkenyl” refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified; and having one or more double bonds in the moiety. Alkenyl of 6 to 26 carbon atoms is exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, in their various isomeric forms, where the unsaturated bond(s) can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s).

[0059] “Alkynyl” refers to hydrocarbyl moieties of the scope of alkenyl, but having one or more triple bonds in the moiety.

[0060] The term “aryl” as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Carboycyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12- membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, indazole, quinoline, benzofuran, and the like. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.

[0061] The term “halo”, “halide”, or “halogen” as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro and bromo.

[0062] The terms “heterocyclyl” or “heterocyclic group” or “heterocycloalkyl” refer to 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. Heterocycloalkyl groups can include substitution by an oxo (=0) group, as in lactams and lactones. Heterocycloalkyl groups can be fully saturated or partially saturated. Heterocycloalkyl groups include, for example, bicyclic ring systems having either or both constituent rings saturated (e.g., 2,3-dihydroindole, 4,5,6,7-tetrahydro-benzofuran, decahydroquinoline, and the like) or partially saturated (e.g., octahydroquinoline and the like).

[0063] The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, and the like.

[0064] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. In preferred embodiments, the substituents on substituted alkyls are selected from C1-6 alkyl, C3-6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.

[0065] As used herein, the definition of each expression, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0066] As used herein, “small molecules” refers to small organic or inorganic molecules of molecular weight below about 3,000 Daltons. In general, small molecules useful for the invention have a molecular weight of less than 3,000 Daltons (Da). The small molecules can be, e.g., from at least about 100 Da to about 3,000 Da (e.g., between about 100 to about 3,000 Da, about 100 to about 2500 Da, about 100 to about 2,000 Da, about 100 to about 1,750 Da, about 100 to about 1,500 Da, about 100 to about 1,250 Da, about 100 to about 1,000 Da, about 100 to about 750 Da, about 100 to about 500 Da, about 200 to about 1500, about 500 to about 1000, about 300 to about 1000 Da, or about 100 to about 250 Da).

[0067] In some embodiments, a “small molecule” refers to an organic, inorganic, or organometallic compound typically having a molecular weight of less than about 1000. In some embodiments, a small molecule is an organic compound, with a size on the order of 1 nm. In some embodiments, small molecule drugs of the invention encompass oligopeptides and other biomolecules having a molecular weight of less than about 1000.

[0068] An “effective amount” is an amount sufficient to effect beneficial or desired results. For example, a therapeutic amount is one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms. An effective amount can be administered in one or more administrations, applications or dosages. A therapeutically effective amount of a composition depends on the composition selected. The compositions can be administered from one or more times per day to one or more times per week; including once every other day. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the compositions described herein can include a single treatment or a series of treatments.

[0069] The terms “decrease,” “reduce,” “reduced”, “reduction”, “decrease,” and “inhibit” are all used herein generally to mean a decrease by a statistically significant amount relative to a reference. However, for avoidance of doubt, “reduce,” “reduction” or “decrease” or “inhibit” typically means a decrease by at least 10% as compared to a reference level and can include, for example, a decrease by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, up to and including, for example, the complete absence of the given entity or parameter ascompared to the reference level, or any decrease between 10-99% as compared to the absence of a given treatment.

[0070] The terms “increased”, “increase” or “enhance” or “activate” are all used herein to generally mean an increase by a statically significant amount; for the avoidance of any doubt, the terms “increased”, “increase” or “enhance” or “activate” means an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level.

[0071] As used herein, the term “modulate” includes up-regulation and down-regulation, e.g., enhancing or inhibiting a response. A “radiopharmaceutical agent,” as defined herein, refers to a pharmaceutical agent which contains at least one radiation-emitting radioisotope. Radiopharmaceutical agents are routinely used in nuclear medicine for the diagnosis and / or therapy of various diseases. The radiolabelled pharmaceutical agent, for example, a radiolabelled antibody, contains a radioisotope (RI) which serves as the radiation source. As contemplated herein, the term “radioisotope” includes metallic and non-metallic radioisotopes. The radioisotope is chosen based on the medical application of the radiolabeled pharmaceutical agents. When the radioisotope is a metallic radioisotope, a chelator is typically employed to bind the metallic radioisotope to the rest of the molecule. When the radioisotope is a non-metallic radioisotope, the non-metallic radioisotope is typically linked directly, or via a linker, to the rest of the molecule.

[0072] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

[0073] Compounds of the Invention

[0074] In some aspects, the invention of the disclosure comprises a compound according to Formula (I): or a pharmaceutically acceptable salt thereof; wherein:

[0075] Y is (C3-C8)cycloalkyl, or 4- to 7-membered heterocycloalkyl; wherein each (C3- C8)cycloalkyl, or 4- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents selected from halo, (C1-C6)alkyl, and (C1-C6)haloalkyl;

[0076] A1is 6-membered aryl or 5- 6-membered heteroaryl; wherein the 6-membered aryl or 5- to 6-membered heteroaryl is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1- C6)aminoalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, and (C3-C8)cycloalkyl;

[0077] A2is hydrogen, 6- to 10-membered aryl, 4- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein each 6- to 10-membered aryl, 4- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, C(O)R1a, C(0)2R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, S(O)(NH)R1a, NR1aR1b, S(O)2R1a, carb oximi dami de, (C1- C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, and 4- to 7-membered heterocycloalkyl; wherein (C1-C6)alkyl, 4- to 7-membered heterocycloalkyl, (C3-C8)cycloalkyl, and (C1-C6)alkoxy are optionally substituted with one or more substituents selected from halo, cyano, hydroxy, C(O)2R1a, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, S(O)(NH)R1a, NR1aR1b, S(O)2R1a, NR1aSO2R1b, carboximidamide, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, 6- to 10-membered aryl, 5- to 6-membered heteroaryl, (C3-C8)cycloalkyl, and 4- to 7- heterocyclyloalkyl;

[0078] R1aand R1bare each independently hydrogen, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C3- C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, (C3-C8)cycloalkylalkyl, 4- to 7-membered heterocycloalkylalkyl, (C1-C6)alkylNRaNRb, or NRaNRb, wherein (C3-C8)cycloalkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more halo, cyano, hydroxy, C(O)Ra, C(O)2Ra, C(O)NRaRb, S(O)NRaRb, S(O)2NRaRb, S(O)(NH)Ra, NRaRb, S(O)2Ra, carboximidamide, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, or 4- to 7- membered heterocycloalkyl, wherein (C3-C8)cycloalkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more halo, cyano, hydroxy, C(O)RX, C(O)2R1, C(O)NRaRb, S(O)NRaRb, S(O)2NRaRb, S(O)(NH)Ra, NRaRb, S(O)2Ra, carboximidamide, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, or 4- to 7-membered heterocycloalkyl or R1aand R1btaken together with the nitrogen to which they are attached form a 3- to 7-membered heterocycloalkyl ring;

[0079] Raand Rbare each independently hydrogen, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C3- C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, (C3-C8)cycloalkylalkyl, or 4- to 7- membered heterocycloalkylalkyl, or Raand Rbtaken together with the nitrogen to which they are attached form a 3- to 7-membered heterocycloalkyl ring; and m is 1 and n is 1; or m is 2 and n is 0. In some embodiments, A2is hydrogen, 6- to 10-membered aryl, 4- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein each 6- to 10-membered aryl, 4- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, S(O)(NH)R1a, NR1aR1b, carboximidamide, (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, (C1-C6)amidoalkyl, (C1- C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, 4- to 7-membered heterocycloalkyl, and 4- to 7-membered heterocycloalkyl(C1-C6)alkyl, wherein (C3-C8)cycloalkyl is optionally substituted with one or more substituents selected from hydroxy, (C1-C6)alkoxy, halo, and (C1-C6)haloalkyl;

[0080] R1aand R1bare each independently hydrogen, (C1-C6)alkyl, or (C1-C6)hydroxyalkyl, or R1aand R1btaken together with the nitrogen to which they are attached form a 3- to 7- membered heterocycloalkyl ring.

[0081] In some embodiments, the compound of Formula (I) has the structure of Formula la: or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the compound of Formula (I) has the structure of Formula lb: or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, the compound of Formula (la) has the structure of Formula lai: or a pharmaceutically acceptable salt thereof; wherein each X is independently N or CRa1, wherein at least two X are CRa1; and

[0084] Ra1is independently for each occurrence hydrogen, halo, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, (C1-C6)alkoxy(C1- C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or (C3-C8)cycloalkyl.

[0085] In some embodiments, the compound of Formula (lb) has the structure of Formula (Ibi): or a pharmaceutically acceptable salt thereof; wherein each X is independently N or CRa1, wherein at least two X are CRa1; and

[0086] Ra1is independently for each occurrence hydrogen, halo, cyano, hydroxy, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, (C1-C6)alkoxy(C1- C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or (C3-C8)cycloalkyl.

[0087] In some embodiments, Y is (C3-C8)cycloalkyl or 4- to 7-membered heterocycloalkyl, wherein each (C3-C8)cycloalkyl or 4- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents selected from halo and (C1-C6)alkyl.

[0088] In some embodiments, Y is (C3-C8)cycloalkyl optionally substituted with one or more substituents selected from halo and (C1-C6)alkyl.

[0089] In some embodiments, Y is cyclobutyl or cyclopentyl, each of which is optionally substituted with one or more substituents selected from halo and (C1-C6)alkyl.

[0090] In some embodiments, Y is cyclopentyl optionally substituted with one or two fluorine atoms.

[0091] In some embodiments, Y is cyclopentyl, 3-fluorocyclopentyl, 2-fluorocyclopentyl, or 3 ,3 -difluorocyclopentyl . In some embodiments, Y is:

[0092] In some embodiments, Y is cyclobutyl optionally substituted with methyl.

[0093] In some embodiments, Y is tetrahydropyranyl.

[0094] In some embodiments, A1is phenyl or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, cyano, (C3- C8)cycloalkyl, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)aminoalkyl, and (C1-C6)haloalkoxy(C1-C6)alkyl.

[0095] In some embodiments, A1is phenyl or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from cyano, fluoro, chloro, cyclopropyl, methyl, and difluoromethoxy.

[0096] In some embodiments, A1is phenyl, pyridyl, pyrimidyl, pyridazinyl, or pyrazinyl each of which is optionally substituted with one or more halo, (C1-C6)hydroxyalkyl, (C1- C6)aminoalkyl, or cyano.

[0097] In some embodiments, A1is phenyl, pyridyl, pyrimidyl, pyridazinyl, or pyrazinyl each of which is optionally substituted with one or more (C1-C6)hydroxy alkyl.

[0098] In some embodiments, wherein A1is phenyl, pyridyl, pyrimidyl, pyridazinyl, or pyrazinyl each of which is optionally substituted with one or more (C1-C6)aminoalkyl.

[0099] In some embodiments, A1is phenyl optionally substituted with one or more (C1- C6)hydroxyalkyl, (C1-C6)aminoalkyl, cyano, fluoro, or chloro. In some embodiments, A1is phenyl optionally substituted with one or more (C1-C6)hydroxy alkyl. In some embodiments, A1is phenyl optionally substituted with one or more (C1-C6)aminoalkyl. In some embodiments, A1is phenyl optionally substituted with one or more cyano. In some embodiments, A1is phenyl optionally substituted with one or more fluoro. In some embodiments, A1is phenyl optionally substituted with one or more chloro. In some embodiments, A1is pyridyl optionally substituted with one or more (C1- C6)hydroxyalkyl, (C1-C6)aminoalkyl, cyano, fluoro, or chloro. In some embodiments, A1is pyridyl optionally substituted with one or more (C1-C6)hydroxyalkyl. In some embodiments, A1is pyridyl optionally substituted with one or more (C1-C6)aminoalkyl. In some embodiments, A1is pyridyl optionally substituted with one or more cyano. In some embodiments, A1is pyridyl optionally substituted with one or more fluoro. In some embodiments, A1is pyridyl optionally substituted with one or more chloro.

[0100] In some embodiments, A1is pyrimidyl optionally substituted with one or more (C1- C6)hydroxyalkyl, (C1-C6)aminoalkyl, cyano, fluoro, or chloro. In some embodiments, A1is pyrimidyl optionally substituted with one or more (C1-C6)hydroxy alkyl. In some embodiments, A1is pyrimidyl optionally substituted with one or more (C1-C6)aminoalkyl. In some embodiments, A1is pyrimidyl optionally substituted with one or more cyano. In some embodiments, A1is pyrimidyl optionally substituted with one or more fluoro. In some embodiments, A1is pyrimidyl optionally substituted with one or more chloro.

[0101] In some embodiments, A1is pyrazinyl optionally substituted with one or more (C1- C6)hydroxyalkyl, (C1-C6)aminoalkyl, cyano, fluoro, or chloro. In some embodiments, A1is pyrazinyl optionally substituted with one or more (C1-C6)hydroxy alkyl. In some embodiments, A1is pyrazinyl optionally substituted with one or more (C1-C6)aminoalkyl. In some embodiments, A1is pyrazinyl optionally substituted with one or more cyano. In some embodiments, A1is pyrazinyl optionally substituted with one or more fluoro. In some embodiments, A1is pyrazinyl optionally substituted with one or more chloro.

[0102] In some embodiments, A1is pyridazinyl optionally substituted with one or more (C1- C6)hydroxyalkyl, (C1-C6)aminoalkyl, cyano, fluoro, or chloro. In some embodiments, A1is pyridazinyl optionally substituted with one or more (C1-C6)hydroxy alkyl. In some embodiments, A1is pyridazinyl optionally substituted with one or more (C1-C6)aminoalkyl. In some embodiments, A1is pyridazinyl optionally substituted with one or more cyano. In some embodiments, A1is pyridazinyl optionally substituted with one or more fluoro. In some embodiments, A1is pyridazinyl optionally substituted with one or more chloro.

[0103] In some embodiments, A1is:

[0104] ; wherein \ denotes the point of attachment to N; and denotes the point of attachment to A2.

[0105] In some embodiments, A1is:

[0106] denotes the point of attachment to A2.

[0107] In some embodiments, A1is: denotes the point of attachment to N; and denotes the point of attachment to A2.

[0108] In some embodiments, A2is phenyl or 5- to 6-membered heteroaryl; each of which is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, S(O)(NH)R1a, NR1aR1b, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, (C1-C6)amidoalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, 4- to 7-membered heterocycloalkyl, and 4- to 7-membered heterocycloalkyl(C1-C6)alkyl; wherein (C3-C8)cycloalkyl is optionally substituted with one or more substituents selected from hydroxy, (C1-C6)alkoxy, halo, and (C1-C6)haloalkyl.

[0109] In some embodiments, A2is 2-pyridyl, 3-pyridyl, or 4-pyridyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkylamine, (C1-C6)alkoxyalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6- membered heteroaryl.

[0110] In some embodiments, A2is a 4- to 7-membered heterocycloalkyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkylamine, (C1-C6)alkoxyalkyl, (C1- C6)alkoxy, (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6- membered heteroaryl.

[0111] In some embodiments, A2is pyrazole, imidazole, tetrahydrofuran, oxazole, isoxazole, 1,2,3-triazole, or 1,2,4-triazole; each of which is optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, (C1-C6)alkylamine, (C1-C6)alkoxyalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl.

[0112] In some embodiments, A2is an N-oxide selected from pyridyl N-oxide, pyrimidinyl N-oxide, pyrazinyl N-oxide, and pyridazinyl N-oxide; each of which is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, (C1-C6)alkylamine, (C1-C6)alkoxyalkyl, and (C1-C6)alkoxy.

[0113] In some embodiments, A2is pyridazinyl optionally substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, (C1-C6)alkylamine, (C1-C6)alkoxyalkyl, and (C1-C6)alkoxy.

[0114] In some embodiments, A2is pyrimidyl optionally substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, (C1-C6)alkylamine, (C1-C6)alkoxyalkyl, and(C1-C6)alkoxy.

[0115] In some embodiments, A2is pyrazinyl optionally substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)hydroxyalkyl, (C1-C6)alkylamine, (C1-C6)alkoxyalkyl, and (C1-C6)alkoxy.

[0116] In some embodiments, A2is: wherein R2is hydrogen or (C1-C6)alkyl, wherein (C1-C6)alkyl is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, C(O)2R1a, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, S(O)(NH)R1a, NR1aR1b, S(O)2R1a, NR1aSO2R1b, carboximidamide, (C1-C6)alkoxy, 6- to 10-membered aryl, 5- to 6-membered heteroaryl, (C3- C8)cycloalkyl, and 4- to 7- heterocyclyloalkyl.

[0117] In some embodiments, R1aand R1b, if present, are each hydrogen.

[0118] In some embodiments, one of R1aand R1b, if present, is hydrogen; and one of R1aand R1b, if present, is (C1-C6)alkyl.

[0119] In some embodiments, R1aand R1b, if present, are each (C1-C6)alkyl.

[0120] In some embodiments, wherein A2is or a pharmaceutically acceptable salt thereof. In some aspects, provided herein is a compound selected from the following table: or a pharmaceutically acceptable salt thereof.

[0121] In some aspects, provided herein is a compound selected from the following table: or a pharmaceutically acceptable salt thereof.

[0122] Methods of Treatment

[0123] One aspect of the invention provides compounds, compositions, and methods useful for preventing or treating a disease. In some aspects, provided herein is a method of preventing or treating an MRGPRX2-mediated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound provided herein. Additionally, methods of preventing or treating an MRGPRX2-mediated disease or disorder comprise administering to a subject in need thereof a therapeutically effective amount of the compound of Formula (I), Formula (la) or (lb), or a pharmaceutically acceptable salt thereof. For example, an MRGPRX2-mediated disease or disorder may be chronic spontaneous urticaria, prurigo nodularis, irritable bowel syndrome, chronic inducible urticaria, atopic dermatitis, osteoarthritis, rosacea, migraine, pseudo-analphylaxis, mast cell activation syndrome, mastocytosis, pruritus, neurodermatitis, contact urticaria, allergic rhinitis, asthma, acute contact dermatitis, ulcerative colitis, crohns disease, idiopathic chronic cough, rheumatoid arthritis, multiple sclerosis, geographic atrophy, endometriosis, seborrheic dermatitis, psoriasis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, neuropathic itch periodontitis autism abdominal aortic aneurysms deep vein thrombosis amyotrophic lateral sclerosis, interstitial cystitis, coronary artery disease, cancer, sickle cell disease, obesity, or ulcers. In some aspects, the MRGPRX2 -mediated disease or disorder is selected from the group consisting of chronic spontaneous urticaria, prurigo nodularis, irritable bowel syndrome, chronic inducible urticaria, atopic dermatitis, osteoarthritis, rosacea, migraine, pseudo-analphylaxis, mast cell activation syndrome, mastocytosis, pruritus, neurodermatitis, contact urticaria, allergic rhinitis, asthma, acute contact dermatitis, ulcerative colitis, Crohn’s disease, idiopathic chronic cough, rheumatoid arthritis, multiple sclerosis, geographic atrophy, endometriosis, seborrheic dermatitis, psoriasis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, neuropathic itch, periodontitis, autism, abdominal aortic aneurysms, deep vein thrombosis, amyotrophic lateral sclerosis, interstitial cystitis, coronary artery disease, cancer, sickle cell disease, obesity, and ulcers.

[0124] In certain embodiments, the MRGPRX2-mediated disease or disorder is prevented. In certain embodiments, the MRGPRX2-mediated disease or disorder is treated. In certain embodiments, the compound is administered orally to the subject.

[0125] In certain embodiments, the compound is administered parenterally to the subject.

[0126] In certain embodiments, the disease is prevented. In other embodiments, the disease is treated.

[0127] Pharmaceutical Compositions, Routes of Administration, and Dosins

[0128] In certain embodiments, the invention is directed to a pharmaceutical composition, comprising a compound of the invention, e.g. a compound of Formula (I), Formula (la) or (lb), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0129] In certain embodiments, the invention is directed to a pharmaceutical composition, comprising a compound of any of the disclosed embodiments, and a pharmaceutically acceptable carrier.

[0130] In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the invention and a pharmaceutically acceptable carrier.

[0131] Pharmaceutical compositions of the invention can be prepared by combining one or more compounds of the invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.

[0132] As stated above, an “effective amount” refers to any amount that is sufficient to achieve a desired biological effect. Combined with the teachings provided herein, by choosing among the various active compounds and weighing factors such as potency, relative bioavailability, patient body weight, severity of adverse side-effects and mode of administration, an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial unwanted toxicity and yet is effective to treat the particular subject. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular compound of the invention being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular compound of the invention and / or other therapeutic agent without necessitating undue experimentation. A maximum dose may be used, that is, the highest safe dose according to some medical judgment. Multiple doses per day may be contemplated to achieve appropriate systemic levels of compounds. Appropriate systemic levels can be determined by, for example, measurement of the patient’s peak or sustained plasma level of the drug. “Dose” and “dosage” are used interchangeably herein.

[0133] In certain embodiments, intravenous administration of a compound may typically be from 0.1 mg / kg / day to 20 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 0.1 mg / kg / day to 2 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 0.5 mg / kg / day to 5 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 1 mg / kg / day to 20 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from 1 mg / kg / day to 10 mg / kg / day.

[0134] Generally, daily oral doses of a compound will be, for human subjects, from about 0.01 milligrams / kg per day to 1000 milligrams / kg per day. It is expected that oral doses in the range of 0.5 to 50 milligrams / kg, in one or more administrations per day, will yield therapeutic results. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, it is expected that intravenous administration would be from one order to several orders of magnitude lower dose per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of the compound.

[0135] For any compound described herein the therapeutically effective amount can be initially determined from animal models. A therapeutically effective dose can also be determined from human data for compounds which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-λnown in the art is well within the capabilities of the ordinarily skilled artisan.

[0136] The formulations of the invention can be administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0137] For use in therapy, an effective amount of the compound can be administered to a subject by any mode that delivers the compound to the desired surface. Administering a pharmaceutical composition may be accomplished by any means known to the skilled artisan. Routes of administration include but are not limited to intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct injection (for example, into a tumor or abscess), mucosal (e.g., topical to eye), inhalation, and topical.

[0138] For intravenous and other parenteral routes of administration, a compound of the invention can be formulated as a lyophilized preparation, as a lyophilized preparation of liposome-intercalated or -encapsulated active compound, as a lipid complex in aqueous suspension, or as a salt complex. Lyophilized formulations are generally reconstituted in suitable aqueous solution, e.g., in sterile water or saline, shortly prior to administration.

[0139] For oral administration, the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate Optionally the oral formulations may also be formulated in saline or buffers, e.g., EDTA for neutralizing internal acid conditions or may be administered without any carriers.

[0140] Also specifically contemplated are oral dosage forms of the above component or components. The component or components may be chemically modified so that oral delivery of the derivative is efficacious. Generally, the chemical modification contemplated is the attachment of at least one moiety to the component molecule itself, where said moiety permits (a) inhibition of acid hydrolysis; and (b) uptake into the blood stream from the stomach or intestine. Also desired is the increase in overall stability of the component or components and increase in circulation time in the body. Examples of such moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline. Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts”, In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N.Y., pp. 367-383 (1981); Newmark et al., J Appl Biochem 4: 185-9 (1982). Other polymers that could be used are poly-1, 3-dioxolane and poly-1, 3, 6-tioxocane. For pharmaceutical usage, as indicated above, polyethylene glycol moieties are suitable.

[0141] For the component (or derivative) the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine. One skilled in the art has available formulations which will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine. Preferably, the release will avoid the deleterious effects of the stomach environment, either by protection of the compound of the invention (or derivative) or by release of the biologically active material beyond the stomach environment, such as in the intestine.

[0142] To ensure full gastric resistance a coating impermeable to at least pH 5.0 is essential. Examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings may be used as mixed films.

[0143] A coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow. Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic (e g powder); for liquid forms a soft gelatin shell may be used The shell material of cachets could be thick starch or other edible paper. For pills, lozenges, molded tablets or tablet triturates, moist massing techniques can be used.

[0144] The therapeutic can be included in the formulation as fine multi-particulates in the form of granules or pellets of particle size about 1 mm. The formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets. The therapeutic could be prepared by compression.

[0145] Colorants and flavoring agents may all be included. For example, the compound of the invention (or derivative) may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents.

[0146] One may dilute or increase the volume of the therapeutic with an inert material. These diluents could include carbohydrates, especially mannitol, α-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch. Certain inorganic salts may also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell.

[0147] Disintegrants may be included in the formulation of the therapeutic into a solid dosage form. Materials used as disintegrates include but are not limited to starch, including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used. Another form of the disintegrants are the insoluble cationic exchange resins. Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

[0148] Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to granulate the therapeutic.

[0149] An anti -frictional agent may be included in the formulation of the therapeutic to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts polytetrafluoroethylene (PTFE) liquid paraffin vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000.

[0150] Glidants that might improve the flow properties of the drug during formulation and to aid rearrangement during compression might be added. The glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate.

[0151] To aid dissolution of the therapeutic into the aqueous environment a surfactant might be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents which can be used and can include benzalkonium chloride and benzethonium chloride. Potential non-ionic detergents that could be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the compound of the invention or derivative either alone or as a mixture in different ratios.

[0152] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Microspheres formulated for oral administration may also be used. Such microspheres have been well defined in the art. All formulations for oral administration should be in dosages suitable for such administration.

[0153] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0154] For topical administration, the compound may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-λnown in the art. Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration.

[0155] For administration by inhalation, compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, di chlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0156] Also contemplated herein is pulmonary delivery of the compounds disclosed herein (or salts thereof). The compound is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream. Other reports of inhaled molecules include Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63: 135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13(suppl. 5): 143-146 (1989) (endothelin-1); Hubbard et al., Anna! Int Med 3:206-212 (1989) (□ 1- antitrypsin); Smith et al., 1989, J Clin Invest 84: 1145-1146 (a- 1 -proteinase); Oswein et al., 1990, "Aerosolization of Proteins", Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (recombinant human growth hormone); Debs et al., 1988, J Immunol 140:3482-3488 (interferon-gamma and tumor necrosis factor alpha) and Platz et al., U.S. Pat. No. 5,284,656 (granulocyte colony stimulating factor; incorporated by reference). A method and composition for pulmonary delivery of drugs for systemic effect is described in U.S. Pat. No. 5,451,569 (incorporated by reference), issued Sep. 19, 1995 to Wong et al.

[0157] Contemplated for use in the practice of this invention are mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.

[0158] Some specific examples of commercially available devices suitable for the practice of this invention are the Ultravent nebulizer, manufactured by Mallinckrodt, Inc., St. Louis, Mo.; the Acorn II nebulizer, manufactured by Marquest Medical Products, Englewood, Colo.; the Ventolin metered dose inhaler, manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and the Spinhaler powder inhaler, manufactured by Fisons Corp., Bedford, Mass.

[0159] All such devices require the use of formulations suitable for the dispensing of the compounds of the invention. Typically, each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and / or carriers useful in therapy. Also, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated. Chemically modified compound of the invention may also be prepared in different formulations depending on the type of chemical modification or the type of device employed.

[0160] Formulations suitable for use with a nebulizer, either jet or ultrasonic, will typically comprise a compound of the invention (or derivative) dissolved in water at a concentration of about 0.1 to 25 mg of biologically active compound of the invention per mL of solution. The formulation may also include a buffer and a simple sugar (e.g., for inhibitor stabilization and regulation of osmotic pressure). The nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the compound of the invention caused by atomization of the solution in forming the aerosol.

[0161] Formulations for use with a metered-dose inhaler device will generally comprise a finely divided powder containing the compound of the invention (or derivative) suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, di chlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant.

[0162] Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing a compound of the invention (or derivative) and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation. The compound of the invention (or derivative) should advantageously be prepared in particulate form with an average particle size of less than 10 micrometers (pm), most preferably 0.5 to 5 , fo μrm most effective delivery to the deep lung.

[0163] Nasal delivery of a pharmaceutical composition of the present invention is also contemplated. Nasal delivery allows the passage of a pharmaceutical composition of the present invention to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the product in the lung. Formulations for nasal delivery include those with dextran or cyclodextran.

[0164] For nasal administration, a useful device is a small, hard bottle to which a metered dose sprayer is attached. In one embodiment, the metered dose is delivered by drawing the pharmaceutical composition of the present invention solution into a chamber of defined volume, which chamber has an aperture dimensioned to aerosolize and aerosol formulation by forming a spray when a liquid in the chamber is compressed. The chamber is compressed to administer the pharmaceutical composition of the present invention. In a specific embodiment, the chamber is a piston arrangement. Such devices are commercially available.

[0165] Alternatively, a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed is used. The opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the drug.

[0166] The compounds, when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

[0167] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0168] Alternatively, the active compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0169] The compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0170] In addition to the formulations described above, a compound may also be formulated as a depot preparation. Such long acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0171] Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and / or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249: 1527-33 (1990).

[0172] The compound of the invention and optionally other therapeutics may be administered per se (neat) or in the form of a pharmaceutically acceptable salt or cocrystal. When used in medicine the salts or cocrystals should be pharmaceutically acceptable, but non- pharmaceutically acceptable salts or cocrystals may conveniently be used to prepare pharmaceutically acceptable salts or cocrystals thereof. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic. Also, such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.

[0173] Suitable buffering agents include: acetic acid and a salt (1-2% w / v); citric acid and a salt (1-3% w / v); boric acid and a salt (0.5-2.5% w / v); and phosphoric acid and a salt (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v); chlorobutanol (0.3-0.9% w / v); parabens (0.01-0.25% w / v) and thimerosal (0.004-0.02% w / v).

[0174] Pharmaceutical compositions of the invention contain an effective amount of a compound as described herein and optionally therapeutic agents included in a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” means one or more compatible solid or liquid filler, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal. The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also are capable of being commingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.

[0175] The therapeutic agent(s), including specifically but not limited to a compound of the invention, may be provided in particles. Particles as used herein means nanoparticles or microparticles (or in some instances larger particles) which can consist in whole or in part of the compound of the invention or the other therapeutic agent(s) as described herein. The particles may contain the therapeutic agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating. The therapeutic agent(s) also may be dispersed throughout the particles. The therapeutic agent(s) also may be adsorbed into the particles. The particles may be of any order release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof, etc. The particle may include, in addition to the therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof. The particles may be microcapsules which contain the compound of the invention in a solution or in a semi-solid state. The particles may be of virtually any shape.

[0176] Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic agent(s). Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogels described in Sawhney H S et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein. These include polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly (isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).

[0177] The therapeutic agent(s) may be contained in controlled release systems. The term “controlled release” is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release formulations. The term “sustained release” (also referred to as “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period. The term “delayed release” is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug there from. “Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.”

[0178] Use of a long-term sustained release implant may be particularly suitable for treatment of chronic conditions. “Long-term” release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30-60 days. Long-term sustained release implants are well-λnown to those of ordinary skill in the art and include some of the release systems described above.

[0179] It will be understood by one of ordinary skill in the relevant arts that other suitable modifications and adaptations to the compositions and methods described herein are readily apparent from the description of the invention contained herein in view of information known to the ordinarily skilled artisan, and may be made without departing from the scope of the invention or any embodiment thereof. Having now described the present invention in detail, the same will be more clearly understood by reference to the following examples, which are included herewith for purposes of illustration only and are not intended to be limiting of the invention.

[0180] EXAMPLES

[0181] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0182] Abbreviations

[0183] AIBN: Azobisisobutyronitrile

[0184] DCC : N,N'-Dicyclohexylcarbodiimide

[0185] DCM: Dichloromethane

[0186] DIEA: N,N-diisopropylethylamine

[0187] DMA: N N-dimethylacetamide DMAP: 4-dimethylaminopyridine

[0188] DME: Dimethoxy ethane

[0189] DMF : N.N-dimethylformamide

[0190] DMSO: Dimethylsulfoxide

[0191] EA: Ethyl acetate

[0192] EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0193] HATU: 1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate m-CPBA: Meta-chloroperbenzoic acid

[0194] MTBE: Methyl tert-butyl ether

[0195] NBS: N-bromosuccinimide

[0196] PE: Petroleum ether

[0197] Py: Pyridine

[0198] PTSA: Para-toluenesulfonic acid

[0199] RuPhos-Pd : 2-Dicy clohexylphosphino-2 ',6 ' - dii sopropoxy- 1 , 1 '-biphenyl) [2-(2 '-amino- 1,1'- biphenyl)]palladium(II) methanesulfonate

[0200] TEA: Triethylamine

[0201] Experimental Procedures

[0202] Example 1: Chemical Synthesis of Compounds of the Disclosure

[0203] Synthesis of Intermediate 1: 2-(cyclopentylamino)pyrimidine-5-carboxylic acid

[0204] Step 1: Preparation of ethyl 2-(cyclopentylamino)pyrimidine-5-carboxylate

[0205] To a solution of ethyl 2-chloropyrimidine-5-carboxylate (3.5 g, 18.8 mmol, 1 equiv) in acetonitrile (30 mL) was added A,A-diisopropylethylamine (4.8 g, 37.5 mmol, 2 equiv) and cyclopentanamine (2.6 g, 30.0 mmol, 1.6 equiv). The mixture was stirred for 5 h at 80 °C. After completion of the reaction the mixture was cooled to room temperature then quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to afford the title compound as a yellow solid (4.0 g, 90.9% yield). LCMS (ESI): m / z [M+H]+calcd for C12H17N3O2: 236.14, found 236.30.

[0206] Step 2: Preparation of 2-(cyclopentylamino)pyrimidine-5-carboxylic acid (Intermediate 1)

[0207] To a solution of ethyl 2-(cyclopentylamino)pyrimidine-5-carboxylate (3.0 g, 12.8 mmol, 1 equiv) in THF (5 mL), methanol (5 mL) and water (5 mL), lithium hydroxide (612 mg, 25.5 mmol, 2 equiv) was added to the solution at room temperature. The resulting mixture was stirred for 2 h at room temperature, then the mixture was concentrated under vacuum. The residue was acidified to pH 2~3 with 4N aqueous hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford the title compound as a yellow oil (2.0 g, 75.7% yield). LCMS (ESI): m / z [M+H]+calcd for C10H13N3O2: 208.10, found 208.15.

[0208] Synthesis of Intermediate 2: 2-(((1R,3R)-3-fluorocyclopentyl)amino)pyrimidine-5- carboxylic acid

[0209] Step 1: Preparation of ethyl 2-(((1R,3S)-3-hydroxycyclopentyl)amino)pyrimidine-5- carboxylate

[0210] To a stirred solution of (1S,3R)-3-aminocyclopentan-1-ol (10 g, 98.9 mmol, 1 equiv) in acetonitrile (200 mL) was added ethyl 2-chloropyrimidine-5-carboxylate (22.14 g, 118.6 mmol, 1.2 equiv) andN,N-diisopropylethylamine (38.33 g, 296.6 mmol, 3 equiv). The reaction mixture was stirred at 80 °C for 3 h, then the mixture was cooled to room temperature, quenched with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-80% ethyl acetate / petr oleum ether) to afford the title compound as a yellow oil (18 g, 72.5% yield). LCMS (ESI): m / z [M+H]+calcd for C12H17N3O3: 252.13, found 252.10.

[0211] Step 2: Preparation of ethyl 2-(((1R,3R)-3-fluorocyclopentyl)amino)pyrimidine-5- carboxylate

[0212] To a stirred solution of ethyl 2-((1R,3S)-3-hydroxycyclopentyl)amino)pyrimidine-5- carboxylate (10 g, 39.8 mmol, 1 equiv) in anhydrous toluene (250 mL) was added pyridine-2- sulfonyl fluoride (7.70 g, 47.8 mmol, 1.2 equiv) and 1,8-diazabicyclo(5.4.0)undec-7-ene (12.12 g, 79.59 mmol, 2 equiv) at 0 °C. The reaction mixture was stirred at room temperature for 5 h, then the reaction was quenched with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to afford the title compound as a white solid (5.5 g, 54.6% yield). LCMS (ESI): m / z [M+H]+calcd for C12H16FN3O2: 254.13, found 254.05.

[0213] Step 3: Preparation of 2-((1R,3R )-3-fluorocyclopentyl)amino)pyrimidine-5-carboxylic acid (Intermediate 2)

[0214] To a solution of ethyl 2-((1R,3R)-3-fluorocyclopentyl)amino)pyrimidine-5-carboxylate (5.5 g, 21.7 mmol, 1 equiv) in tetrahydrofuran (20 mL), methanol (10 mL), water (10 mL) was added lithium hydroxide (0.78 g, 32.6 mmol, 1.5 equiv). The reaction mixture was stirred at room temperature for 2 h, then the mixture was acidified to pH = 5 with IN hydrochloric acid. The precipitated solids were collected by filtration and washed with water to afford the title compound as a white solid (4.8 g, 98.1% yield). LCMS (ESI): m / z [M+H]+calcd for C10H12FN3O2: 226.09, found 226.05.

[0215] Synthesis of Intermediate 3: (2-(cyclopentylamino)pyrimidin-5-yl)(2,6- diazaspiro [3.4] octan-6-yl)methanone

[0216] Scheme 3

[0217] Intermediate 1

[0218] Step 1: Preparation of tert-butyl 6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro [3.4] octane-2-carboxylate

[0219] To a stirred solution of Intermediate 1 (5 g, 24.1 mmol, 1 equiv) in anhydrous DMF (75 mL) was added tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (5.12 g, 24.1 mmol, 1 equiv) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (10.15 g, 36.19 mmol, 1.5 equiv) followed by 1 -methylimidazole (24.4 g, 120 mmol, 5 equiv). The reaction mixture was stirred at room temperature for 2 h, then the reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (6.4 g, 66.9% yield). LCMS (ESI): m / z [M+H]+calcd for C21H31N5O3: 402.25, found 402.25.

[0220] Step 2: Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(2,6-diazaspiro[3.4]octan-6- yl)methanone (Intermediate 3)

[0221] To a stirred solution of tert-butyl 6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octane-2-carboxylate (3.0 g, 7.47 mmol, 1 equiv) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for a 3 h, then the resulting mixture was concentrated to dryness. The crude product was recrystallized from petroleum ether / ethyl acetate to afford the TFA salt of the title compound as a white solid (2.1 g, 70.5% yield). LCMS (ESI): m / z [M+H]+calcd for C16H23N5O: 302.19, found 302.15.

[0222] Synthesis of Intermediate 4: (2-(((1R,3R)-3-fluorocyclopentyl)amino)pyrimidin-5- yl)(2,6-diazaspiro [3.4] octan-6-yl)methanone Step 1: Preparation of tert-butyl 6-(2-((( 1 / ?.3 / ?)-3-fluorocyclopentyl)amino)pyrimidine- 5-carbonyl)-2,6-diazaspiro[3.4]octane-2-carboxylate

[0223] To a stirred solution of Intermediate 2 (3 g, 13.3 mmol, 1 equiv) in anhydrous DMF (30 mL) was added tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (2.83 g, 13.3 mmol, 1 equiv) and N, N,N ’,N ’-tetramethylchloroformamidinium hexafluorophosphate (5.61 g, 19.9 mmol, 1.5 equiv) followed by 1 -methylimidazole (5.47 g, 66.6 mmol, 5 equiv). The reaction mixture was stirred at room temperature for 2 h, then the reaction was quenched with water (20 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (5.5 g, 98.4% yield). LCMS (ESI): m / z [M+H]+calcd for C21H30FN5O3: 420.24, found 420.25.

[0224] Step 2: Preparation of (2-((1R,3R )-3-fluorocyclopentyl)amino)pyrimidin-5-yl)(2,6- diazaspiro[3.4]octan-6-yl)methanone (Intermediate 4)

[0225] To a stirred solution of tert-butyl 6-(2-((1R,3R)-3-fluorocyclopentyl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (5.5 g, 13.1 mmol, 1 equiv) in dichloromethane (20 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 3 h, then the resulting mixture was concentrated to dryness. The crude product was re-crystallized from petroleum ether / ethyl acetate to afford the TFA salt of the title compound as a white solid (4 g, 73.3% yield). LCMS (ESI): m / z [M+H]+calcd for C16H22FN5O: 320.18, found 320.15.

[0226] Synthesis of Intermediate 5: (6-(4-bromophenyl)-2,6-diazaspiro[3.4]octan-2-yl)(2-

[0227] (cyclopentylamino)pyrimidin-5-yl)methanone

[0228] Scheme 5

[0229] Step 1: Preparation of tert-butyl 6-(4-bromophenyl)-2,6-diazaspiro[3.4]octane-2- To a stirred solution of 4-bromoiodobenzene (6.93 g, 24.5 mmol, 1.3 equiv) in anhydrous 1,4- dioxane (60 mL) was added tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (4 g, 18.8 mmol, 1.00 equiv) and cesium carbonate (18.42 g, 56.53 mmol, 3 equiv) followed by Xphos (0.90 g, 1.88 mmol, 0.1 equiv) and XPhos-Pd-G3 (1.59 g, 1.88 mmol, 0.1 equiv) at room temperature. The reaction mixture was stirred at 90 °C for 3 h under a nitrogen atmosphere. The reaction mixture was then quenched with water (80 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to afford the title compound as a yellow solid (1.5 g, 21.7% yield). LCMS (ESI): m / z [M+H]+calcd for C17H23BrN2O2: 367.09, found 367.10.

[0230] Step 2: Preparation of 6-(4-bromophenyl)-2,6-diazaspiro[3.4]octane

[0231] To a stirred solution of tert-butyl 6-(4-bromophenyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (1.5 g, 4.08 mmol, 1 equiv) in anhydrous dichloromethane (8 mL) was added trifluoroacetic acid (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h, then the resulting mixture was concentrated under reduced pressure. The mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate, then the resulting mixture was extracted with 4: 1 dichloromethane / methanol (50 mL x 3). The combined organic layers were then dried over dried over sodium sulfate, filtered, and concentrated to the title compound as a yellow solid (1.08 g, 98.9% yield). LCMS (ESI): m / z [M+H]+calcd for C12H15BrN2 267.04, found 267.05.

[0232] Step 3: Preparation of (6-(4-bromophenyl)-2,6-diazaspiro[3.4]octan-2-yl)(2- (cyclopentylamino)pyrimidin-5-yl)methanone (Intermediate 5)

[0233] To a stirred solution of Intermediate 1 (0.90 g, 4.34 mmol, 1.20 equiv) in anhydrous DMF (10 mL) was added 6-(4-bromophenyl)-2,6-diazaspiro[3.4]octane (0.97 g, 3.63 mmol, 1.00 equiv) and propanephosphonic acid anhydride (3.47 g, 10.9 mmol, 3 equiv) and triethylamine (1.84 g, 18.2 mmol, 5 equiv) at room temperature. The reaction mixture was stirred at room temperature overnight, then the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-60% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (860 mg, 51.9% yield). LCMS (ESI): m / z [M+H]+calcd for C22H26BrN5O: 456.13, found 456.25.

[0234] Synthesis of Intermediate 6: (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone

[0235] Step 1: Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone (Intermediate 6)

[0236] To a solution of 5-[2-(4-bromophenyl)-2,6-diazaspiro[3.4]octane-6-carbonyl]-N- cyclopentylpyrimidin-2-amine (6 g, 13.1 mmol, 1 equiv) in dioxane (100 mL) was added bis(pinacolato)diboron (5.01 g, 19.7 mmol, 1.5 equiv), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.96 g, 1.32 mmol, 0.1 equiv) and potassium acetate (3.87 g, 39.4 mmol, 3 equiv). The mixture was stirred at 100 °C for 4 h under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (100 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue obtained was purified by preparative HPLC (Cl 8 column, 0-100% acetonitrile / water) to afford the title compound as a yellow solid (3.5 g, 52.9% yield). LCMS (ESI): m / z [M+H]+calcd for C28H38BN5O3: 504.31, found: 504.50.

[0237] Synthesis of Intermediate 7: (2-(cyclopentylamino)pyrimidin-5-yl)(2,6- diazaspiro [3.4] octan-2-yl)methanone

[0238] Scheme 7

[0239] Step 1: Preparation of tert-butyl 2-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro [3.4] octane-6-carboxylate

[0240] To a stirred solution of Intermediate 1 (5 g, 24.1 mmol, 1 equiv) in anhydrous DMF (75 mL) was added tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (5.12 g, 24.1 mmol, 1 equiv) and chloro-A(A(A" AMetramethylformarnidiniurn hexafluorophosphate (10.15 g, 36.19 mmol, 1.5 equiv) followed by 1 -methylimidazole (24.4 g, 120 mmol, 5 equiv). The reaction mixture was stirred at room temperature for 2 h. The reaction was diluted by water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (5.4 g, 55.6% yield). LCMS (ESI): m / z [M+H]+calcd for C21H31N5O3: 402.25, found 402.25.

[0241] Step 2: Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(2,6-diazaspiro[3.4]octan-2- yl)methanone (Intermediate 7)

[0242] To a stirred solution of tert-butyl 2-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octane-6-carboxylate (3.0 g, 7.47 mmol, 1 equiv) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated to dryness to afford the TFA salt of the title compound as a yellow oil (2.4 g, 80.5% yield), which was used without purification. LCMS (ESI): m / z [M+H]+calcd for C16H23N5O: 302.19, found 302.15.

[0243] Synthesis of Intermediate 8: (2-(((1R,3R)-3-fluorocyclopentyl)amino)pyrimidin-5-yl)(2,6- diazaspiro [3.4] octan-2-yl)methanone

[0244] Scheme 8

[0245] Step 1: Preparation of tert-butyl 2-(2-((1R,3R )-3-fluorocyclopentyl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro [3.4] octane-6-carboxylate

[0246] To a stirred solution of Intermediate 2 (3 g, 13.3 mmol, 1 equiv) in anhydrous DMF (30 mL) was added tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (2.83 g, 13.3 mmol, 1 equiv) and chloro- N,N,N',N-'tetramethylformarnidinium hexafluorophosphate (5.61 g, 19.9 mmol, 1.5 equiv) followed by 1 -methylimidazole (5.47 g, 66.6 mmol, 5 equiv). The reaction mixture was stirred at room temperature for 2 h. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (4.8 g, 85.6%). LCMS (ESI): m / z [M+H]+calcd for C21H30FN5O3: 420.24, found 420.25.

[0247] Step 2: Preparation of (2-(((1R,3R)-3-fluorocyclopentyl)amino)pyrimidin-5-yl)(2,6- diazaspiro[3.4]octan-2-yl)methanone (Intermediate 8)

[0248] To a stirred solution of tert-butyl 2-(2-(((1R,3R)-3-fluorocyclopentyl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro[3.4]octane-6-carboxylate (4.5 g, 10.7 mmol, 1 equiv) in di chloromethane (10 mL) was added trifluoroacetic acid (4 mL). The reaction mixture was stirred at room temperature for 3 h. The resulting mixture was concentrated to dryness, and the product was re-crystallized from a mixture of ethyl acetate and petroleum ether to afford the TFA salt of the title compound as a white solid (4.4 g, 80.3% yield). LCMS (ESI): m / z [M+H]+calcd for C16H22FN5O: 320.18, found 320.15.

[0249] Synthesis of Intermediate 9: (6-(4-bromophenyl)-2,6-diazaspiro[3.4]octan-2-yl)(2-

[0250] (cyclopentylamino)pyrimidin-5-yl)methanone

[0251] Scheme 9

[0252] Step 1: Preparation of tert-butyl 6-(4-bromophenyl)-2,6-diazaspiro[3.4]octane-2- carboxylate

[0253] To a solution of tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate (10 g, 47.1 mmol, 1 equiv) in dioxane (200 mL) was added 4-bromoiodobenzene (26.65 g, 94.21 mmol, 2.0 equiv), tris(dibenzylideneacetone)dipalladium(0) (4.31 g, 4.71 mmol, 0.1 equiv), XantPhos (5.45 g, 9.42 mmol, 0.2 equiv) and cesium carbonate (46.04 g, 141.3 mmol, 3.0 equiv). The mixture was stirred at 80° C for 4 h under a nitrogen atmosphere. The mixture was cooled to room temperature then diluted with water (300 mL) and extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to afford the title compound as a yellow solid (14.5 g, 82.5% yield). LCMS (ESI): m / z [M+H]+ calcd for CnlfeBr^Ch: 367.09, found 367.15.

[0254] Step 2: Preparation of 6-(4-bromophenyl)-2,6-diazaspiro[3.4]octane

[0255] To a solution of tert-butyl 6-(4-bromophenyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (14.5 g, 39.5 mmol, 1 equiv) in di chloromethane (160 mL) was added trifluoroacetic acid (40 mL). The mixture was stirred at room temperature for 2 h. The reaction was then concentrated and the residue taken up in sodium bicarbonate solution. The resulting mixture was extracted with a 5: 1 mixture of dichloromethane and methanol (3 x 300 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound as a yellow solid (9.5 g), which was used without purification. LCMS (ESI): m / z [M+H]+ calcd for C12H15BrN2: 267.04, found 267.00.

[0256] Step 3: Preparation of (6-(4-bromophenyl)-2,6-diazaspiro[3.4]octan-2-yl)(2- (cyclopentylamino)pyrimidin-5-yl)methanone (Intermediate 9)

[0257] To a solution of 6-(4-bromophenyl)-2,6-diazaspiro[3.4]octane (9 g, 33.7 mmol, 1 equiv) in DMF (100 mL) was added Intermediate 1 (7.68 g, 37.1 mmol, 1.1 equiv), chloro-N,N,N(N'- tetramethylformamidinium hexafluorophosphate (14.18 g, 50.53 mmol, 1.5 equiv) and 1- methylimidazole (8.30 g, 101 mmol, 3.0 equiv). The mixture was stirred at room temperature for 2 h. The reaction was diluted with ethyl acetate (1000 mL) and washed with water (3 x 200 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-10% methanol / dichloromethane) to afford the title compound as a yellow solid (12.3 g, 80.0% yield). LCMS (ESI): m / z [M+H]+ calcd for C22H26BrN5O: 456.13, found: 456.25.

[0258] Synthesis of Intermediate 10: (2-(cyclopentylamino)pyrimidin-5-yl)(6-(4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2,6-diazaspiro[3.4]octan-2-yl)methanone

[0259] Intermediate 9

[0260] Step 1: Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(6-(4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)-2,6-diazaspiro[3.4]octan-2-yl)methanone (Intermediate 6)

[0261] To a solution of Intermediate 9 (6 g, 13.1 mmol, 1 equiv) in dioxane (80 mL) was added bis(pinacolato)diboron (5.01 g, 19.7 mmol, 1.5 equiv), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.96 g, 1.32 mmol, 0.1 equiv) and potassium acetate (3.87 g, 39.4 mmol, 3.0 equiv). The mixture was stirred at 100 °C for 4 h under a nitrogen atmosphere. The reaction was cooled to room temperature then diluted with water (100 mL) and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (0-100% acetonitrile / water) to afford the title compound as a yellow solid (3.7 g, 55.9% yield). LCMS (ESI): m / z [M+H]+ calcd for C28H38BN5O3: 504.31, found 504.40.

[0262] Synthesis of Compound 1: (2-(((1R,3R)-3-fluorocyclopentyl)amino)pyrimidin-5-yl)(2-(4- (6-(hydroxymethyl)pyrazin-2-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone

[0263] Scheme 11

[0264] Step 1: Preparation of (2-((1R,3R )-3-fluorocyclopentyl)amino)pyrimidin-5-yl)(2-(4-(6- (hydroxymethyl)pyrazin-2-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone (Compound 1)

[0265] To a solution of Intermediate 4 (150 mg, 0.470 mmol, 1 equiv) in dioxane (4 mL) was added [6-(4-bromophenyl)pyrazin-2-yl]methanol (149 mg, 0.564 mmol, 1.2 equiv), cesium carbonate (336 mg, 1.03 mmol, 2.2 equiv), RuPhos (22 mg, 0.047 mmol, 0.1 equiv), and RuPhos-Pd-G3 (39 mg, 0.047 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred for 2 h at 90 °C under nitrogen. The reaction mixture was then cooled to room temperature, quenched with water (20 mL), and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% methanol / dichloromethane) followed by preparative HPLC (XB ridge Prep OBD column, 24-49% acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a light yellow solid (84.4 mg, 35.7% yield). LCMS (ESI): m / z [M+H]+calcd for C27H30FN7O2: 504.25, found 504.25. 'H NMR (300 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.52 (d, J= 16.1 Hz, 3H), 8.00 (s, 2H), 7.83 (s, 1H), 6.53 (d, J= 9.2 Hz, 2H), 5.58 (t, J= 5.9 Hz, 1H), 5.08 - 5.41 (m, 1H), 4.65 (d, J= 5.8 Hz, 2H), 4.31 - 4.56 (m, 1H), 3.77 - 4.09 (m, 5H), 3.48 - 3.77 (m, 3H), 1.95 - 2.25 (m, 5H), 1.69 - 1.92 (m, 2H), 1.50 - 1.69 (m, 1H).19F NMR (282 MHz, DMSO-d6) δ -167.25.

[0266] Synthesis of Compound 2: 3-(3-chloro-4-(6-(2-(cyclopentylamino)pyrimidine-5- carbonyl)-2,6-diazaspiro [3.4] octan-2-yl)phenyl)pyrazine 1-oxide

[0267] Scheme 12

[0268] Step 1: 3-(4-bromo-3-chlorophenyl)pyrazine 1-oxide

[0269] To a stirring solution (4-bromo-3-chlorophenyl)boronic acid (5 g, 24.897 mmol, 1 equiv) in dioxane (100 mL) and water (10 mL) was added of 3 -chloropyrazine 1-oxide (4.75 g, 29.9 mmol, 1.2 equiv), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.64 g, 4.98 mmol, 0.2 equiv) and potassium carbonate (6.88 g, 49.8 mmol, 2 equiv). The mixture was stirred for 16 h at 90 °C under nitrogen. The reaction was cooled to room temperature, then was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petr oleum ether) to afford the title compound (3.68 g, 62.8% yield). LCMS (ESI): m / z [M+H]+ calcd for C0oH7BrN2: 286.93, found 286.80.

[0270] Step 2: Preparation of 3-(3-chloro-4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)- 2,6-diazaspiro[3.4]octan-2-yl)phenyl)pyrazine 1-oxide (Compound 2)

[0271] To a stirred solution of 3-(4-bromo-3-chlorophenyl)pyrazin-l-ium-l-olate (100 mg, 0.350 mmol, 1 equiv) in dioxane (2 mL) was added Intermediate 3 (105 mg, 0.350 mmol, 1 equiv), Ruphos (65 mg, 0.140 mmol, 0.4 equiv), cesium carbonate (228 mg, 0.700 mmol, 2 equiv), and RuPhos-Pd-G3 (58 mg, 0.070 mmol, 0.2 equiv) at room temperature. The reaction mixture was stirred under nitrogen at 90 °C for 16 h, then was stirred overnight at room temperature. The reaction mixture was then quenched by addition of water (5 mL), and the resulting mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (XB ridge Prep OBD C18 Column, 32-50% acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a yellow solid (78.2 mg, 44.1% yield). LCMS (ESI): m / z [M+H]+ calcd for C26H28CIN7O2: 506.20, found 506.20. 'H NMR (300 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.46 - 8.49 (m, 3H), 8.13 - 8.21 (m, 1H), 8.00 (s, 1H), 7.89 - 7.95 (m, 1H), 7.71 (d, J = 13 Hz, 1H), 6.57 - 6.61 (m, 1H), 3.97 - 4.25 (m, 5H), 3.81 (s, 1H), 3.66 (s, 2H), 3.50 - 3.52 (m, 1H), 2.15 (t, J= 6.8 Hz, 2H), 1.83 - 1.87 (m, 2H), 1.63 - 1.68 (m, 2H), 1.46 - 1.56 (m, 4H). Synthesis of Compound 4: (2-(4-(5-(aminomethyl)pyridin-3-yl)phenyl)-2,6- diazaspiro[3.4]octan-6-yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone

[0272] Step 1: Preparation of tert-butyl Az-{[5-(4-bromophenyl)pyridin-3-yl]methyl}carbamate

[0273] To a solution of 4-bromophenylboric acid (350 mg, 1.74 mmol, 1 equiv) in dioxane (5 mL) and water (0.5 mL) was added tert-butyl N-[(5-bromopyridin-3-yl)methyl]carbamate (500 mg, 1.74 mmol, 1.0 equiv), tetrakis(triphenylphosphine)palladium(0) (201 mg, 0.174 mmol, 0.10 equiv) and potassium carbonate (722 mg, 5.23 mmol, 3.0 equiv). The mixture was stirred for 6 h at 100 °C under a nitrogen atmosphere. The reaction was then cooled to room temperature and quenched with water (20 mL) at 0 °C. The resulting mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0- 95% ethyl acetate / petroleum ether) to afford the title compound as an off-white solid (520 mg, 82.1% yield). LCMS (ESI): m / z [M+H]+ calcd for Ci7Hi9BrN2O2: 363.06, found 363.00.

[0274] Step 2: Preparation of tert-butyNl- {[5-(4-{6-[2-(cyclopentylamino)pyrimidine-5- carbonyl]-2,6-diazaspiro[3.4]octan-2-yl}phenyl)pyridin-3-yl]methyl}carbamate

[0275] To a solution of tert-butyl N-{ [5-(4-bromophenyl)pyridin-3-yl]methyl}carbamate (400 mg, 1.1 mmol, 1 equiv) in dioxane (4 mL) was added Intermediate 3 (331 mg, 1.1 mmol, 1.00 equiv), X-Phos (52 mg, 0.11 mmol, 0.1 equiv), X-Phos-Pd-G3 (95 mg, 0.11 mmol, 0.1 equiv) and cesium carbonate (1.08 g, 3.3 mmol, 3.01 equiv). The mixture was stirred for 4 h at 90 °C under a nitrogen atmosphere, then was cooled to room temperature. The reaction was quenched with layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-15% methanol / di chloromethane) to afford the title compound as a white solid (460 mg, 71.5% yield). LCMS (ESI): m / z [M+H]+calcd for C33H41N7O3: 584.33, found 584.20.

[0276] Step 3: Preparation of (2-(4-(5-(aminomethyl)pyridin-3-yl)phenyl)-2,6- diazaspiro [3.4] octan-6-yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone (Compound 4)

[0277] To a solution of tert-butyl N-{[5-(4-{6-[2-(cyclopentylamino)pyrimidine-5-carbonyl]-2,6- diazaspiro[3.4]octan-2-yl}phenyl)pyridin-3-yl]methyl}carbamate (300 mg, 0.51 mmol, 1 equiv) in di chloromethane (3 mL), trifluoroacetic acid (1 mL) was added and the reaction mixture was stirred for 1 h at room temperature. The mixture was concentrated and purified by preparative HPLC (XB ridge Prep OBD C18 Column, 20-42% acetonitrile / water with 10 mM ammonium bicarbonate and 0.5% ammonia) to afford the title compound as a white solid (41.4 mg, 16.7% yield). LCMS (ESI): m / z [M+H]+calcd for C28H33N7O: 484.28, found 484.30. 'H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.53 (s, 2H), 8.39 (s, 1H), 7.93 (s, 1H), 7.74 (d, J = 6.6 Hz, 1H), 7.56 (d, J= 5.4 Hz, 2H), 6.52 - 6.54 (m, 2H), 4.21 (q, J = 6.9 Hz, 1H), 3.80 - 3.83 (m, 4H), 3.77 (s, 2H) , 3.68 (s, 2H), 3.54 (s, 1H), 2.15 (t, J= 6.6 Hz, 2H), 1.86 - 1.89 (m, 2H), 1.66 - 1.68 (m, 2H), 1.49 - 1.52 (m, 4H).

[0278] Synthesis of Compound 5: 3-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro [3.4] octan-2-yl)-2,3-difluorophenyl)pyrazine 1-oxide

[0279] Step 1: Preparation of 3-(4-bromo-2,3-difluorophenyl)pyrazin-l-ium-l-olate To a solution of 4-bromo-2,3-difluorophenylboronic acid (500 mg, 2.11 mmol, 1 equiv) in dioxane (5 mL) and water (0.5 mL) was added 3-chloropyrazin-l-ium-l-olate (276 mg, 2.11 mmol, 1 equiv), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (154 mg, 0.211 mmol, O.lequiv) and potassium carbonate (875 mg, 6.33 mmol, 3 equiv). The mixture was stirred for 6 h at 60 °C under a nitrogen atmosphere. The reaction was then cooled to room temperature and quenched with water (10 mL) at 0 °C. The resulting mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (10 mL), dried over sodium suflate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% methanol / dichloromethane) to afford the title compound as an off- white solid (400 mg, 66.0% yield). LCMS (ESI): m / z [M+H]+calcd for : 286.96, found 286.95.

[0280] Step 2: Preparation of 3-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)-2,3-difluorophenyl)pyrazine 1-oxide (Compound 5)

[0281] To a solution of 3-(4-bromo-2,3-difluorophenyl)pyrazin-l-ium-l-olate (200 mg, 0.69 mmol, 1 equiv) in dioxane (4 mL) was added Intermediate 3 (209 mg, 0.69 mmol, 1 equiv), X-Phos (33 mg, 0.07 mmol, 0.1 equiv), X-Phos-Pd-G3 (60 mg, 0.07 mmol, 0.11 equiv) and cesium carbonate (408 mg, 1.25 mmol, 3.01 equiv) at room temperature under a nitrogen atmosphere. The mixture was stirred for 4 h at 90 °C under a nitrogen atmosphere, then was cooled to room temperature. The reaction was quenched with water (10 mL) at 0 °C, then the resulting mixture was extracted with ethyl acetate (2 x lOmL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-12% methanol / dichloromethane) and purified further by preparative HPLC (XB ridge Prep Cl 8 OBD Column, 19-44% acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a yellow solid (28.5 mg, 8.1% yield). LCMS (ESI): m / z [M+H]+calcd for C26H27F2N7O2: 508.22, found 508.20. 'H NMR (300 MHz, DMSO-d6) δ 8.59 (d, J = 4.1 Hz, 1H), 8.52 (s, 3H), 8.27 (d, J= 2.7 Hz, 1H), 7.65 - 7.74 (m, 2H), 6.49 (d, J= 7.8 Hz, 1H), 4.11 - 4.21(m, 5H), 3.84 (s, 1H), 3.68 (s, 2H), 3.44 - 3.68(m, 1H), 2.18 (t, J = 6.9 Hz, 2H), 1.88 - 1.90 (m, 2H), 1.66 - 1.68 (m, 2H), 1.51 - 1.53 (m, 4H).19F NMR (282 MHz, DMSO-d6) δ -141.7, -162.1.

[0282] Synthesis of Compound 7 and Compound 8: 3-(4-(6-(2-(((15,21?)-2- fluorocyclopentyl)amino)pyrimidine-5-carbonyl)-2,6-diazaspiro[3.4]octan-2- yl)phenyl)pyrazine 1-oxide and 3-(4-(6-(2-(((H?,2X)-2- fluorocyclopentyl)amino)pyrimidine-5-carbonyl)-2,6-diazaspiro[3.4]octan-2- yl)phenyl)pyrazine 1-oxide

[0283]

[0284] Step 1: Preparation of cis-2-(2-fluorocyclopentyl)isoindoline-l, 3-dione

[0285] To a solution of trans-2-fluorocyclopentan-l-ol (1 g, 9.604 mmol, 1 equiv) in THF (15 mL) was added phthalimide (1.41 g, 9.60 mmol, 1 equiv) and triphenylphosphine (3.78 g, 14.4 mmol, 1.5 equiv). Di ethyl azodi carb oxy late (3.35 g, 19.2 mmol, 2 equiv) was then added at 0 °C under nitrogen, and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound as a yellow oil (1.5 g, 67.0% yield). LCMS (ESI): m / z [M+H]+calcd for C13H12FNO2: 234.09, found 234.05.

[0286] Step 2: Preparation of cis-2-fluorocyclopentan-l-amine

[0287] Cis 2 (2 fluorocyclopentyl)isoindoline l 3 dione (1 5 g 6 43 mmol 1 equiv) was dissolved in then cooled to room temperature, and the reaction mixture was concentrated under vacuum. The residue was triturated with diethyl ether and ethyl acetate, and the resulting solid was collected by filtration to afford the title compound as a white solid (600 mg, 90.0% yield). LCMS (ESI): m / z [M+H]+calcd for C5H10FN: 104.08, found 104.10.

[0288] Step 3: Preparation of cis-ethyl 2-((2-fluorocyclopentyl)amino)pyrimidine-5-carboxylate To a solution of cis-2-fluorocy cl opentan- 1 -amine (1.3 g, 12.6 mmol, 1 equiv) in acetonitrile (20 mL) was added ethyl 2-chloropyrimidine-5-carboxylate (2.33 g, 12.6 mmol, 1 equiv) and N,N-diisopropylethylamine (3.26 g, 25.208 mmol, 2 equiv), and the mixture was stirred for 1 h at 70 °C. The mixture was then cooled to room temperature, quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow solid (800 mg, 25.1% yield). LCMS (ESI): m / z [M+H]+calcd for C12H16FN3O2: 254.13, found 254.05.

[0289] Step 4: Preparation of cis-2-((2-fluorocyclopentyl)amino)pyrimidine-5-carboxylic acid

[0290] To a solution of cis-ethyl 2-((2-fluorocyclopentyl)amino)pyrimidine-5-carboxylate (800 mg, 3.16 mmol, 1 equiv) in tetrahydrofuran (6 mL), methanol (2 mL), and water (2 mL) was added lithium hydroxide (227 mg, 9.48 mmol, 3 equiv). The reaction mixture was stirred at room temperature for 2 h, then was adjusted to pH = 5 with IN hydrochloric acid. The precipitated solids were collected by filtration and washed with water to afford the title compound as a white solid (400 mg, 56.2% yield). LCMS (ESI): m / z [M+H]+calcd for C10H12FN3O2: 226.09, found 226.20.

[0291] Step 5: Preparation of cis-tert-butyl 6-(2-((-2-fluorocyclopentyl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro [3.4] octane-2-carboxylate

[0292] To a solution of cis-2-((2-fluorocyclopentyl)amino)pyrimidine-5-carboxylic acid (2 g, 8.88 mmol, 1 equiv) in acetonitrile (30 mL) was added tert-butyl 2,6-diazaspiro[3.4]octane-2- carboxylate (1.89 g, 8.88 mmol, 1 equiv), chloro-Af,N,N',N'-tetramethylformamidinium hexafluorophosphate (2.99 g, 10.7 mmol, 1.2 equiv) and 1 -methylimidazole (2.19 g, 26.6 mmol, 3 equiv). The resulting mixture was stirred at room temperature for 5 h, then the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% methanol / dichloromethane) to afford the title compound as a yellow solid (3 g, 80.5% yield). LCMS (ESI): m / z [M+H]+calcd for C21H30FN5O3 420.24, found 420.30.

[0293] Step 6: Preparation of cis-(2-((-2-fluorocyclopentyl)amino)pyrimidin-5-yl)(2,6- diazaspiro [3.4] octan-6-yl)methanone

[0294] To a solution of cis-tert-butyl 6-(2-((-2-fluorocyclopentyl)amino)pyrimidine-5-carbonyl)-2,6- diazaspiro

[0034] octane-2-carboxylate (3 g 7 15 mmol 1 equiv) in di chloromethane (50 mL) temperature for 2 h, then the reaction mixture was concentrated to dryness. The residue was then triturated with a mixture of diethyl ether and ethyl acetate, and the precipitated solids were collected by filtration and washed with ethyl acetate to afford the TFA salt of the title compound as a white solid (2 g, 67.2% yield). LCMS (ESI): m / z [M+H]+calcd for C16H22FN5O: 320.18, found: 320.10.

[0295] Step 7: Preparation of 3-(4-(6-(2-(((15,21?)-2-fluorocyclopentyl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)phenyl)pyrazine 1-oxide and 3-(4-(6-(2- (((H?,25)-2-fluorocyclopentyl)amino)pyrimidine-5-carbonyl)-2,6-diazaspiro[3.4]octan-2- yl)phenyl)pyrazine 1-oxide (Compound 7 and Compound 8)

[0296] To a stirred solution of 3-(4-bromophenyl)pyrazin-l-ium-l-olate (200 mg, 0.797 mmol, 1 equiv) in anhydrous 1,4-di oxane (8 mL) was added (cis)-(2-((2- fluorocyclopentyl)amino)pyrimidin-5-yl)(2,6-diazaspiro[3 ,4]octan-6-yl)methanone (255 mg, 0.797 mmol, 1 equiv), potassium carbonate (330 mg, 2.391 mmol, 3 equiv), Xantphos (46 mg, 0.080 mmol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium(0) (73 mg, 0.080 mmol, 0.1 equiv). The reaction mixture was stirred at 90 °C for 3 h under a nitrogen atmosphere. The reaction was cooled to room temperature, then was quenched with water (20 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-15% methanol / di chloromethane), then further purified by chiral preparative HPLC (CHIRALPAK IE 2*25 cm, 5 μm column, 50:50 methanol / dichlorom ethane) to afford the two enantiomers.

[0297] Compound 7 was isolated as the second eluting peak as a yellow solid (52.3 mg, 13.4% yield). LCMS (ESI): m / z [M+H]+calcd for C26H28FN7O2: 490.23, found 490.20. 'H NMR (300 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.56 (s, 2H), 8.48 (d, J = 4.1 Hz, 1H), 8.09 - 8.17 (m, 1H), 7.92 - 8.01 (m, 2H), 7.72 - 7.78 (m, 1H), 6.44 - 6.54 (m, 2H), 5.03 (d, J= 55.3 Hz, 1H), 4.17 (d, J= 27.8 Hz, 1H), 3.82 - 3.96 (m, 5H), 3.51 - 3.71 (m, 3H), 2.17 (t, J = 6.9 Hz, 2H), 1.75 - 1.96 (m, 5H), 1.56 - 1.67 (m, 1H).19F NMR (282 MHz, DMSO-d6) δ -189.5.

[0298] Compound 8 was isolated as the first eluting peak as a yellow solid (38.6 mg, 9.9% yield). LCMS (ESI): m / z [M+H]+calcd for C26H28FN7O2: 490.23, found 490.20.1H NMR (300 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.55 (s, 2H), 8.48 (d, J= 4.1 Hz, 1H), 8.12 - 8.14 (m, 1H), 7.97 - 8.11 (m, 2H), 7.72 - 7.78 (m, 1H), 6.48 - 6.51 (m, 2H), 5.11 (d, 55.3 Hz, 1H), 4.15 (d, J=

[0299] 27.8 Hz, 1H), 3.84 - 3.93 (m, 5H), 3.54 - 3.68 (m, 3H), 2.16 (t, J = 6.9 Hz, 2H), 1.82 - 1.97 (m, 5H), 1.60 - 1.78 (m, 1H).19F NMR (282 MHz, DMSO-d6) δ -189.5.

[0300] Synthesis of Compound 9: 3-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro [3.4] octan-2-yl)-3-fluorophenyl)pyrazine 1-oxide

[0301] Scheme 16

[0302] Step 1: Preparation of 3-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)-3-fluorophenyl)pyrazine 1-oxide (Compound 9)

[0303] To a solution of 3-(4-bromo-3-fluorophenyl)pyrazin-l-ium-l-olate (80 mg, 0.29 mmol, 1 equiv, prepared similarly to the synthesis of Compound 5, step 1) in dioxane (4 mL) was added Intermediate 3 (89 mg, 0.29 mmol, 1.00 equiv), RuPhos (14 mg, 0.03 mmol, 0.1 equiv), RuPhos-Pd-G3 (25 mg, 0.03 mmol, 0.1 equiv) and cesium carbonate (291 mg, 0.89 mmol, 3.01 equiv). The mixture was stirred for 4 h at 90 °C under a nitrogen atmosphere, then the mixture was cooled to room temperature. The reaction was quenched with water (10 mL) at 0 °C, then the resulting mixture was extracted with ethyl acetate (2 x lOmL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% methanol / dichloromethane) and further purified by preparative HPLC (YMC Triart Cl 8 Column, 29-44% acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as an yellow solid (38.1 mg, 26.1% yield). LCMS (ESI): m / z [M+H]+calcd for C26H28FN7O2: 490.23, found 490.15. 'H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.50 (d, J= 3.6 Hz, 3H), 8.17 (d, J= 3.6 Hz, 2H), 7.84 (s, 1H), 7.72 (d, J= 6.0 Hz, 1H), 6.61 (s, 1H), 4.20 (q, J= 6.9 Hz, 1H), 4.05 (s, 1H), 3.97 (d, J= 13.5 Hz, 4H), 3.83 (s, 1H), 3.67 (s, 2H), 3.53 (s, 1H), 2.17 (t, J= 6.9 Hz, 2H), 1.88 (d, .7= 4.0 Hz, 1H), 1.67 (s, 2H), 1.47 - 1.51 (m, 4H).19F NMR (282 MHz, DMSO-d6) δ -133.47.

[0304] Synthesis of Compound 10 and Compound 11: 3-(3-chloro-4-(6-(2-( -2- fluorocyclopentyl)amino)pyrimidine-5-carbonyl)-2,6-diazaspiro[3.4]octan-2- yl)phenyl)pyrazine 1-oxide and 3-(3-chloro-4-(6-(2-( -2- fluorocyclopentyl)amino)pyrimidine-5-carbonyl)-2,6-diazaspiro[3.4]octan-2- yl)phenyl)pyrazine 1-oxide

[0305] Step 1: Preparation of 3-(4-bromo-3-chlorophenyl)pyrazine 1-oxide

[0306] To a solution of 4-bromo-3-chlorophenylboronic acid (500 mg, 2.13 mmol, 1 equiv) in dioxane (10 mL) and water (1 mL) was added 3 -chloropyrazine 1-oxide (277 mg, 2.13 mmol, 1 equiv), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (155 mg, 0.213 mmol, 0.1 equiv), and potassium carbonate (587 mg, 4.25 mmol, 2 equiv). The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature and was quenched with water (10 mL) and extracted with ethyl acetate (3 x 30 mL).The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0- 50% ethyl acetate / petroleum ether) to afford the title compound as a yellow solid (300 mg, 49.4% yield). LCMS (ESI): m / z [M+H]+calcd for 286.93, found 286.80.

[0307] Step 2: Preparation of 3-(3-chloro-4-(6-(2-(((15,21?)-2- fluorocyclopentyl)amino)pyrimidine-5-carbonyl)-2,6-diazaspiro[3.4]octan-2- yl)phenyl)pyrazine 1-oxide and 3-(3-chloro-4-(6-(2-(((lR,25)-2- fluorocyclopentyl)amino)pyrimidine-5-carbonyl)-2,6-diazaspiro[3.4]octan-2- yl)phenyl)pyrazine 1-oxide (Compound 11 and Compound 12) To a solution of cis-(2-((2-fluorocyclopentyl)amino)pyrimidin-5-yl)(2,6-diazaspiro[3.4]octan- 6-yl)methanone (300 mg, 0.939 mmol, 1 equiv, prepared as described in the synthesis of Compound 7 and Compound 8) in 1,4-di oxane (10 mL) was added 3-(4-bromo-3- chlorophenyl)pyrazin-l-ium-l-olate (268 mg, 0.939 mmol, 1 equiv), Ruphos (44 mg, 0.094 mmol, 0.1 equiv), Ruphos-Pd-G3 (80 mg, 0.094 mmol, 0.1 equiv), and cesium carbonate (612 mg, 1.88 mmol, 2 equiv). The resulting mixture was stirred overnight at 90 °C under nitrogen. The reaction was cooled to room temperature then was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered aand concentrated. The residue was purified by silica gel chromatography (0-30% methanol / dichloromethane) to afford a mixture of isomers yellow solid (180 mg). The mixture of enantiomers was separated by chiral HPLC (CHIRALPAK IA column, 20% 1 :3 hexanes / dichloromethane and 80% ethanol, with 0.5% ammonia) to afford the two title compounds.

[0308] Compound 10 (second eluting isomer) was isolated as a yellow solid (57 mg, 11.6% yield). LCMS (ESI): m / z [M+H]+calcd for 524.19, found 524.20. 'H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.47 - 8.58 (m, 3H), 8.19 - 8.22 (m, 1H), 7.91 - 8.10 (m, 2H), 7.73 (d, J = 7.5 Hz, 1H), 6.62 - 6.68 (m, 1H), 4.94 - 5.12 (m, 1H), 4.06 - 4.25 (m, 5H), 3.82 - 8.85 (m,lH), 3.68 (s, 2H), 3.53 - 3.56 (m, 1H), 2.18 (t, J= 6.9 Hz, 2H), 1.72 - 2.06 (m, 5H), 1.72 - 1.87 (m, 1H).19F NMR (282 MHz, DMSO-d6) δ -189.54.

[0309] Compound 11 (first eluting isomer) was isolated as a yellow solid (65 mg, 13.2% yield). LCMS (ESI): m / z [M+H]+calcd for 524.19, found 524.25. 'H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.47 - 8.58 (m, 3H), 8.19 - 8.22 (m, 1H), 7.91 - 8.10 (m, 2H), 7.73 (d, J = 7.5 Hz, 1H), 6.62 - 6.68 (m, 1H), 4.94 - 5.12 (m, 1H), 4.06 - 4.25 (m, 5H), 3.82 - 8.85 (m,lH), 3.68 (s, 2H), 3.53 - 3.56 (m, 1H), 2.18 (t, J = 6.9 Hz, 2H), 1.72 - 2.06 (m, 5H), 1.72 - 1.87 (m, 1H).19F NMR (282 MHz, DMSO-d6) δ -189.54.

[0310] Synthesis of Compound 12: 5-(6-(2-(((1R,3R)-3-fluorocyclopentyl)amino)pyrimidine-5- carbonyl)-!, 6-di:izaspiro|3.4|octan-2-yl)-2-( l / / -pyrazol-4-yl)isonicotinonitrile

[0311] Scheme 18

[0312]

[0313] Step 1: Preparation of 5-fluoro-2-( (1t-(tetrahydro-2 / / -pyran-2-yl)-l / / -pyrazol-4-yl) isonicotinonitrile

[0314] To a solution of 2-bromo-5-fluoropyridine-4-carbonitrile (1 g, 4.98 mmol, 1 equiv) and 1- (oxan-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) pyrazole (1.38 g, 4.98 mmol, 1 equiv) in dioxane (10 mL) and water (ImL) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.36 g, 0.497 mmol, 0.1 equiv) and potassium carbonate (2.06 g, 14.9 mmol, 3 equiv). The mixture was stirred at 100 °C for 2 h under nitrogen. The reaction was then cooled to room temperature and quenched with water (30 mL), then extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% methanol / di chloromethane) to afford the title compound as a white solid (800 mg, 59.2% yield). LCMS (ESI): m / z [M+H]+ calcd for C14H13FN4O: 273.11, found 273.05.

[0315] Step 2: Preparation of 5-(6-(2-(((1R,3R)-3-fluorocyclopentyl) amino) pyrimidine-5- carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-( (tetr:i1h-ydro-2 / / -pyr:in-2-yl)-l / / -pyr:izol-4- yl)isonicotinonitrile

[0316] To a stirring solution Intermediate 4 (200 mg, 0.626 mmol, 1 equiv) in acetonitrile (10 mL) was added 5-fluoro-2-(l-(tetrahydro-2J / -pyran-2-yl)-17 / -pyrazol-4-yl) isonicotinonitrile (171 mg, 0.626 mmol, 1 equiv) and N,N-diisopropylethylamine (243 mg, 1.88 mmol, 3 equiv). The reaction mixture was stirred at 70 °C for 2 h, then was cooled to room temperature. The reaction mixture was quenched by addition of water (5 mL), and the resulting mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% methanol / di chloromethane) to afford the title compound as a white solid (150 mg 42% yield) LCMS (ESI): m / z [M+H]+ calcd for C30H34FN9O2: 572 29 found Step 3: Preparation of 5-(6-(2-(((1R,3R)-3-fluorocyclopentyl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-(lH-pyrazol-4-yl)isonicotinonitrile (Compound 12)

[0317] To a stirred solution of 5-(6-(2-(((U?,3 / ?)-3-fluorocyclopentyl)amino)pyrimidine-5-carbonyl)- 2,6-diazaspiro[3.4]octan-2-yl)-2-(l-(tetrahydro-2J / -pyran-2-yl)-U / -pyrazol-4- yl)isonicotinonitrile (100 mg, 0.175 mmol, 1 equiv) in di chloromethane (4 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 1 h, then the mixture was concentrated. The residue was purified by preparation HPLC (50 / 50 acetonitrile / water with 0.1% trifluoroacetic acid) to afford the title compound as a white solid (33.1 mg, 38.8% yield). LCMS (ESI): m / z [M+H]+calcd for C25H26FN9O: 488.23, found 488.20. 'H NMR (300 MHz, DMSO-d6) δ 12.94 (s, 1H), 8.54 (s, 2H), 7.92 - 8.30 (m, 3H), 7.82 (d, J = 7.5 Hz, 2H), 5.22 (d, J = 54.0 Hz, 1H), 4.37- 4.53 (m, 1H), 4.05 - 4.31 (m, 4H), 3.86 (s, 1H), 3.47 - 3.76 (m, 3H), 1.93 - 2.34 (m, 5H), 1.66 - 1.93 (m, 2H), 1.47 - 1.65 (m, 1H).19F NMR (282 MHz, DMSO-d6) δ -167.28.

[0318] Synthesis of Compound 14 and Compound 15: (R)-(2-(4-(5-(l-aminoethyl)pyridin-3- yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)(2-(cyclopentylamino)pyrimidin-5- yl)methanone and (S)-(2-(4-(5-(l-aminoethyl)pyridin-3-yl)phenyl)-2,6- diazaspiro[3.4]octan-6-yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone

[0319] Scheme 19

[0320]

[0321] Step 1: Preparation of 5-(4-bromophenyl)nicotinonitrile

[0322] To a solution of 4-bromoiodobenzene (1 g, 3.54 mmol, 1 equiv) and 2-methoxypyrimidin-5- ylboronic acid (67 mg, 0.438 mmol, 1 equiv) in dioxane (10 mL) and water (1 mL) were added [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.26 g, 0.354 mmol, 0.1 equiv) and sodium carbonate (1.12 g, 10.6 mmol, 3 equiv). The mixture was stirred at 90 °C for 2 h under nitrogen, then was cooled to room temperature. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound (800 mg, 80.3% yield) as a white solid. LCMS (ESI): m / z [M+H]+calcd for CnELBrlSh: 258.98, found 259.20.

[0323] Step 2: Preparation of tert-butyl 2-(4-(5-cyanopyridin-3-yl) phenyl)-2,6-diazaspiro [3.4]octane-6-carboxylate

[0324] To a solution of 5-(4-bromophenyl) nicotinonitrile (700 mg, 2.70 mmol, 1 equiv) and tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (573 mg, 2.70 mmol, 1 equiv) in dioxane (10 mL) was added XPhos-Pd-G3 (228 mg, 0.270 mmol, 0.1 equiv), Xphos (257 mg, 0.540 mmol, 0.2 equiv) and cesium carbonate (2.6 g, 8.11 mmol, 3 equiv). The mixture was stirred at 90 °C for 2 h under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a white solid (900 mg, 76.8% yield). LCMS (ESI): m / z [M+H]+calcd for C24H32N4O2: 391.21, found 391.30.

[0325] Step 3: Preparation of tert-butyl 2-(4-(5-(l-aminoethyl)pyridin-3-yl)phenyl)-2,6- diazaspiro [3.4] octane-6-carboxylate A solution of tert-butyl 2-(4-(5-cyanopyridin-3-yl)phenyl)-2,6-diazaspiro[3.4]octane-6- carboxylate (800 mg, 2.05 mmol, 1 equiv) in THF (10 mL) was treated with methyllithium (1.6 M in diethyl ether, 1.27 mL, 2.05 mmol, 1 equiv) at -78 °C for 1 h under a nitrogen atmosphere, followed by the dropwise addition of sodium borohydride (155 mg, 4.098 mmol, 2 equiv) in methanol at room temperature. After stirring for 2h at room temperature, the reaction mixture was quenched by addition of water (5 mL). The resulting mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% methanol / di chloromethane) to afford the title compound as a white solid (600 mg, 65.2% yield). LCMS (ESI): m / z [M+H]+calcd for C24H32N4O2: 409.26, found 409.30.

[0326] Step 4: Preparation of tert-butyl 2-(4-(5-(l-(((benzyloxy)carbonyl)amino)ethyl)pyridin-3- yl)phenyl)-2,6-diazaspiro [3.4] octane-6-carboxylate

[0327] To a solution of tert-butyl 2-(4-(5-(l-aminoethyl)pyridin-3-yl)phenyl)-2,6- diazaspiro[3.4]octane-6-carboxylate (500 mg, 1.22 mmol, 1 equiv) in ethyl alcohol (2 mL) and water (2 mL) was added potassium carbonate (507 mg, 3.672 mmol, 3 equiv), followed by the dropwise addition of benzyl 2,5-dioxopyrrolidin-l-yl carbonate (366 mg, 1.47 mmol, 1.2 equiv). The reaction mixture was stirred for 2 h at room temperature, then was quenched by addition of water (5 mL). The resulting mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% methanol / dichloromethane) to afford the title compound as a white solid (480 mg, 67.2% yield). LCMS (ESI): m / z [M+H]+calcd for C32H38N4O4: 543.29, found 543.55.

[0328] Step 5: Preparation of benzyl (l-(5-(4-(2,6-diazaspiro[3.4]octan-2-yl)phenyl)pyridin-3- yl)ethyl)carbamate

[0329] To a stirred solution of tert-butyl 2-(4-(5-(l-(((benzyloxy)carbonyl)amino)ethyl)pyridin-3- yl)phenyl)-2,6-diazaspiro[3.4]octane-6-carboxylate (400 mg, 0.737 mmol, 1 equiv) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 1 h. Diethyl ether was then added to precipitate the product, which was collected by filtration and used without further purification (260 mg, 71.7%). LCMS (ESI): m / z [M+H]+calcd for C27H30N4O2: 443.24, found 443.15.

[0330] Step 6: Preparation of benzyl (l-(5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)- 2,6-diazaspiro[3.4]octan-2-yl)phenyl)pyridin-3-yl)ethyl)carbamate

[0331] To a stirring solution benzyl (l-(5-(4-(2,6-diazaspiro[3.4]octan-2-yl)phenyl)pyridin-3- yl)ethyl)carbamate (200 mg, 0.452 mmol, 1 equiv) in DMF (5 mL) was added Intermediate 1 (93 mg, 0.452 mmol, 1 equiv), HATU (257 mg, 0.678 mmol, 1.5 equiv) and N,N- diisopropylethylamine (233 mg, 1.808 mmol, 4 equiv). The reaction mixture was stirred for 1 h at room temperature, then was quenched by addition of water (5 mL). The resulting mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% methanol / di chloromethane) to afford the title compound as a white solid (220 mg, 70.8% yield). LCMS (ESI): m / z [M+H]+calcd for C37H41N7O3: 632.33, found 632.25.

[0332] Step 6: Preparation of (R)-(2-(4-(5-(l-aminoethyl)pyridin-3-yl)phenyl)-2,6- diazaspiro [3.4] octan-6-yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone and (S)-(2-(4- (5-(l-aminoethyl)pyridin-3-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)(2- (cyclopentylamino)pyrimidin-5-yl)methanone (Compound 14 and Compound 15)

[0333] To a stirring solution benzyl (l-(5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)phenyl)pyridin-3-yl)ethyl)carbamate (200 mg, 0.317 mmol, 1 equiv) in hexafluoroisopropanol (10 mL) was added aluminum trichloride (422 mg, 3.17 mmol, 10 equiv), and the resulting mixture was stirred at room temperature for 1 h. The reaction was quenched by addition of water (5 mL), then was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% methanol / dichloromethane), then enantiomers were separated by chiral HPLC (CHIRALPAK IC column, 1 : 1 :2 ethanol / dichloromethane / methyl tert-butyl ether with 0.5% ammonia) Compound 14 (second eluting isomer) was isolated as a white solid (13.9 mg, 17.5% yield). LCMS (ESI): m / z [M+H]+calcd for C29H35N7O: 498.29, found 298.20. 'H NMR (500 MHz, DMSO-d6) δ 8.65 (d, J = 7.7 Hz, 1H), 8.51 (d, J= 24.0 Hz, 2H), 8.35 - 8.45 (m, 1H), 7.85 - 8.00 (m, 1H), 7.77 (dd, J= 11.3, 7.2 Hz, 1H), 7.42 - 7.61 (m, 2H), 6.55 (dd, J= 20.7, 8.1 Hz, 2H), 4.19 (t, J = 6.8 Hz, 1H), 4.07 - 4.14 (m, 1H), 3.74 - 3.90 (m, 5H), 3.62 - 3.71 (m, 2H), 3.49 - 3.57 (m, 1H), 2.15 (t, J= 6.9 Hz, 2H), 1.81 - 1.94 (m, 2H), 1.67 (s, 2H), 1.43 - 1.57 (m, 4H), 1.28 - 1.39 (m, 3H).

[0334] Compound 15 (first eluting isomer) was isolated as a white solid (139 mg, 17.5% yield). LCMS (ESI): m / z [M+H]+calcd for C29H35N7O: 498.29, found 498.20. 'H NMR (500 MHz, DMSO-d6) δ 8.62 - 8.67 (m, 1H), 8.51 (d, J= 24.2 Hz, 2H), 8.41 (d, J= 22.4 Hz, 1H), 7.85 - 8.01 (m, 1H), 7.73 - 7.80 (m, 1H), 7.39 - 7.60 (m, 2H), 6.55 (dd, J= 20.8, 8.0 Hz, 2H), 4.19 (t, J = 6.8 Hz, 1H), 4.09 (d, J = 6.4 Hz, 1H), 3.74 - 3.91 (m, 5H), 3.62 - 3.72 (m, 2H),3.49 - 3.58 (m, 1H), 2.15 (t, J = 6.9 Hz, 2H), 1.82 - 1.94 (m, 2H), 1.67 (s, 2H), 1.43 - 1.59 (m, 4H), 1.30 - 1.38 (m, 3H).

[0335] Synthesis of Compound 16: 2-(6-(2-(((1R,3R)-3-fluorocyclopentyl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)-5-(pyrimidin-5-yl)benzonitrile Scheme 20

[0336] Step 1: Preparation of 5-bromo-2-(6-(2-((1R,3R )-3-fluorocyclopentyl)amino)pyrimidine- 5-carbonyl)-2,6-diazaspiro [3.4] octan-2-yl)benzonitrile

[0337] To a stirring solution Intermediate 4 (500 mg, 1.57 mmol, 1 equiv) in acetonitrile (5 mL) was added of 5-bromo-2-fluorobenzonitrile (313 mg, 1.57 mmol, 1 equiv) and N,N- diisopropylethylamine (809 mg, 6.26 mmol, 4 equiv). The mixture was stirred for 5 h at 70° C, then was cooled to room temperature. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound (470 mg, 60.1% yield). LCMS (ESI): m / z [M+H]+calcd for C23H24BrFNeO: 499.12, found 499.15.

[0338] Step 2: Preparation of 2-(6-(2-((1R,3R )-3-fluorocyclopentyl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)-5-(pyrimidin-5-yl)benzonitrile (Compound 16)

[0339] To a stirred solution of 5-bromo-2-(6-(2-((1R,3R)-3-fluorocyclopentyl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)benzonitrile (150 mg, 0.300 mmol, 1 equiv) in 1,4- dioxane (2 mL) and water (0.2 mL) was added of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrimidine (37 mg, 0.300 mmol, 1 equiv), tetrakis(triphenylphosphine)palladium(0) (69 mg, 0.060 mmol, 0.2 equiv), and potassium carbonate (83 mg, 0.600 mmol, 2 equiv). The reaction mixture was stirred under nitrogen at 90 °C for 16 h, then was stirred overnight at room temperature. The reaction mixture was quenched by addition of water (5 mL), then the resulting mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (XBridge Prep OBD Cl 8 Column, 32-50% acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a white solid (55.1 mg, 36.7% yield). LCMS (ESI): m / z [M+H]+calcd for C27H27FN8O2: 499.23, found 499 20 'H NMR (300 MHz DMSO-d6) 5 9 11 (s 3H) 8 54 (s 2H) 8 04 (s 1H) 7 91 (s 1H) 1H), 4.17 (s, 4H), 3.87 (s, 1H), 3.71 (s, 2H), 3.55 (s, 1H), 1.94 - 2.33 (m, 5H), 1.67 - 1.94 (m, 2H), 1.51 - 1.62 (m, 1H).19F NMR (282 MHz, DMSO-d6) δ -165.34, -167.26.

[0340] Synthesis of Compound 18: (2-(5-fluoro-6-(pyrimidin-5-yl)pyridin-3-yl)-2,6- diazaspiro[3.4]octan-6-yl)(2-((1R,3R )-3-fluorocyclopentyl)amino)pyrimidin-5- yl)methanone

[0341] Step 1: Preparation of 5-(5-bromo-3-fluoropyridin-2-yl)pyrimidine

[0342] To a solution of 2, 5 -dibromo-3 -fluoropyridine (0.5 g, 1.96 mmol, 1 equiv) and 5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (0.40 g, 1.96 mmol, 1 equiv) in dioxane (5 mL) and water (1 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.45 g, 0.392 mmol, 0.2 equiv) and potassium carbonate (0.54 g, 3.92 mmol, 2 equiv). The reaction mixture was stirred at 90 °C under for 16 h under nitrogen. The reaction mixture was then cooled to room temperature and quenched by addition of water (10 mL), then was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (1-10% methanol / di chloromethane) to afford the title compound as a white solid (0.41 g, 82.3% yield). LCMS (ESI): m / z [M+H]+calcd for C9H5BrFN3: 253.97, found 253.95.

[0343] Step 2: Preparation of (2-(5-fluoro-6-(pyrimidin-5-yl)pyridin-3-yl)-2,6- diazaspiro[3.4]octan-6-yl)(2-((1R,3R )-3-fluorocyclopentyl)amino)pyrimidin-5- yl)methanone (Compound 18)

[0344] To a solution of Intermediate 4 (100 mg, 0.313 mmol, 1 equiv) and 5-(5-bromo-3- fluoropyridin-2-yl)pyrimidine (79 mg, 0.313 mmol, 1 equiv) in dioxane (3 mL) was added RuPhos (14 mg, 0.031 mmol, 0.1 equiv), RuPhos-Pd-G3 (26 mg, 0.031 mmol, 0.1 equiv) and cesium carbonate (204 mg, 0.626 mmol, 2 equiv). The reaction mixture was stirred under nitrogen at 90 °C for 16 h. The reaction mixture was then cooled to room temperature and was quenched by addition of water (20 mL), then was extracted with ethyl acetate. The combined organic layers were then dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (1-10% methanol / di chloromethane) to afford the title C25H26F2N8O: 493.22, found 493.20. 'H NMR (300 MHz, DMSO-d6) δ 9.16 (d, J= 6.0 Hz, 3H), 8.54 (s, 2H), 7.72 - 7.92 (m, 2H), 6.81 - 7.02 (m, 1H), 5.22 (d, J= 54.0 Hz, 1H), 4.34 - 4.55 (m, 1H), 3.88 - 4.11 (m, 4H), 3.85 (s, 1H), 3.71 (s, 2H), 3.54 (s, 1H), 1.95 - 2.37 (m, 5H), 1.66 - 1.92 (m, 2H), 1.47 - 1.65 (m, 1H).19F NMR (282 MHz, DMSO-d6) δ -123.39, -165.36.

[0345] Synthesis of Compound 21: 3-(4-(6-(2-((1R,3R )-3-fluorocyclopentyl)amino)pyrimidine-

[0346] 5-carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)phenyl)pyrrolidin-2-one

[0347] Preparation of 3-(4-(6-(2-((1R,3R )-3-fluorocyclopentyl)amino)pyrimidine-5-carbonyl)- 2,6-diazaspiro [3.4] octan-2-yl)phenyl)pyrrolidin-2-one (Compound 21)

[0348] To a solution of Intermediate 4 (133 mg, 0.41 mmol, 1 equiv) in dioxane (4 mL) was added 3-(4-bromophenyl)pyrrolidin-2-one (100 mg, 0.41 mmol, 1 equiv), XPhos (20 mg, 0.042 mmol, 0.1 equiv), XPhos-Pd-G3 (35 mg, 0.044 mmol, 0.1 equiv) and cesium carbonate (408 mg, 1.25 mmol, 3 equiv). The mixture was stirred for 4 h at 90 °C under a nitrogen atmosphere, then was cooled to room temperature. The reaction was quenched with water (10 mL) at 0 °C, then the resulting mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (XB ridge Prep Cl 8 OBD Column, 19-44% acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a white solid (19.2 mg, 9.6 %). LCMS (ESI): m / z [M+H]+calcd for C26H31FN6O2: 479.25, found 479.25.1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 2H), 7.80 (d, J= 7.4 Hz, 1H), 7.70 (s, 1H), 7.03 (s, 2H), 6.40 (s, 2H), 5.22 (d, J= 54.0 Hz, 1H), 4.46 (q, J= 13 Hz, 1H), 3.61 - 3.80 (m, 7H), 3.50 - 3.58 (m, 2H), 3.25 - 3.28 (m, 2H), 2.24 - 2.45 (m, 1H), 1.98 - 2.21 (m, 6H), 1.65 - 1.89 (m, 2H), 1.45 - 1.65 (m, 1H).19F NMR (282 MHz, DMSO-d6) δ -167.27.

[0349] Synthesis of Compound 22: 3-(4-(6-(2-((1R,3R )-3-fluorocyclopentyl)amino)pyrimidine- 5-carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)phenyl)pyridazine 1-oxide

[0350] Step 1: Preparation of 3-(4-bromophenyl)pyridazine

[0351] To a stirred solution of 4-bromophenylboric acid (1 g, 4.98 mmol, 1 equiv) in dioxanae (20mL) and water (2 mL) was added 3-bromopyridazine (0.79 g, 4.98 mmol, 1 equiv), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.36 g, 0.498 mmol, 0.1 equiv) and potassium carbonate (2.06 g, 14.9 mmol, 3 equiv). The reaction mixture was stirred for 3 h at 80 °C under nitrogen, then was cooled to room temperature. The reaction was then quenched by addition of water (10 mL), and the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0- 10% methanol / dichloromethane) to afford the title compound as a white solid (600 mg, 51.2% yield). LCMS (ESI): m / z [M+H]+calcd for CioH7BrN2: 234.98, found 235.07.

[0352] Step 2: Preparation of 3-(4-bromophenyl)pyridazin-l-ium-l-olate

[0353] To a solution of 3-(4-bromophenyl)pyridazine (500 mg, 2.13 mmol, 1 equiv) in dichloromethane (5 mL) was added 85% meta-chloroperoxybenzoic acid (1.29 g, 6.38 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was quenched by addition of saturated sodium bicarbonate solution (10 mL) and extracted with dichloromethane (20 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (0-40% acetonitrile / water) to afford the title compound as a white solid (350 mg, 65.5% yield).

[0354] Step 3: Preparation of 3-(4-(6-(2-(((lR,3R)-3-fluorocyclopentyl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)phenyl)pyridazine 1-oxide (Compound 22)

[0355] To a stirred solution of 3-(4-bromophenyl)pyridazin-l-ium-l-olate (200 mg, 0.797 mmol, 1 equiv) in dioxane (20 mL) was added Intermediate 4 (254 mg, 0.797 mmol, 1 equiv), BrettPhos (171mg 0 319 mmol 0 4 equiv) BrettPhos Pd G3 (144 mg 0 159 mmol 0 2 equiv) and cesium carbonate (778 mg, 2.391 mmol, 3 equiv). The reaction mixture was stirred for 2 h at 100 °C under nitrogen, then was cooled to room temperature. The reaction mixture was quenched by addition of water (10 mL), and the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to afford the title compound as a white solid (58.2 mg, 14.9% yield). LCMS (ESI): m / z [M+H]+calcd for C26H28FN7O2: 490.23, found 490.25. 'HNMR (300 MHz, DMSO- de) δ 8.54 (s, 2H), 8.16 (d, J= 6.2 Hz,l H), 7.77-7.90 (m, 4H), 7.68 (d, J= 8.3 Hz, 1H), 6.5 - 6.57 (m, 2H), 5.10 - 5.34 (s, 1H), 4.46 (q, J= 7.2 Hz, 1H), 3.80 - 3.95 (s, 5H), 3.52 - 3.72 (m, 3H) 2.17 (t, J= 6.9Hz, 5H), 2.08 (s, 1H), 1.62 - 1.92 (m,2H), 1.55 - 1.58 (m, 1H).19F NMR (282 MHz, DMSO-d6) 5 -167.28.

[0356] Synthesis of Compound 23: 3-(6-(2-(((H?,3R)-3-fluorocyclopentyl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)-6-(LH-pyrazol-4-yl)pyrazine-2-carbonitrile

[0357] Step 1: Preparation of 6-bromo-3-(6-(2-(((lR,31?)-3-fluorocyclopentyl)amino)pyrimidine- 5-carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)pyrazine-2-carbonitrile

[0358] To a solution of Intermediate 4 (500 mg, 1.57 mmol, 1 equiv) and 6-bromo-3-chloropyrazine- 2-carbonitrile (308 mg, 1.41 mmol, 0.90 equiv) in acetontirle (15 mL), was added N,N- diisopropylethylamine (609 mg, 4.71 mmol, 3.01 equiv). The mixture was stirred at 80 °C for 2 h, then was cooled to room temperature. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (30-80% ethyl acetate / petroleum ether) to afford the title compound as a yellow solid (600 mg, 76.4% yield). LCMS (ESI): m / z [M+H]+calcd for C2iH22BrFN8O: 501.11, found 501.05.

[0359] Step 2: Preparation of 3-(6-(2-(((1R,3R)-3-fluorocyclopentyl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)-6-( (tetr:i1h-ydro-2 / / -pyran-2-yl)-l / / -pyrazol-4- yl)pyrazine-2-carbonitrile

[0360] To a solution of 6-bromo-3-(6-(2-((1R,3R)-3-fluorocyclopentyl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)pyrazine-2-carbonitrile (300 mg, 0.598 mmol, 1 equiv) and 1(-tetrahydro-2J / -pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-UT- pyrazole (250 mg, 0.897 mmol, 1.50 equiv) in dioxane (10 mL) and water (1 mL) was added potassium carbonate (249 mg, 1.80 mmol, 3.01 equiv) and tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmol, 0.10 equiv). The mixture was stirred at 110 °C for 2 h under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (1-10% methanol / dichloromethane) to afford the title compound as a yellow solid (290 mg, 84.6% yield). LCMS (ESI): m / z [M+H]+calcd for C29H33FN10O2: 573.28, found 573.45.

[0361] Step 3: Preparation of 3-(6-(2-((1R,3R )-3-fluorocyclopentyl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)-6-( l / / -pyr:izol-4-yl)pyrazine-2-carbonitrile (Compound 23)

[0362] To a stirred solution of 3-(6-(2-((1R,3R)-3-fluorocyclopentyl)amino)pyrimidine-5-carbonyl)- 2,6-diazaspiro[3.4]octan-2-yl)-6-(l-(tetrahydro-2J / -pyran-2-yl)-U / -pyrazol-4-yl)pyrazine-2- carbonitrile (200 mg, 0.349 mmol, 1 equiv) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL), and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness under reduced pressure and the residue was purified by preparative HPLC (YMC-Actus Triart Cl 8 ExRS column, 16-46% acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a yellow solid (96.5 mg, 56.5% yield). LCMS (ESI): m / z [M+H]+calcd for C24H25FN10O: 489.22, found 489.30. 'HNMR (300 MHz, DMSO-cfj 5 13.13 (s, 1H), 8.76 - 8.82 (m, 1H), 8.54 (s, 2H), 7.98 - 8.34 (m, 2H), 7.82 (d, J = 7.4 Hz, 1H), 5.10 - 5.34 (m, 1H), 4.37 - 4.55 (m, 1H), 4.18 - 4.34 (m, 4H), 3.86 (s, 1H), 3.51 - 3.74 (m, 3H), 2.25 - 2.02 (m, 5H), 1.69 - 1.92 (m, 2H), 1.50 - 1.65 (m, 1H).19F NMR (282 MHz, DMSO-d6) δ -167.29.

[0363] Synthesis of Compound 24: 4-fluoro-2-(6-(2-(((1R,3R)-3- fluorocyclopentyl)amino)pyrimidine-5-carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)-5-(lEZ- pyrazol-4-yl)benzonitrile

[0364] Step 1: Preparation of 2-chloro-4-fluoro-5-[l-(oxan-2-yl)pyrazol-4-yl]benzonitrile

[0365] To a solution of (1o-xan-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (500 mg, 1.798 mmol, 1 equiv) in dioxane (5 mL) and water (0.5 mL) was added 5-bromo-2-chloro-

[0366] 4-fluorobenzonitrile (506 mg, 2.157 mmol, 1.20 equiv), potassium carbonate (571 mg, 4.134 mmol, 2.30 equiv) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (132 mg, 0.180 mmol, 0.10 equiv). The resulting mixture was stirred for 2 h at 90 °C under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-80% ethyl acetate / petroleum ether) to afford the title compound as a brown solid (320 mg, 58.2% yield). LCMS (ESI): m / z [M+H]+calcd for C15H13CIFN3O: 306.07, found 306.05.

[0367] Step 2: Preparation of 4-fluoro-2-[6-(2-{[1R,3R )-3-fluorocyclopentyl]amino}pyrimidine-

[0368] 5-carbonyl)-2,6-diazaspiro[3.4]octan-2-yl]-5-[l-(oxan-2-yl)pyrazol-4-yl]benzonitrile

[0369] A solution of 2-chloro-4-fluoro-5-[l-(oxan-2-yl)pyrazol-4-yl]benzonitrile (150 mg, 0.491 mmol, 1 equiv) in dioxane (5 mL) was added Intermediate 4 (235 mg, 0.736 mmol, 1.5 equiv), cesium carbonate (368 mg, 1.129 mmol, 2.3 equiv), RuPhos (23 mg, 0.049 mmol, 0.1 equiv), and RuPhos-Pd-G3 (41 mg, 0.049 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 100 °C under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% methanol / dichloromethane) to afford the title compound as a brown solid (280 mg, 96.9% yield). LCMS (ESI): m / z [M+H]+calcd for C31H34F2N8O2: 589.28, found 589.35.

[0370] Step 3: Preparation of 4-fluoro-2-(6-(2-((1R,3R )-3-fluorocyclopentyl)amino)pyrimidine- 5-carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)-5-( 1 / / -pyrazol-4-yl)benzonitrile (Compound A solution of 4-fluoro-2-[6-(2-{[(lA,3A)-3-fluorocyclopentyl]amino}pyrimidine-5-carbonyl)- 2,6-diazaspiro[3.4]octan-2-yl]-5-[l-(oxan-2-yl)pyrazol-4-yl]benzonitrile (200 mg, 0.340 mmol, 1 equiv) was dissolved in TFA (1 mL) and DCM (2 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated to dryness and purified by preparative HPLC (XBridge Prep OBD column, 32-52% acetonitrile / water with 0.1% formic acid) to afford the title compound as a white solid (77 mg, 45.0% yield). LCMS (ESI): m / z [M+H]+calcd for C26H26F2N8O: 505.22, found 505.20. 'HNMR (300 MHz, DMSO- de) δ 8.53 (s, 2H), 7.95 (d, J = 16.1 Hz, 3H), 7.81 (d, J = 7.5 Hz, 1H), 6.49 (d, J = 13.0 Hz, 1H), 5.05 - 5.38 (m, 1H), 4.38 - 4.59 (m, 1H), 4.05 - 4.19 (m, 4H), 3.80 - 3.90 (m, 1H), 3.77 - 3.61 (m, 1H), 3.50 - 3.59 (m, 2H), 1.97 - 2.30 (m, 5H), 1.68 - 1.96 (m, 2H), 1.51 - 1.66 (m, 1H).19F NMR (282 MHz, DMSO-d6) δ -105.612, 167.305.

[0371] Synthesis of Compound 25: 2-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro [3.4] octan-2-yl)phenyl)pyrimidin-4(lH)-one

[0372] Step 1: Preparation of 2-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro [3.4] octan-2-yl)phenyl)pyrimidin-4(lH)-one (Compound 25)

[0373] To a solution of Intermediate 6 (100 mg, 0.199 mmol, 1 equiv) and 2-chloro-U / -pyrimidin- 4-one (25 mg, 0.199 mmol, 1 equiv) in dioxane and water (1 mL) was added XPhos (18 mg, 0.040 mmol, 0.2 equiv), XPhos-Pd-G3 (16 mg, 0.020 mmol, 0.1 equiv) and potassium carbonate (82 mg, 0.597 mmol, 3 equiv). The mixture was stirred at 90 °C for 2 h under nitrogen, then was cooled to room temperature. The reaction mixture was then quenched with water (30 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% methanol / dichlorom ethane) and further purified by preparative HPLC (YMC Triart C18 Column, acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a white solid (51.9 mg, 54.9% yield). LCMS (ESI): m / z [M+H]+calcd for C26H29N7O2: 472.24, found 472.20.1H NMR (500 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.51 (s, 2H), 7.97 - 8.07 (m, 2H), 7.94 (s, 1H), 7.66 - 7.75 (m, 1H), 6.40 - 6.56 (m, 2H), 6.13 (d, J= 6.3 Hz, 1H), 4.20 (d, J= 7.1 Hz, 1H), 3.93 - 4.01(m, 1H), 3.78 - 3.92(m, 4H), 3.68 (s, 2H), 3.48 - 3.58 (m, 1H), 2.16 (t, J= 6.9 Hz, 2H), 1.82 - 1.94 (m, 2H), 1.61 - 1.73 (m, 2H), 1.45 - 1.58 (m, 4H).

[0374] Synthesis of Compound 26: 5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro [3.4] octan-2-yl)phenyl)imidazolidine-2, 4-dione

[0375] Step 1: Preparation of 5-(4-bromophenyl)imidazolidine-2, 4-dione

[0376] To a stirred solution of O-phenyl carbamate (1.8 g, 13.1 mmol, 1 equiv) in anhydrous THF (20 mL) was added methyl 2-amino-2-(4-bromophenyl)acetate (3.52 g, 14.4 mmol, 1.1 equiv) and triethylamine (10 mL). The reaction mixture was stirred at 90 °C for 12 h, then was cooled to room temperature. The reaction mixture was then quenched with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petr oleum ether) to afford the title compound as a brown oil (450 mg, 13.5% yield).

[0377] Step 2: Preparation of 5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro [3.4] octan-2-yl)phenyl)imidazolidine-2, 4-dione (Compound 26)

[0378] To a stirred solution of Intermediate 3 (300 mg, 0.995 mmol, 1 equiv) in anhydrous 1,4- dioxane (5 mL) was added 5-(4-bromophenyl)imidazolidine-2, 4-dione (254 mg, crude) and cesium carbonate (973 mg, 2.985 mmol, 3 equiv) followed by XPhos (46 mg, 0.100 mmol, 0.1 equiv) and XPhos-Pd-G3 (83 mg, 0.100 mmol, 0.1 equiv). The reaction mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere, then was cooled to room temperature. The reaction mixture was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-15% methanol / dichlorom ethane) and further purified by preparative HPLC (XBridge Prep Cl 8 title compound as a white solid (2.2 mg, 0.5% yield). LCMS (ESI): m / z [M+H]+calcd for C25H29N7O3: 476.24, found 476.25. 'H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.51 (s, 2H), 8.26 (s, 1H), 7.72 (s, 1H), 7.07 - 7.12 (m, 2H), 6.41 - 6.48 (m, 2H), 4.99 (s, 1H), 4.20 (d, J = 7.8 Hz, 1H), 3.73 - 3.81 (m, 4H), 3.65 (s, 2H), 3.48 - 3.56 (m, 2H), 2.13 (t, J = 6.9 Hz, 2H), 1.89 (s, 2H), 1.68 (s, 2H), 1.48 - 1.54 (m, 4H).

[0379] Synthesis of Compound 27: 4-(4-(6-(2-((1R,3R )-3-fluorocyclopentyl)amino)pyrimidine-

[0380] 5-carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)phenyl)oxazolidin-2-one

[0381] Intermediate 4

[0382] Step 1: Preparation of 4-(4-(6-(2-(((1R,3R)-3-fluorocyclopentyl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro [3.4] octan-2-yl)phenyl)oxazolidin-2-one (Compound 27)

[0383] To a solution of Intermediate 4 (110 mg, 0.34 mmol, 1 equiv) in dioxane (4 mL) was added 4-(4-bromophenyl)-l,3-oxazolidin-2-one (84 mg, 0.35 mmol, 1 equiv), XPhos (16 mg, 0.034 mmol, 0.1 equiv), XPhos-Pd-G3 (27 mg, 0.034 mmol, 0.1 equiv) and cesium carbonate (332 mg, 1.02 mmol, 2.96 equiv). The mixture was stirred for 4 h at 90 °C under a nitrogen atmosphere, then was cooled to room temperature. The reaction was then quenched with water (10 mL) at 0°C. The resulting mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (XB ridge Prep Shield RP18 OBD Column, 15-45% acetonitrile / water with 10 mM ammonium bicarbonate and 0.5% ammonia) to afford the title compound as a white solid (38 mg, 22.9% yield). LCMS (ESI): m / z [M+H]+calcd for C25H29FN6O3: 481.23, found 481.20. 'H NMR (300 MHz, DMSO-d6) 5 8.53 (s, 2H), 8.03 (s, 1H), 7.81 (d, J= 7.3 Hz, 1H), 7.15 (s, 2H), 6.46 (s, 2H), 5.22 (d, J= 54.0 Hz, 1H), 4.75 - 4.85 (m, 1H), 4.55 - 4.65 (m, 1H), 4.46 (q, J= 7.3 Hz, 1H), 3.93 (s, 1H), 3.50 - 3.85 (m, 7H), 3.45 (s, 1H), 2.00 - 2.30 (m, 5H), 1.60 - 1.90 (m, 2H), 1.51 - 1.65 (m, 1H).

[0384] Synthesis of Compound 29: 2-(6-(2-(((1R,3R)-3-fluorocyclopentyl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)-5-( lH-pyrazol-4-yl)nicotinonitrile

[0385] Step 1: Preparation of 2-chloro-5-(l-(tetr:ihydro-2 / / -pyran-2-yl)-l / / -pyrazol-4- yl)nicotinonitrile

[0386] To a solution of 2-chloro-5-iodopyridine-3-carbonitrile (1 g, 3.78 mmol, 1 equiv) in dioxane (15 mL) and water (1.5 mL) was added 3-(4-bromo-3-chlorophenyl)pyrazin-l-ium-l-olate (268 mg, 0.939 mmol, 1 equiv), tetrakis(triphenylphosphine)palladium(0) (0.44 g, 0.378 mmol, 0.1 equiv) and potassium carbonate (1.57 g, 11.3 mmol, 3 equiv). The mixture was stirred for 3 h at 95 °C under a nitrogen atmosphere, then was cooled to room temperature. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-15% methanol / di chloromethane) to afford the title compound as a yellow solid (500 mg, 45.7% yield). LCMS (ESI): m / z [M+H]+ calcd for C14H13CIFN7O2: 289.08, found 289.10.

[0387] Step 2: Preparation of 2-(6-(2-((1R,3R )-3-fluorocyclopentyl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)-5-( (tetr:i1h-ydro-2 / / -pyran-2-yl)-l / / -pyrazol-4- yl)nicotinonitrile

[0388] To a solution of 2-chloro-5-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)nicotinonitrile (250 mg, 0.866 mmol, 1 equiv) in acetonitrile (5 mL) was added Intermediate 4 (276 mg, 0.866 mmol, 1 equiv) and N,N-diisopropylethylamine (335 mg, 2.598 mmol, 3 equiv). The mixture was stirred for 4 h at 70 °C, then was cooled to room temperature. The reaction was quenched with water (10 mL), and the resulting mixture was extracted with ethyl acetate (3 x20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0- 15% methanol / dichloromethane) to afford the title compound as a yellow solid (170 mg, 34.3% yield). LCMS (ESI): m / z [M+H]+ calcd for C30H34FN9O2: 572.29, found 572.20.

[0389] Step 3: Preparation of 2-(6-(2-((1R,3R )-3-fluorocyclopentyl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)-5-( l / / -pyrazol-4-yl)nicotinonitrile (Compound To a solution of 2-(6-(2-((1R,3R)-3-fluorocyclopentyl)amino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)-5-(l-(tetrahydro-2J / -pyran-2-yl)-U / -pyrazol-4-yl)nicotinonitrile (170 mg, 0.297 mmol, 1 equiv) in dichloromethane (3 mL) was added trifluoroacetic acid (1.5 mL, 0.013 mmol, 0.04 equiv) at 0 °C. The mixture was stirred for 1 h at room temperature, then the mixture was concentrated to dryness. The residue was purified by preparative HPLC (Xselect CSH Phenyl Hexy Column, 28-52% acetonitrile / water with 0.1% formic acid) to afford the title compound as a yellow solid (81.4 mg, 56.1% yield). LCMS (ESI): m / z [M+H]+calcd for C25H26FN9O: 488.23, found 488.20. 'H NMR (300 MHz, DMSO-d6) δ 8.62 - 8.68 (m, 1H), 8.54 (s, 2H), 8.24 (s, 1H), 8.08 (s, 2H), 7.83 (d, J= 13 Hz, 1H), 5.10 - 5.34 (m, 1H), 4.46 - 4.52 (m, 2H), 4.39 - 4.46 (m, 2H), 4.21 - 4.28 (m, 1H), 4.12 - 4.20 (m, 1H), 3.85 (s, 1H), 3.70 (s, 1H), 3.51 - 3.57 (m, 1H), 2.14 - 2.32 (m, 4H), 2.04 - 2.09 (m, 1H), 1.81 - 1.92 (m, 1H), 1.66 - 1.81 (m, 1H), 1.48 - 1.61 (m, 1H).19F NMR (282 MHz, DMSO-d6) δ -167.277.

[0390] Synthesis of Compound 31: 3-(5-fluoro-6-(6-(2-(((1R,3R)-3- fluorocyclopentyl)amino)pyrimidine-5-carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)pyridin- 3-yl)pyrazine 1-oxide

[0391] Step 1: Preparation of (5-fluoro-6-(6-(2-(((1R,3R)-3- fluorocyclopentyl)amino)pyrimidine-5-carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)pyridin- 3-yl)boronic acid

[0392] To a stirring solution 2,3-difluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (0.23 g, 0.939 mmol, 1 equiv) in acetonitrile (3 mL) was added Intermediate 4 (0.3 g, 0.939 mmol, 1.00 equiv) and N,N-diisopropylethylamine (0.36 g, 2.817 mmol, 3 equiv) and the mixture was stirred at 70 °C for 3 h. The mixture was then cooled to room temperature, quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petr oleum ether) to afford the title compound (0.18 g, 41.8% yield). LCMS (ESI): m / z [M+H]+calcd for C21H25BF2N6O: 459.20, found 459.10.

[0393] Step 2: Preparation of 3-(5-fluoro-6-(6-(2-(((1R,3R)-3- fluorocyclopentyl)amino)pyrimidine-5-carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)pyridin- 3-yl)pyrazine 1-oxide (Compound 31)

[0394] To a stirred solution of (5-fluoro-6-(6-(2-(((1R,3R)-3-fluorocyclopentyl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)pyridin-3-yl)boronic acid (180 mg, 0.393 mmol, 1 equiv) in dioxane (2 mL) and water (0.2 mL) was added of 3 -chloropyrazine 1-oxide (51 mg, 0.393 mmol, 1 equiv), potassium carbonate (108.57 mg, 0.786 mmol, 2 equiv) and tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.079 mmol, 0.2 equiv). The reaction mixture was stirred under nitrogen at 90 °C for 16 h, then was stirred overnight at room temperature. The reaction mixture was quenched by addition of water (5 mL), then was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (XBridge Prep OBD C18 Column, 32-50% acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a yellow solid (57.2 mg, 28.6% yield). LCMS (ESI): m / z [M+H]+calcd for C25H26F2N8O2: 509.22, found 509.15. 'H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.68 (d, J= 10.8 Hz, 1H), 8.44 - 8.51 (m, 3H), 8.18 - 8.24 (m, 1H), 8.06 (t, J= 11.8 Hz, 1H), 7.81 (d, J= 7.5 Hz, 1H), 5.21 (d, J= 28.0 Hz, 1H), 4.39 - 4.49 (m, 1H), 4.05 - 4.25 (m, 4H), 3.84 (s, 1H), 3.68 (d, J= 9.1 Hz, 2H), 3.53 (t, J= 6.9 Hz, 1H), 2.12 - 2.27 (m, 3H), 2.02 - 2.12(m, 2H), 1.69 - 1.89 (m, 2H), 1.54 - 1.56 (s, 1H).19F NMR (377 MHz, DMSO-d6) δ -139.94, -140.21 (d, J= 11.2 Hz), -167.25 (d, J= 7.4 Hz).

[0395] Synthesis of Compound 32: 2-fluoro-6-(6-(2-(((l / ?,3 / ?)-3- fluorocyclopentyl)amino)pyrimidine-5-carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)-3-(lH- pyrazol-4-yl)benzonitrile

[0396] Scheme 31

[0397] Step 1: Preparation of 6-chloro-2-niioro-3-(l-(tetr:ihydro-2 / / -pyran-2-yl)-l / / -pyrazol-4- yl)benzonitrile

[0398] To a stirred solution of 3-bromo-6-chloro-2-fluorobenzonitrile (600 mg, 2.56 mmol, 1 equiv) in 1,4-dioxane (10 mL) and water (1 mL) was added (tetrahydro1--2H-pyran-2-yl)-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-17 / -pyrazole (712 mg, 2.56 mmol, 1 equiv) and potassium carbonate (1061 mg, 7.677 mmol, 3 equiv) followed by [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (209 mg, 0.256 mmol, 0.1 equiv). The reaction mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere, then was cooled to room temperature. The reaction was then quenched by water (20 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-15% methanol / dichloromethane) to afford the title compound as a yellow oil (600 mg, 76.7% yield). LCMS (ESI): m / z [M+H]+calcd for C15H13CIFN3O: 306.07, found 306.05.

[0399] Step 2: Preparation of 2-fluoro-6-(6-(2-(((1R,3R)-3-fluorocyclopentyl)amino)pyrimidine- 5-carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)-3-(l-(tetrahydro-2Z / -pyran-2-yl)-lZ / -pyrazol-

[0400] 4-yl)benzonitrile

[0401] To a stirred solution of 6-chloro-2-fluoro-3-( l -(tetrahydro-27 / -pyran-2-yl)- l7 / -pyrazol-4- yl)benzonitrile (200 mg, 0.626 mmol, 1 equiv) in anhydrous 1,4-dioxane (10 mL) was added Intermediate 4 (211 mg, 0.689 mmol, 1.1 equiv) and cesium carbonate (612 mg, 1.878 mmol, 3 equiv) followed by RuPhos (30 mg, 0.063 mmol, 0.1 equiv) and RuPhos-Pd-G3 (52 mg, 0.063 mmol, 0.1 equiv). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched by water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% methanol / dichloromethane) to afford the title compound as a yellow solid (250 mg, 67.8% yield). LCMS (ESI): m / z [M+H]+calcd for C31H34F2N8O2: 589.28, found 589.35.

[0402] Step 3: Preparation of 2-fluoro-6-(6-(2-((1R,3R )-3-fluorocyclopentyl)amino)pyrimidine-

[0403] 5-carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)-3-( 1 / / -pyr:izol-4-yl)benzonitrile (Compound 32) To a stirred solution of 2-fluoro-6-(6-(2-((1R,3R)-3-fluorocyclopentyl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)-3-(l-(tetrahydro-2J / -pyran-2-yl)-U / -pyrazol-4- yl)benzonitrile (200 mg, 0.340 mmol, 1 equiv) in anhydrous dichloromethane (5 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 2 h, then was concentrated to dryness. The residue was purified by silica gel chromatography (0- 20% methanol / dichloromethane), then was purified further by preparative HPLC (XBridge Prep Shield RO 18 OBD Column, 25-40% (v / v) acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as off-white solid (62.6 mg, 36.5% yield). LCMS (ESI): m / z [M+H]+calcd for C26H26F2N8O: 505.22, found 505.20. 'HNMR (400 MHz, DMSO- de) δ 13.05 (s, 1H), 8.54 (s, 2H), 8.08 (s, 1H), 7.72 - 7.88 (m, 3H), 6.37 - 6.47 (m, 1H), 5.22 (d, J = 53.8 Hz, 1H), 4.41 - 4.52 (m, 1H), 4.05 - 4.22 (m, 4H), 3.51 - 3.89 (m, 4H), 2.19 - 2.25 (m, 3H), 2.03 - 2.14 (m, 2H), 1.70 - 1.90 (m, 2H), 1.50 - 1.61 (m, 1H).19F NMR (376 MHz, DMSO-d6) δ -111.11 (d, J = 32.6 Hz), -167.29.

[0404] Synthesis of Compound 34: 3-(3-chloro-4-(6-(2-(((1R,3R)-3- fluorocyclopentyl)amino)pyrimidine-5-carbonyl)-2,6-diazaspiro[3.4]octan-2- yl)phenyl)pyrazine 1-oxide

[0405] Step 1: Preparation of 3-(4-bromo-3-chlorophenyl)pyrazine 1-oxide

[0406] To a solution of 4-bromo-3-chlorophenylboronic acid (500 mg, 2.13 mmol, 1 equiv) in dioxane (6 mL) and water (0.6 mL) was added 3-bromopyrazin-l-ium-l-olate (371 mg, 2.13 mmol, 1 equiv), potassium carbonate (881 mg, 6.375 mmol, 3 equiv) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (155 mg, 0.213 mmol, 0.1 equiv). The mixture was stirred for 3 h at 90 °C under a nitrogen atmosphere, then was cooled to room temperature. The reaction was then quenched with water (10 mL) at 0 °C, and the resulting washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to afford the title compound as a yellow solid (300 mg, 49.4% yield). LCMS (ESI): m / z [M+H]+calcd for CioH6BrClN20: 284.94, found 284.80.

[0407] Step 2: Preparation of 3-(3-chloro-4-(6-(2-(((1R,3R)-3- fluorocyclopentyl)amino)pyrimidine-5-carbonyl)-2,6-diazaspiro[3.4]octan-2- yl)phenyl)pyrazine 1-oxide (Compound 34)

[0408] To a solution of Intermediate 4 (300 mg, 0.939 mmol, 1 equiv) in dioxane (6 mL) was added 3-(4-bromo-3-chlorophenyl)pyrazine 1-oxide (268 mg, 0.939 mmol, 1 equiv), RuPhos (43 mg, 0.094 mmol, 0.1 equiv), RuPhos-Pd-G3 (79 mg, 0.094 mmol, 0.1 equiv) and cesium carbonate (459 mg, 1.408 mmol, 1.5 equiv). The mixture was stirred for 12 h at 70 °C under a nitrogen atmosphere, then was cooled to room temperature. The reaction was then quenched with water (20 mL) and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-15% methanol / dichloromethane) to afford the title compound as a yellow solid (259.6 mg, 52.7% yield). LCMS (ESI): m / z [M+H]+calcd for C26H27CIFN7O2: 524.19, found 524.20. 'H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.47 - 8.57 (m, 3H), 8.19 (dd, J= 4.1, 1.5 Hz, 1H), 8.02 (s, 1H), 7.92 - 7.98 (m, 1H), 7.81 (d, J = 7.5 Hz, 1H), 6.62 - 6.68 (m, 1H), 5.10 - 5.35 (m, 1H), 4.37 - 4.55 (m, 1H), 4.06 - 4.19 (m, 4H), 3.65 - 3.86 (m, 3H), 3.52 - 3.57 (m, 1H), 2.12 - 2.27 (m, 4H), 2.08 - 2.11 (m, 1H), 2.05 - 2.08 (m, 1H), 1.67 - 1.94 (m, 2H).19F NMR (282 MHz, DMSO-d6) δ -167.285.

[0409] Synthesis of Compound 35: 3-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)phenyl)pyridazin-4(1H)-one

[0410] Scheme 33

[0411]

[0412] Step 1: Preparation of 3-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-4(lH)-one To a stirring solution of 3 -chloro- lJT-pyridazin-4-one (500 mg, 3.83 mmol, 1 equiv) in DMF (15 mL) was added a solution of sodium hydride (120 mg, 5.00 mmol, 1.31 equiv) at 0 °C. The mixture was stirred at room temperature for 1 h, then 2-(trimethylsilyl)ethoxymethyl chloride (767 mg, 4.60 mmol, 1.20 equiv) was added at 0°C. The reaction was stirred at room temperature for 1 h, then was quenched with water (20 mL) and the resulting mixture was extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-80% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (600 mg, 60.0% yield). LCMS (ESI): m / z [M+H]+ calcd for CioHnCfNhCLSi: 261.07, found 261.05.

[0413] Step 2: Preparation of 3-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)phenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-4(lH)- one

[0414] To a solution of 3 -chloro- l -((2-(trimethylsilyl)ethoxy)methyl)pyridazin-4( IT / )-one (170 mg, 0.576 mmol, 1 equiv) and Intermediate 6 (301 mg, 0.598 mmol, 1.00 equiv) in dioxane (10 mL) and water (8 mL) was added potassium carbonate (249 mg, 1.802 mmol, 3.01 equiv) and [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (44 mg, 0.060 mmol, 0.10 equiv). The mixture was stirred at 100 °C for 2 h under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (1-10% methanol / dichloromethane) to afford the title compound as a yellow solid (120 mg, 35.2% yield). LCMS (ESI): m / z [M+H]+ calcd for C32H43N7O3Si: 602.32, found 602.55.

[0415] Step 3: Preparation of 3-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- A solution of 3-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6-diazaspiro[3.4]octan- 2-yl)phenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-4(U7)-one (130 mg, 0.216 mmol, 1 equiv) in trifluoroacetic acid (4 mL) and water (2 mL) was stirred at room temperature for 1 h. The mixture was concentrated to dryness and the residue was purified by preparative HPLC (Cl 8 column, 20-40% acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a yellow solid (24.4 mg, 23.9% yield). LCMS (ESI): m / z [M+H]+calcd for C26H29N7O2: 472.24, found 472.30. 'H NMR (500 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.50 (s, 2H), 7.99 - 8.15 (m, 3H), 7.70 (s, 1H), 6.40 - 6.48 (m, 2H), 6.20 - 6.33 (m, 1H), 4.15 - 4.23 (m, 1H), 3.76 - 3.89 (m, 5H), 3.65 - 3.68 (m, 2H), 3.51 - 3.54 (m, 1H), 2.14 (t, J = 6.7 Hz, 2H), 1.83 - 1.85 (m, 2H), 1.67 (s, 2H), 1.44 - 1.55 (m, 4H).

[0416] Synthesis of Compound 38: 3-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro [3.4] octan-2-yl)phenyl)-5-(trifluoromethyl)pyrazine 1-oxide

[0417] Step 1: Preparation of 2-(4-bromophenyl)-6-(trifluoromethyl)pyrazine

[0418] To a solution of 2-bromo-6-(trifluoromethyl)pyrazine (0.32 g, 1.42 mmol, 1 equiv) in dioxane (5 mL) and water (0.5 mL) was added 2-(4-bromophenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (479 mg, 1.70 mmol, 1.2 equiv), potassium carbonate (489 mg, 3.54 mmol, 2.5 equiv) and [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.1 g, 0.14 mmol, 0.1 equiv). The reaction mixture was stirred for 4 h at 90 °C under nitrogen, then was cooled to room temperature. The mixture was then quenched with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-60% ethyl acetate / petroleum ether) to afford the title compound as a brown solid (0.3 g, 70.2% yield). LCMS (ESI): m / z [M+H]+calcd for C11H6BH3N2: 302.97, found 303.15. To a mixture of 2-(4-bromophenyl)-6-(trifluoromethyl)pyrazine (300 mg, 0.993 mmol, 1 equiv) in dichloromethane (5 mL) was added 85% meta-chloroperbenzoic acid (403 mg, 1.99 mmol, 2 equiv). The mixture was stirred for 3 h at room temperature, then was quenched by the addition of water (10 mL) at 0 °C. The resulting mixture was extracted with di chloromethane (3 x 10 mL), then the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (3:1 ethyl acetate / petr oleum ether) to afford the title compound as a white solid (120 mg, 37.7% yield). LCMS (ESI): m / z [M+H]+calcd for CnHeBrFs^O: 318.96, found 319.00.

[0419] Step 3: Preparation of 3-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)phenyl)-5-(trifluoromethyl)pyrazine 1-oxide (Compound 38)

[0420] To a solution of 3-(4-bromophenyl)-5-(trifluoromethyl)pyrazine 1-oxide (100 mg, 0.313 mmol, 1 equiv) in dioxane (3 mL) was added Intermediate 3 (113 mg, 0.376 mmol, 1.2 equiv), cesium carbonate (204 mg, 0.626 mmol, 2.0 equiv) and Pd-PEPP SLIP ent (30 mg, 0.313 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 100 °C under nitrogen, then was cooled to room temperature. The reaction mixture was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0- 20% methanol / dichloromethane) and purified further by preparative HPLC (XSelect CSH column, 44-60% acetonitrile / water with 0.1% formic acid) to afford the title compound as a yellow solid (4.5 mg, 2.7% yield). LCMS (ESI): m / z [M+H]+calcd for C27H28F3N7O2: 540.23, found 540.25. 'H NMR (300 MHz, DMSO-d6) δ 9.01 - 9.51 (m, 1H), 8.70 (s, 1H), 8.52 (s, 2H), 7.85 - 8.10 (m, 2H), 7.67 - 7.77 (m, 1H), 6.45 - 6.85 (m, 2H), 4.14 - 4.24 (m, 1H), 3.81 - 4.14 (m, 4H), 3.61 - 3.73 (m, 2H), 3.50 - 3.60 (m, 2H), 2.11 - 2.21 (m, 2H), 1.82 - 1.97 (m, 2H), 1.60 - 1.78 (m, 2H), 1.41 - 1.60 (m, 4H).19F NMR (282 MHz, DMSO-d6) δ -66.67, - 67.61, -190.60.

[0421] Synthesis of Compound 39: 5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro [3.4] octan-2-yl)-3-(trifluoromethyl)phenyl)pyrimidine 1-oxide Step 1: Preparation of 5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)-3-(trifluoromethyl)phenyl)pyrimidine 1-oxide (Compound 39) To a solution of Intermediate 3 (90 mg, 0.299 mmol, 1 equiv) in dioxane (3 mL) was added 5-[4-bromo-3-(trifluoromethyl)phenyl]pyrimidin-l-ium-l-olate (114 mg, 0.359 mmol, 1.2 equiv, prepared similarly to compound 34, step 1), cesium carbonate (243 mg, 0.747 mmol, 2.5 equiv), XPhos (14 mg, 0.030 mmol, 0.1 equiv) and XPhos-Pd-G3 (25 mg, 0.030 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 100 °C under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% methanol / dichloromethane) and further purified by preparative HPLC (YMC-Actus Triart ExRS column, 37-50% acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a white solid (8.6 mg, 5.3%). LCMS (ESI): m / z [M+H]+calcd for C27H28F3N7O2: 540.23, found 540.25. 'H NMR (500 MHz, DMSO-d6) δ 8.97 (s, 2H), 8.64 (s, 1H), 8.51 (s, 2H), 7.92 (s, 2H), 7.71 (s, 1H), 6.54 - 6.80 (m, 1H), 4.19 - 4.28 (m, 1H), 3.99 - 4.19 (m, 4H), 3.78 - 3.99 (m, 1H), 3.61 - 3.75 (m, 2H), 3.49 - 3.61 (m, 1H), 2.10 - 2.20 (t, J = 6.9 Hz, 2H), 1.80 - 1.98 (m, 2H), 1.63 - 1.71 (m, 2H), 1.48 - 1.61 (m, 4H).

[0422] Synthesis of Compound 41: 3-amino-5-(4-(6-(2-(cyclopentylamino)pyrimidine-5- carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)phenyl)pyrazin-2(TH)-one Step 1: Preparation of 3-(benzyloxy)-6-chloropyrazin-2-amine

[0423] To a stirring solution of 3-bromo-6-chloropyrazin-2-amine (1 g, 4.80 mmol, 1 equiv) in tetrahydrofuran (20 mL) was added a solution of sodium hydride (230 mg, 5.75 mmol, 1.20 equiv, 60%) at 0 °C, and the mixture was stirred at room temperature for 1 h. Benzyl alcohol (0.52 g, 4.80 mmol, 1 equiv) was then added in the mixture at 0 °C, and the resulting mixture was stirred at 80 °C for 1 h. The reaction mixture was then cooled to room temperature, quenched with water (30 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-80% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (200 mg, 17.6% yield). LCMS (ESI): m / z [M+H]+calcd for C11H10CIN3O: 236.05, found 236.05.

[0424] Step 2: Preparation of (2-(4-(6-amino-5-(benzyloxy)pyrazin-2-yl)phenyl)-2,6- diazaspiro[3.4]octan-6-yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone

[0425] To a solution of 3-(benzyloxy)-6-chloropyrazin-2-amine (160 mg, 0.679 mmol, 1 equiv) and Intermediate 6 (342 mg, 0.679 mmol, 1.00 equiv) in dioxane (8 mL) and water (0.8 mL) was added potassium carbonate (282 mg, 2.040 mmol, 3.01 equiv) and tetrakis(triphenylphosphine)palladium(0) (79 mg, 0.068 mmol, 0.10 equiv). The mixture was stirred at 100 °C for 2 h under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (1-10% methanol / dichloromethane) to afford the title compound as a yellow solid (140 mg, 35.7% yield). LCMS (ESI): m / z [M+H]+calcd for C33H36N8O2: 577.30, found 577.2.

[0426] Step 3: Preparation of 3-amino-5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)- 2,6-diazaspiro [3.4] octan-2-yl)phenyl)pyrazin-2(TH)-one (Compound 41)

[0427] To a solution of (2-(4-(6-amino-5-(benzyloxy)pyrazin-2-yl)phenyl)-2,6-diazaspiro[3.4]octan-

[0428] 6-yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone (240 mg, 0.416 mmol, 1 equiv) in dichloromethane (5 mL) was added boron tribromide (1 M solution in dichloromethane, 1042.56 mg, 4.160 mmol, 10 equiv) slowly at -78 °C. The mixture was stirred at -78 °C for 0.5 h, then was quenched by addition of ice water. The mixture was then concentrated to dryness and the residue was purified by preparative HPLC (XB ridge Prep Shield RP18 OBD Column,

[0429] 7-37% acetonitrile / water with 0.1% formic acid) to the title compound as a white solid (9.2 mg, 4.5% yield). LCMS (ESI): m / z [M+H]+calcd for C26H30N8O2: 487.25, found 487.30. 'H NMR (500 MHz, DMSO-d6) δ 11.63 (s, 1H), 8.50 (s, 2H), 7.70 (s, 1H), 7.54 - 7.60 (m, 2H), 6.94 (s, 1H), 6.59 (s, 2H), 6.40 - 6.43 (m, 2H), 4.17 - 4.22 (m, 1H), 3.78 - 3.82 (m, 2H), 3.73 - 3.76 (m, 2H), 3.62 - 3.68 (m, 2H), 3.49 - 3.55 (m, 2H), 2.14 (t, J= 6.9 Hz, 2H), 1.87 - 1.90 (m, 2H), 1.65 - 1.69 (m, 2H), 1.45 - 1.53 (m, 4H). Synthesis of Compound 45: 2-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)-5-( LH-pyrazolo[3,4-b]pyrazin-6-yl)benzonitrile

[0430] Step 1: Preparation of 2-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)-5-( l / / -pyr:izolo|3.4-b|pyrazin-6-yl)benzonitrile (Compound 45)

[0431] To a stirred solution of (3-cyano-4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)phenyl)boronic acid (200 mg, 0.448 mmol, 1.00 equiv, prepared similarly to Compound 31, step 1) in 1,4-dioxane (10 mL) and water (1 mL) was added 6- chloro-U / -pyrazolo[3,4-b]pyrazine (70 mg, 0.448 mmol, 1 equiv) and potassium carbonate (186 mg, 1.344 mmol, 3 equiv) followed by [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (37 mg, 0.045 mmol, 0.1 equiv). The reaction mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere, then was cooled to room temperature. The reaction was then quenched by water (20 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-15% methanol / di chloromethane), then purified further be preparative HPLC (YMC Triart Cl 8 Column, 25-45% acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a yellow solid (50.8 mg, 21.8% yield). LCMS (ESI): m / z [M+H]+calcd for C28H28N10O: 521.25, found 521.30. ‘H NMR (400 MHz, DMSO- de) δ 13.95 (s, 1H), 9.23 (s, 1H), 8.53 (s, 2H), 8.40 (s, 2H), 8.30 (s, 1H), 7.73 (d, J = 7.3 Hz, 1H), 6.72 (s, 1H), 4.21 (d, J= 15.0 Hz, 5H), 3.51 - 3.92 (m, 4H), 2.21 (t, J = 6.9 Hz, 2H), 1.89 (s, 2H), 1.60 (d, J= 65.9 Hz, 6H).

[0432] Synthesis of Compound 49: 4-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)phenyl)-6-oxo-l,6-dihydropyridine-3-carbonitrile

[0433] Intermediate 6

[0434] Step 1: Preparation of 4-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)phenyl)-6-oxo-l,6-dihydropyridine-3-carbonitrile (Compound 49)

[0435] To a solution of Intermediate 6 (lOOmg, 0.199 mmol, 1 equiv) and 4-bromo-6- hydroxypyridine-3 -carbonitrile (39 mg, 0.199 mmol, 1 equiv) in dioxane (10 mL) and water (ImL) was added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (145 mg, 0.199 mmol, 01 equiv) and potassium carbonate (82 mg, 0.597 mmol, 3 equiv). The mixture was stirred at 100 °C for 2 h under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% methanol / dichloromethane), then further purified by preparative HPLC (XB ridge Prep Cl 8 OBD Column, acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a white solid (29.1 mg, 29.4% yield). LCMS (ESI): m / z [M+H]+calcd for C28H29N7O2: 496.24, found 496.25. 'H NMR (500 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.51 (s, 2H), 8.29 (s, 1H), 7.71 (s, 1H), 7.41 (d, J = 9.4 Hz, 2H), 6.51 (d, J= 10.5 Hz, 2H), 6.31 (s, 1H), 1.15 - 4.25 (m, 1H), 3.76 - 3.97 (m, 5H), 3.68 (s, 2H), 3.48 - 3.58 (m, 1H), 2.16 (t, J = 6.9 Hz, 2H), 1.82 - 1.95 (m, 2H), 1.61 - 1.74 (m, 2H), 1.43 - 1.58 (m, 4H).

[0436] Synthesis of Compound 51: (2-(4-(5-amino-lH-pyrazol-4-yl)phenyl)-2,6- diazaspiro[3.4]octan-6-yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone

[0437] Scheme 39

[0438] Step 1: Preparation of tert-butyl (4-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-

[0439] 2.6-diazaspiro[3.4]octan-2-yl)phenyl)-lH-pyrazol-5-yl)carbamate

[0440] To a stirring solution Intermediate 6 (200 mg, 0.397 mmol, 1 equiv) in dioxane (3 mL) and water (0.3 mL) was added tert-butyl (4-bromo-U / -pyrazol-5-yl)carbamate (208 mg, 0.794 mmol, 2 equiv), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (58 mg, 0.079 mmol, 0.2 equiv) and potassium carbonate (110 mg, 0.794 mmol, 2 equiv). The mixture was stirred for 16 h at 100 °C under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petr oleum ether) to afford the title compound (140 mg, 63.0% yield). LCMS (ESI): m / z [M+H]+calcd fo : 559.31, found 559.45.

[0441] Step 2: Preparation of (2-(4-(5-amino-1H-pyrazol-4-yl)phenyl)-2,6-diazaspiro[3.4]octan- 6-yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone (Compound 51)

[0442] To a stirred solution of tert-butyl N-[4-(4-{6-[2-(cyclopentylamino)pyrimidine-5-carbonyl]-

[0443] 2.6-diazaspiro[3.4]octan-2-yl}phenyl)-2H-pyrazol-3-yl]carbamate (130 mg, 0.233 mmol, 1 equiv) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL) and the reaction was stirred at room temperature for 4 h. The reaction mixture was then quenched by addition of water (5 mL), and was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (XBridge Prep OBD Cl 8 Column, 32-50% acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a yellow solid (25.9 mg, 24.2% yield). LCMS (ESI): m / z [M+H]+calcd for C25H30N8O: 459.26, found 459.30. 'H NMR (500 MHz, DMSO-d6) δ11.60 (s, 1H), 8.51 - 8.62 (m, 2H), 7.70 (s, 1H), 7.57 (s, 1H), 7.29 (s, 2H), 6.23 - 6.63 (m, 2H), 4.38 (s, 1H), 4.17 - 4.24 (m, 1H), 3.52 - 3.84 (m, 7H), 2.13 (t, J= 6.9 Hz, 2H), 1.87 - 1.89 (m, 2H), 1.66 - 1.69 (m, 2H), 1.49 - 1.53 (m, 4H).

[0444] Synthesis of Compound 53: 5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6-

[0445]

[0446] Step 1: Preparation of 5-(4-bromo-2,3-difluorophenyl) pyrimidine

[0447] To a solution of b1ro-mo-2,3-difluoro-4-iodobenzene (1 g, 3.14 mmol, 1 equiv) and 5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl) pyrimidine (0.65 g, 3.14 mmol, 1 equiv) in dioxane (lOmL) and water (ImL) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.23 g, 0.314 mmol, 0.1 equiv) and potassium carbonate (1.30 g, 9.41 mmol, 3 equiv). The mixture was stirred at 90 °C for 2 h under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% methanol / dichloromethane) to afford the title compound as a white solid (800 mg, 85.6% yield). LCMS (ESI): m / z [M+H]+calcd for 270.96, found 271.10.

[0448] Step 2: Preparation of 5-(4-bromo-2,3-difluorophenyl) pyrimidine 1-oxide

[0449] To a solution of 5 -(4-bromo-2, 3 -difluorophenyl) pyrimidine (400 mg, 1.48 mmol, 1 equiv) in dichloromethane (10 mL) was added 85% meta-chloroperbenzoic acid (598 mg, 2.95 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was then quenched with water (20 mL) and extracted with di chloromethane (30 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% methanol / dichloromethane) to afford the title compound as a white solid (260 mg, 56.4% yield). LCMS (ESI): m / z [M+H]+calcd for CioH5BrF2N20: 286.96, found 287.20.

[0450] Step 3: Preparation of 5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- To a solution of Intermediate 3 (100 mg, 0.332 mmol, 1 equiv) and 5-(4-bromo-2,3- difluorophenyl) pyrimidin-l-ium-l-olate (95.25 mg, 0.332 mmol, 1 equiv) in dioxane (5 mL) were added RuPhos (30 mg, 0.066 mmol, 0.2 equiv), RuPhos-Pd-G3 (27 mg, 0.033 mmol, 0.1 equiv) and cesium carbonate (324 mg, 0.996 mmol, 3 equiv) . The mixture was stirred at 100 °C for 2 h under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% methanol / dichloromethane), then was purified further by preparative HPLC (XB ridge Prep OBD C18 Column, acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a white solid (32.7 mg, 19.2% yield). LCMS (ESI): m / z [M+H]+calcd for C26H27F2N7O2: 508.22, found 508.25. 'HNMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.78 (s, 1H), 8.41 - 8.59 (m, 3H), 7.74 (d, J = 7.2 Hz, 1H), 7.30 - 7.44 (m, 1H), 6.42 - 6.57 (m, 1H), 4.18 - 4.27 (m, 1H), 3.94 - 4.14 (m, 4H), 3.84(s, 1H), 3.68 (s, 2H), 3.48 - 3.58 (m, 1H), 2.18 (t, J= 6.9 Hz, 2H), 1.82 - 1.96 (m, 2H), 1.62 - 1.74 (m, 2H), 1.43 - 1.59 (s, 4H).

[0451] Synthesis of Compound 57: 5-(3-chloro-4-(6-(2-(cyclopentylamino)pyrimidine-5- carbonyl)-!, 6-diazaspiro [3.4] octan-2-yl)phenyl)pyrimidine 1-oxide

[0452] Step 1: Preparation of 5-(3-chloro-4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)- 2,6-diazaspiro[3.4]octan-2-yl)phenyl)pyrimidine 1-oxide (Compound 57)

[0453] To a stirred solution of 5-(4-bromo-3-chlorophenyl)pyrimidine 1-oxide (100 mg, 0.350 mmol, 1 equiv, prepared similarly to Compound 53, steps 1 and 2) in dioxane (2 mL) was added Intermediate 3 (106 mg, 0.350 mmol, 1 equiv), XPhos (67 mg, 0.140 mmol, 0.4 equiv), cesium carbonate (171 mg, 0.525 mmol, 1.5 equiv) and XPhos-Pd-G3 (119 mg, 0.140 mmol, 0.4 equiv). The mixture was stirred for 16 h at 90 °C under nitrogen, then was cooled to room temperature. The reaction was then quenched by addition of water (5 mL), and the resulting mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (XBridge Prep OBD C18 Column, 32-50% yellow solid (42.6 mg, 24.0% yield). LCMS (ESI): m / z [M+H]+calcd for C26H28CIN7O2: 506.20, found 506.20. *HNMR (300 MHz, DMSO-d6) δ 8.95 (d, J= 4.5 Hz, 2H), 8.63 (s, 1H), 8.52 (s, 2H), 7.80 (s, 1H), 7.63 - 7.77 (m, 2H), 6.61 - 6.73 (m, 1H), 4.14 - 4.21 (m, 1H), 4.07 (d, J = 12.4 Hz, 4H), 3.83 (s, 1H), 3.44 - 3.73 (m, 3H), 2.17 (t, J = 6.9 Hz, 2H), 1.79 - 1.97 (m, 2H), 1.66 - 1.68 (m, 2H), 1.41 - 1.60 (m, 4H).

[0454] Synthesis of Compound 61: 3-(3-chloro-4-(6-(2-((tetrahydro-2Z7-pyran-4- yl)amino)pyrimidine-5-carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)phenyl)pyrazine 1-oxide

[0455] Step 1: Preparation of ethyl 2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5- carboxylate

[0456] To a solution of oxan-4-amine (2.5 g, 24.7 mmol, 1 equiv) in acetonitrile (30 mL) was added ethyl 2-chloropyrimidine-5-carboxylate (4.61 g, 24.7 mmol, 1 equiv) and N,N- diisopropylethylamine (9.58 g, 74.1 mmol, 3 equiv). The mixture was stirred for 2 h at 80 °C, then was cooled to room temperature. The reaction was then quenched with water (50 mL) and the resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic The residue was then purified by silica gel chromatography (0-15% methanol / dichloromethane) to afford the title compound as a white solid (1.5 g, 24.1% yield). LCMS (ESI): m / z [M+H]+calcd for C12H17N3O3: 252.13, found: 252.20.

[0457] Step 2: Preparation of 2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid

[0458] To a solution of ethyl 2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylate (3 g, 11.9 mmol, 1 equiv) in tetrahydrofuran (15 mL), water (15 mL), and methanol (15 mL) was added lithium hydroxide (571 mg, 23.9 mmol, 2 equiv). The reaction mixture was stirred at room temperature for 2 h, then the resulting mixture was partially concentrated under vacuum. The mixture was then acidified to pH = 5 with IN hydrochloric acid. The precipitated solids were collected by filtration and washed with water (10 mL) to afford the title compound as a white solid (3 g). LCMS (ESI): m / z [M+H]+calcd for C10H13N3O3: 224.10, found 224.15.

[0459] Step 3: Preparation of tert-butyl 6-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro [3.4] octane-2-carboxylate

[0460] To a stirred solution of 2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5-carboxylic acid (3 g, 13.4 mmol, 1 equiv) in anhydrous DMF (60 mL) was added tert-butyl 2,6- diazaspiro[3.4]octane-2-carboxylate (2.85 g, 13.4 mmol, 1 equiv) and chloro-A^A^V',#- tetramethylformamidinium hexafluorophosphate (421 mg, 20.2 mmol, 1.5 equiv) followed by 1 -methylimidazole (5.5 g, 67.2 mmol, 5 equiv). The reaction mixture was stirred at room temperature for 2 h, then the reaction was quenched with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (3.8 g, 67.8% yield). LCMS (ESI): m / z [M+H]+calcd for C21H31N5O4: 418.24, found 418.30.

[0461] Step 4: Preparation of (2,6-diazaspiro[3.4]octan-6-yl)(2-((tetrahydro-2H-pyran-4- yl)amino)pyrimidin-5-yl)methanone

[0462] To a stirred solution of tert-butyl 6-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-5- carbonyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (3.0 g, 7.18 mmol, 1 equiv) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 3 h, then the resulting mixture was concentrated to dryness to afford the TFA salt of the title compound as a yellow oil (2.5 g, 83.5% yield). LCMS (ESI): m / z [M+H]+calcd for C16H23N5O2: 318.19, found 318.20.

[0463] Step 5: Preparation of 3-(4-bromo-3-chlorophenyl)pyrazine 1-oxide

[0464] To a solution of 4-bromo-3-chlorophenylboronic acid (400 mg, 1.70 mmol, 1 equiv) in dioxane (5 mL) and water (0.5 mL) was added 3-chloropyrazin-l-ium-l-olate (221 mg, 1.70 mmol, 1 equiv), potassium carbonate (704 mg, 5.10 mmol, 3 equiv) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (124 mg 0 170 mmol 0 1 equiv) The temperature. The reaction was then quenched with water (20 mL) and was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Cl 8 column, acetonitrile / water) to afford the title compound as a yellow solid (150 mg, 30.9% yield). LCMS (ESI): m / z [M+H]+calcd for CioH6BrClN20: 284.94, found 284.80.

[0465] Step 6: Preparation of 3-(3-chloro-4-(6-(2-((tetrahydro-2 / / -pyran-4- yl)amino)pyrimidine-5-carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)phenyl)pyrazine 1-oxide (Compound 61)

[0466] To a solution of (2,6-diazaspiro[3.4]octan-6-yl)(2-((tetrahydro-2J / -pyran-4- yl)amino)pyrimidin-5-yl)methanone (130 mg, 0.410 mmol, 1 equiv, prepared similarly to Intermediate 3) in dioxane (4 mL) was added 3-(4-bromo-3-chlorophenyl)pyrazine 1-oxide (116 mg, 0.410 mmol, 1 equiv), RuPhos (19 mg, 0.041 mmol, 0.1 equiv), RuPhos-Pd-G3 (34 mg, 0.041 mmol, 0.1 equiv) and cesium carbonate (400 mg, 1.23 mmol, 3 equiv). The mixture was stirred for 4 h at 90 °C under a nitrogen atmosphere, then was cooled to room temperature. The reaction was then quenched with water (20 mL) at 0 °C, and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-15% methanol / dichlorom ethane) and was further purified by preparative HPLC (Cl 8 Column, 0-100% acetonitrile / water) to afford the title compound as a yellow solid (19.3 mg, 9.0% yield). LCMS (ESI): m / z [M+H]+calcd for C26H28CIN7O3: 522.19, found 522.20. *HNMR (500 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.48 - 8.54 (m, 3H), 8.16 - 8.20 (m, 1H), 7.99 - 8.05 (m, 1H), 7.92 - 7.96 (m, 1H), 7.71 (d, J = 7.7 Hz, 1H), 6.60 - 6.69 (m, 1H), 3.93 - 4.19 (m, 5H), 3.80 - 3.89 (m, 3H), 3.67 (s, 3H), 3.53 (s, 1H), 3.35 - 3.41 (m, 1H), 2.16 (t, J= 6.9 Hz, 2H), 1.80 (d, J= 12.6 Hz, 2H), 1.47 - 1.57 (m, 2H).

[0467] Synthesis of Compound 63: 5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro [3.4] octan-2-yl)phenyl)pyrazin-2(TH)-one

[0468] Scheme 43 Intermediate 6

[0469] Step 1: Preparation of 5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)pyrazin-2(lH)-one

[0470] To a stirring solution of 5-bromopyrazin-2(177)-one (1 g, 5.72 mmol, 1 equiv) in DMF (20 mL) was added a solution of sodium hydride (300 mg, 7.50 mmol, 1.31 equiv, 60% in mineral oil) at 0 °C. The mixture was stirred at room temperature for 1 h, then 2- (trimethylsilyl)ethoxymethyl chloride (1.14 g, 6.86 mmol, 1.2 equiv) was added in the mixture at 0 °C. The reaction was stirred at room temperature for 1 h, then was quenched with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (10-80% ethyl aetate / petroleum ether) to afford the title compound as a yellow oil (1.13 g, 64.7% yield). LCMS (ESI): m / z [M+H]+calcd for CioHnBr^ChSi: 305.02, found 304.90.

[0471] Step 2: Preparation of 5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)phenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)pyrazin-2(lH)-one

[0472] To a solution of 5-bromo-l-{[2-(trimethylsilyl)ethoxy]methyl}pyrazin-2-one (150 mg, 0.491 mmol, 1 equiv) and Intermediate 6 (248 mg, 0.493 mmol, 1.00 equiv) in dioxane (8 mL) and water (0.8 mL) was added potassium carbonate (204 mg, 1.48 mmol, 3.00 equiv) and tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.049 mmol, 0.10 equiv). The mixture was stirred at 100 °C for 2 h under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (1-10% methanol / dichloromethane) to afford the title compound as a yellow solid (230 mg, 77.7% yield). LCMS (ESI): m / z [M+H]+calcd for C32H43N7O3Si: 602.32, found 602.10.

[0473] Step 3: Preparation of 5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)phenyl)pyrazin-2(TH)-one (Compound 63)

[0474] To a stirred solution of 5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- (200 mg, 0.332 mmol, 1 equiv) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 2 h, then the mixture was concentrated to dryness. The residue was purified by preparative HPLC (XBridge Prep OBD Cl 8 Column, 20-45% acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a yellow solid (40.1 mg, 25.5% yield). LCMS (ESI): m / z [M+H]+calcd for 472.24, found 472.35. 'H NMR (300 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.50 (s, 2H), 8.05 (s, 1H), 7.91 (s, 1H), 7.63 - 7.75 (m, 3H), 6.40 - 6.52 (m, 2H), 4.12 - 4.25 (m, 1H), 3.73 - 3.84 (m, 5H), 3.49 - 3.69 (m, 3H), 2.13 (t, J= 6.8 Hz, 2H), 1.80 - 1.90 (m, 2H), 1.66 (s, 2H), 1.39 - 1.56 (m, 4H).

[0475] Synthesis of Compound 66: (2-(cyclopentylamino)pyrimidin-5-yl)(2-(2,3-difluoro-4-

[0476] (pyrimidin-5-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone

[0477] Step 1: Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(2,3-difluoro-4-

[0478] (pyrimidin-5-yl)phenyl)-2,6-diazaspiro [3.4] octan-6-yl)methanone (Compound 66)

[0479] To a solution of 5 -(4-bromo-2, 3 -difluorophenyl) pyrimidine (100 mg, 0.369 mmol, 1 equiv, as prepared for Compound 53, step 1) and Intermediate 3 (111 mg, 0.369 mmol, 1 equiv) in dioxane (5 mL) were added RuPhos (34 mg, 0.074 mmol, 0.2 equiv) RuPhos-Pd-G3 (31 mg, 0.037 mmol, 0.1 equiv) and cesium carbonate (36 mg, 1.11 mmol, 3 equiv). The mixture was stirred at 100 °C for 2 h under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% methanol / dichloromethane) and further purified by preparative HPLC (XBridge Prep OBD Cl 8 Column, acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a white solid (75.9 mg, 41.7% yield). LCMS (ESI): m / z [M+H]+calcd for C26H27F2N7O: 492.23, found 492.20. 'HNMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.97 (s, 2H), 8.52 (s, 2H), 7.74 (d, J = 7.3 Hz, 1H), 7.28 - 7.40 (m, 1H), 6.43 - 6.58 (m, 1H), 4.14 - 4.28 (m, 1H), 3.92 - 4.12 (m, 4H), 3.85 (s, 1H), 3.46 - 3.75 (m, 3H), 2.18 (t, J = 6.9 Hz, 2H), 1.86 - 1.94 (m, 2H), 1.61 - 1.77 (s, 2H), 1.44 - 1.60 (m, 4H).19F NMR (376 MHz, DMSO-d6) δ -144.582, -160.598. Synthesis of Compound 69: 5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro [3.4] octan-2-yl)phenyl)pyridazine-3-carbonitrile

[0480] Step 1: Preparation of 5-(4-bromophenyl)pyridazine-3-carbonitrile

[0481] To a solution of (5-chloropyridazine-3-carbonitrile (108 mg, 0.78 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (65.3 mg, 0.08 mmol), potassium phosphate tribasic (496 mg, 2.34 mmol) and (4- bromophenyl)boronic acid (188 mg, 0.94 mmol). The resulting mixture was heated at 90 °C for 2 hours under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-50% ethyl acetate / petr oleum ether) to afford the title compound as a white solid (210 mg, 60.1% yield). LCMS (ESI): m / z [M+H]+calcd for CiiELBrNs: 259.97, found 259.95.

[0482] Step 2: Preparation of 5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)phenyl)pyridazine-3-carbonitrile (Compound 69)

[0483] To a solution of 5-(4-bromophenyl)pyridazine-3-carbonitrile (210 mg, 0.81 mmol, 1.0 equiv) and Intermediate 3 (292.6 mg, 0.97 mmol, 1.1 equiv) in dioxane (3 mL) was added XPhos (42 mg, 0.08 mmol, 0.1 equiv), XPhos-Pd-G3 (75 mg, 0.08 mmol) and cesium carbonate (784 mg, 2.43 mmol, 3.0 equiv). The reaction mixture was then stirred at 90 °C for 2 hours under a nitrogen atmosphere. The reaction was cooled to room temperature and quenched with water (10 mL), then extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (1-10% methanol / dichloromethane) to afford the title compo nd as a hite solid (9 9 mg 2 5% ield) LCMS (ESI): m / [M+H]+calcd for C27H28N8O: 481.24, found 481.24. ‘HNMR (300 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.29 - 8.67 (m, 3H), 7.81 - 8.08 (m, 2H), 7.64 - 7.80 (m, 1H), 6.44 - 6.67 (m, 2H), 4.10 - 4.28 (m, 1H), 3.72 - 4.09 (m, 5H), 3.68 (s, 2H), 3.42 - 3.56 (m, 2H), 2.15 (t, J= 6.8 Hz, 2H), 1.78 - 1.96 (m, 2H), 1.64 - 1.66 (m, 2H), 1.24 - 1.58 (m, 4H).

[0484] Synthesis of Compound 70: 5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro [3.4] octan-2-yl)phenyl)pyrrolidin-2-one

[0485] Step 1: Preparation of 5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)phenyl)pyrrolidin-2-one (Compound 70)

[0486] To a stirred solution of Intermediate 3 (251 mg, 0.833 mmol, 1 equiv) in anhydrous 1,4- dioxane (5 mL) was added 5-(4-bromophenyl)pyrrolidin-2-one (200 mg, 0.833 mmol, 1 equiv) and cesium carbonate (814 mg, 2.499 mmol, 3 equiv), followed by XPhos (40 mg, 0.083 mmol, 0.1 equiv) and XPhos-Pd-G3 (70 mg, 0.083 mmol, 0.1 equiv). The reaction mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere, then was cooled to room temperature. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-15% methanol / di chloromethane) and was further purified by preparative HPLC (YMC Triart Cl 8 Column, 25-45% acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a white solid (69 mg, 18.0% yield). LCMS (ESI): m / z [M+H]+calcd for C26H32N6O2: 461.26, found 461.25. 'H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 2H), 7.94 (s, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.09 (d, J= 7.8 Hz, 2H), 6.42 (s, 2H), 4.53 (t, J= 6.9 Hz, 1H), 4.14 - 4.26 (m, 1H), 3.48 - 3.81 (m, 8H), 2.31 - 2.42 (m, 1H), 2.08 - 2.24 (m, 4H), 1.86 (d, J = 13.9 Hz, 2H), 1.60 - 1.77 (m, 3H), 1.42 - 1.58 (m, 4H).

[0487] Synthesis of Compound 74: 5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro [3.4] octan-2-yl)phenyl)nicotinamide Intermediate 6

[0488] Step 1: Preparation of 5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)phenyl)nicotinamide (Compound 74)

[0489] To a stirred solution of Intermediate 6 (120 mg, 0.238 mmol, 1.00 equiv) in 1,4-dioxane (8 mL) and water (0.8 mL) was added 5-bromonicotinamide (72 mg, 0.357 mmol, 1.50 equiv) and potassium carbonate (99 mg, 0.714 mmol, 3 equiv), followed by [1,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mg, 0.024 mmol, 0.1 equiv). The reaction mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere, then was cooled to room temperature. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-15% methanol / di chloromethane) and purified further by preparative HPLC (YMC Triart Cl 8 Column, 25-45% acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a white solid (44.8 mg, 37.8% yield). LCMS (ESI): m / z [M+H]+calcd for C28H31N7O2: 498.26, found 498.25. 'H NMR (400 MHz, DMSO-d6) 5 8.94 (s, 1H), 8.88 (s, 1H), 8.52 (s, 2H), 8.37 (s, 1H), 8.23 (s, 1H), 7.58 - 7.77 (m, 4H), 6.55 - 6.57 (m, 2H), 3.80 - 3.83 (m, 1H), 3.66 - 3.72 (m, 5H), 3.55 - 3.70 (m, 3H), 2.17 (t, J = 7.0 Hz, 2H), 1.88 - 1.89 (m, 2H), 1.66 - 1.68 (m, 2H), 1.49 - 1.52 (m, 4H).

[0490] Synthesis of Compound 75: (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(l-(2- hydroxyethyl)- LH-pyrazol-4-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone

[0491] Scheme 48

[0492] Step 1: Preparation of (21--((tert-butyldimethylsilyl)oxy)ethyl)-4-iodo-LH-pyrazole

[0493] To a stirring solution of 4-bromopyrazole (500 mg, 3.40 mmol, 1 equiv) in DMF (10 mL) was added cesium carbonate (3.33 g, 10.20 mmol, 3.00 equiv) at 0 °C, and the mixture was stirred at room temperature for 1 h. Then tert-butyl(2-iodoethoxy)dimethylsilane (1.46 g, 5.10 mmol, 1.50 equiv) was added at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (30-100% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (700 mg, 58.4% yield). LCMS (ESI): m / z [M+H]+calcd for CnH2iIN2OSi: 353.05, found 353.00.

[0494] Step 2: Preparation of (2-(4-( 1(2--(( / cr / ‘-biityldinietliylsilyl)oxy)ethyl)-l / / -pyrazol-4- yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)(2-(cyclopentylamino)pyrimidin-5- yl)methanone

[0495] To a solution of (21--((tert-butyldimethylsilyl)oxy)ethyl)-4-iodo-U / -pyrazole (300 mg, 0.852 mmol, 1 equiv) and Intermediate 6 (429 mg, 0.852 mmol, 1.00 equiv) in dioxane (10 mL) and water (1 mL) was added potassium carbonate (353 mg, 2.554 mmol, 3.00 equiv) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (63 mg, 0.086 mmol, 0.10 equiv). The mixture was stirred at 100 °C for 2 h under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (1-10% methanol / dichloromethane) to afford the title compound as a yellow solid (220 mg, 42.9% yield). LCMS (ESI): m / z [M+H]+calcd for CssfEnNvChSi: 602.36, found 602.20.

[0496] Step 3: Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(l-(2-hydroxyethyl)- lH-pyrazol-4-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone (Compound 75) To a stirred solution of (2-(4-(l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-U / -pyrazol-4- yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone (200 mg, 0.332 mmol, 1 equiv) in tetrahydrofuran (3 mL) was added triethylamine trishydrofluoride (1 mL). The reaction mixture was stirred at 60 °C for 2 h, then was cooled to room temperature. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by preparative HPLC (C18 column, 31-61% acetonitrile / water) to afford the title compound as a pink solid (58.0 mg, 35.8% yield). LCMS (ESI): m / z [M+H]+calcd for C27H33N7O2: 488.27, found 488.25. 'H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 2H), 7.95 (s, 1H), 7.68 - 7.76 (m, 2H), 7.32 - 7.40 (m, 2H), 6.40 - 6.46 (m, 2H), 4.92 (t, J= 5.3 Hz, 1H), 4.16 - 4.27 (m, 1H), 4.12 (t, J= 5.6 Hz, 2H), 3.63 - 3.83 (m, 7H), 3.50 - 3.56 (s, 3H), 2.14 (t, J= 6.9 Hz, 2H), 1.86 - 1.91 (m, 2H), 1.65 - 1.71 (m, 2H), 1.48 - 1.58 (m, 4H).

[0497] Synthesis of Compound 76: 3-(5-cyano-6-(6-(2-(cyclopentylamino)pyrimidine-5- carbonyl)-2,6-diazaspiro[3.4]octan-2-yl)pyridin-3-yl)pyrazine 1-oxide

[0498] Step 1: Preparation of (6-chloro-5-cyanopyridin-3-yl)boronic acid

[0499] To a solution of 5-bromo-2-chloropyridine-3-carbonitrile (1 g, 4.60 mmol, 1 equiv) in dioxane

[0500] (15 L) dd d bi ( i l t )dib (1 75 6 90 l 1 5 i ) t i t t (1.35 g, 13.8 mmol, 3 equiv) and [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.34 g, 0.460 mmol, 0.1 equiv). The mixture was stirred for 3 h at 100 °C under a nitrogen atmosphere, then was cooled to room temperature. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Cl 8 column, acetonitrile / water) afford the title compound as a yellow oil (400 mg, 47.7% yield). LCMS (ESI): m / z [M+H]+calcd for C6H4BCIN2O2: 183.01, found 183.05.

[0501] Step 2: Preparation of (5-cyano-6-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro [3.4] octan-2-yl)pyridin-3-yl)boronic acid

[0502] To a solution of Intermediate 3 (420 mg, 1.39 mmol, 1 equiv) in acetonitrile (5 mL) was added 6-chloro-5-cyanopyridin-3-ylboronic acid (330 mg, 1.81 mmol, 1.30 equiv) and N,N- diisopropylethylamine (540 mg, 4.18 mmol, 3 equiv). The mixture was stirred for 3 h at 70 °C, then was cooled to room temperature. The crude reaction mixture was loaded directly and purified by preparative HPLC (Cl 8 column, acetonitrile / water) afford the title compound as a yellow oil (300 mg, 48.1% yield). LCMS (ESI): m / z [M+H]+calcd for C22H26BN7O3: 448.22, found 448.10.

[0503] Step 3: Preparation of 3-(5-cyano-6-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)pyridin-3-yl)pyrazine 1-oxide (Compound 76)

[0504] To a solution of (5-cyano-6-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)pyridin-3-yl)boronic acid (200 mg, 0.447 mmol, 1 equiv) in dioxane (4 mL) and water (0.4 mL) was added 3 -chloropyrazine 1-oxide (64 mg, 0.492 mmol, 1.1 equiv), bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (29 mg, 0.045 mmol, 0.1 equiv) and potassium carbonate (185 mg, 1.34 mmol, 3 equiv). The mixture was stirred for 4 h at 90 °C under a nitrogen atmosphere, then was cooled to room temperature. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (3 x 20mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-15% methanol / dichloromethane) afford the title compound as an off-white solid (160 mg, 71.9% yield). LCMS (ESI): m / z [M+H]+calcd for 498.23, found 498.25. ‘HNMR (500 MHz, DMSO- d6) δ 8.95 - 9.04 (m, 2H), 8.43 - 8.64 (m, 4H), 8.22 - 8.26 (m, 1H), 7.70 (d, J= 7.8 Hz, 1H), 4.16 - 4.39 (m, 5H), 3.87 (s, 1H), 3.66 - 3.73 (m, 2H), 3.54 (s, 1H), 2.19 (t, J= 6.9 Hz, 2H), 1.83 - 1.91 (m, 2H), 1.66 - 1.69 (m, 2H), 1.44 - 1.56 (m, 4H).

[0505] Synthesis of Compound 77: (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(5-(2- hydroxypropan-2-yl)pyridin-3-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone

[0506] Intermediate 6

[0507] Step 1: Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(5-(2-hydroxypropan- 2-yl)pyridin-3-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone (Compound 77)

[0508] To a stirred solution of Intermediate 6 (150 mg, 0.298 mmol, 1 equiv) in dioxane (5 mL) and water (0.5 mL) was added 2-(5-bromopyridin-3-yl)propan-2-ol (64 mg, 0.298 mmol, 1 equiv) and [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21mg, 0.030 mmol, 0.1 equiv) and potassium carbonate (82 mg, 0.596 mmol, 2 equiv). The reaction mixture was stirred at 100 °C for 2 h under nitrogen, then was cooled to room temperature. The reaction was then quenched by addition of water (10 mL) and was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-10% methanol / dichloromethane) and further purified by preparative HPLC (XBridge Prep OBD column, 20-50% acetonitrile / water with 10 mM ammonium bicarbonate and 0.5% ammonia) to afford the title compound as a white solid (31.4 mg, 20.7% yield). LCMS (ESI): m / z [M+H]+calcd for C30H36N6O2: 513.29, found 513.30. 'H NMR (300 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.47 - 8.59 (m, 3H), 7.97 (s, 1H), 7.73 (d, J = 7.3 Hz, 1H), 7.56 (s, 2H), 6.62 - 6.49 (m, 2H), 5.25 (s, 1H), 4.16 - 4.27 (m, 1H), 3.92 - 3.74 (m, 5H), 3.47 - 3.74 (m, 3H), 2.16 (t, J = 6.8 Hz,2H), 1.90 - 1.81(m, 2H), 1.70 - 1.62 (m, 2H), 1.52 - 1.39 (m, 10H).

[0509] Synthesis of Compound 80: (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(5-(l- hydroxyethyl)pyridin-3-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone

[0510] Scheme 51

[0511] Step 1: Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(5-(l- hydroxyethyl)pyridin-3-yl)phenyl)-2,6-diazaspiro [3.4] octan-6-yl)methanone (Compound 80)

[0512] To a stirred solution of Intermediate 6 (180 mg, 0.356 mmol, 1 equiv) in dioxane (5 mL) and water (0.5 mL) was added (5-b1r-omopyridin-3-yl)ethanol (71 mg, 0.356 mmol, 1 equiv) and [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (26 mg, 0.036 mmol, 0.1 equiv) and potassium carbonate (98 mg, 0.712 mmol, 2 equiv). The reaction mixture was stirred at 100 °C for 2 h under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-10% methanol / di chloromethane) and further purified by preparative HPLC (Cl 8 column) to afford the title compound as a white solid (31.3mg, 17.6% yield). LCMS (ESI): m / z [M+H]+calcd for C29H34N6O2: 499.28, found 499.30. 'H NMR (300 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.52 (s, 2H), 8.43 (d, J = 2.0 Hz, 1H), 7.88 (s, 1H), 7.73 (d, J= 7.2 Hz, 1H), 7.56 (d, J= 7.7 Hz, 2H), 6.49 - 6.62 (m, 2H), 5.37 (br, 1H), 4.83 (q, J = 6.4 Hz, 1H), 4.21 (q, J = 6.8 Hz, 1H), 3.74 - 3.93 (m, 5H), 3.48 - 3.74 (m, 3H), 2.16 (t, J= 6.9 Hz, 2H), 1.89 (s, 2H), 1.68 (s, 2H), 1.44 - 1.58 (m, 4H), 1.40 (d, J= 6.4 Hz, 3H).

[0513] Synthesis of Compound 82: 6-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro [3.4] octan-2-yl)phenyl)pyrazin-2(TH)-one

[0514] Intermediate 6

[0515] Step 1: Preparation of 6-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- To a solution of Intermediate 6 (100 mg, 0.199 mmol, 1 equiv) in dioxane (2 mL) and water (0.2 mL) was added 6-bromo-lH-pyrazin-2-one (41 mg, 0.239 mmol, 1.2 equiv), potassium carbonate (68 mg, 0.498 mmol, 2.5 equiv) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14 mg, 0.020 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 100 °C under nitrogen, then the reaction was cooled to room temperature. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% methanol / dichloromethane) to afford the title compound as a yellow solid (57.0 mg, 60.8% yield). LCMS (ESI): m / z [M+H]+calcd for C26H29N7O2: 472.24, found 472.25. *H NMR (500 MHz, DMSO-d6) δ 10.91 - 12.79 (m, 1H), 8.51 (s, 2H), 7.37 - 8.01 (m, 5H), 6.49 (d, J= 10.4 Hz, 1H), 4.09 - 4.30 (m, 1H), 3.84 (d, J= 12.3 Hz, 5H), 3.68 (s, 2H), 3.54 (s, 1H), 2.11 - 2.31 (m, 2H), 1.80 - 1.92 (m, 2H), 1.60 - 1.74 (m, 2H), 1.44 - 1.58 (m, 4H).

[0516] Synthesis of Compound 83: 6-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro [3.4] octan-2-yl)phenyl)pyrazine-2-carbonitrile

[0517] Intermediate 6

[0518] Step 1: Preparation of 6-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro [3.4] octan-2-yl)phenyl)pyrazine-2-carbonitrile (Compound 83)

[0519] To a stirred solution of Intermediate 6 (100 mg, 0.199 mmol, 1 equiv) in dioxane (5mL) and water (0.5 mL) was added 2-chloro-6-cyano-pyrazine (33 mg, 0.239 mmol, 1.2 equiv) and [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14 mg, 0.020 mmol, 0.1 equiv). The reaction mixture was stirred at 100 °C for 4 h under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% methanol / dichloromethane) to afford the title compound as a yellow solid (27 mg, 28.3% yield). LCMS (ESI): m / z [M+H]+calcd for C27H28N8O: 481.24, found 481.30. ‘H NMR (300 MHz, DMSO-tf) δ 9.42 (s, 1H), 8.94 (s, 1H), 8.52 (s, 2H), 8.04 (s, 2H), 7.68 - 7.77 (m, 1H), 6.55 (s, 2H), 4.16 - 4.24 (m, 1H), 3.81-3.92 (m, 5H), 3.69 (s, 2H), 3.55 (s,lH),2.17 (t, J= 6.9 Hz, 2H), 1.77 - 1.93 (m, 2H), 1.59 - 1.72 (m, 2H), 1.37 - 1.56 (m, 4H).

[0520] Synthesis of Compound 85: 3-cyano-5-(4-(6-(2-(cyclopentylamino)pyrimidine-5- carbonyl)-2,6-diazaspiro [3.4] octan-2-yl)phenyl)pyridine 1-oxide

[0521] Step 1: Preparation of 3-(4-Bromophenyl)-5-cyanopyridin-l-ium-l-olate

[0522] To a solution of 5-(4-bromophenyl)pyridine-3-carbonitrile (150 mg, 0.579 mmol, 1 equiv, prepared as described for Compound 15) in di chlormethane (3 mL) was added 85% metachloroperbenzoic acid (234 mg, 1.16 mmol, 2.0 equiv) at 0 °C. The mixture was allowed to warm to room temperature and was stirred for 5 h. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with water (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (1 : 10 methanol / dichloromethane) to afford the title compound as a white solid (120 mg, 75.3% yield). LCMS (ESI): m / z [M+H]+calcd for Ci2H7BrN2O: 274.97, found 274.95.

[0523] Step 2: Preparation of 3-cyano-5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)phenyl)pyridine 1-oxide (Compound 85)

[0524] To a solution of 3-(4-bromophenyl)-5-cyanopyridin-l-ium-l-olate (50 mg, 0.182 mmol, 1 equiv) in dioxane (2 mL) was added Intermediate 3 (109 mg, 0.364 mmol, 2.0 equiv), cesium carbonate (148 mg, 0.455 mmol, 2.5 equiv) and { l,3-bis[2,6-bis(heptan-4-yl)phenyl]-4,5- dichloro-2,3-dihydro-lH-imidazol-2-yl}dichloro(3-chloro-llambda4-pyridin-l-yl)palladium (17 mg, 0.018 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 100 °C under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (20 mL) and e tracted ith eth l acetate (3 20 mL) The combined organic la ers ere dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% methanol / dichloromethane) and was re-crystallized from water to afford the title compound as a yellow solid (16 mg, 18.2% yield). LCMS (ESI): m / z [M+H]+ calcd for C28H29N7O2: 496.24, found 496.20. 'H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.69 (s, 1H), 8.51 (s, 2H), 8.11 (s, 1H), 7.58 - 7.81 (m, 3H), 6.39 - 6.61 (m, 2H), 4.20 (d, J= 7.0 Hz, 1H), 3.75 - 3.99 (m, 5H), 3.67 (s, 2H), 3.53 (s, 1H), 2.12 - 2.24 (m, 2H), 1.81 - 1.98 (m, 2H), 1.60 - 1.75 (m, 2H), 1.49 - 1.61 (m, 4H).

[0525] Synthesis of Compound 87: 5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro [3.4] octan-2-yl)phenyl)pyridazine 1-oxide

[0526] Step 1: Preparation of 4-(4-bromophenyl)pyridazine

[0527] To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridazine (500 mg, 2.43 mmol, 1 equiv) in dioxane (10 mL) and water (1 mL ) was added 4-bromoiodobenzene (280 mg, 0.990 mmol, 0.41 equiv), potassium carbonate (503 mg, 3.64 mmol, 1.5 equiv) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (177 mg, 0.243 mmol, 0.1 equiv). The mixture was stirred for 4 h at 100 °C under a nitrogen atmosphere, then was cooled to room temperature. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-15% methanol / dichloromethane) to afford the title compound as a yellow oil (110 mg, 19.3% yield). LCMS (ESI): m / z [M+H]+ calcd for CioH7BrN2: 234.98, found 234.95.

[0528] Step 2: Preparation of 5-(4-bromophenyl)pyridazine l-oxide& 4-(4- To a solution of 4-(4-bromophenyl)pyridazine (110 mg, 0.468 mmol, 1 equiv) in dichloromethane (3 mL ) was added 85% meta-chloroperbenzoic acid (189 mg, 0.936 mmol, 2 equiv) at 0 °C. The mixture was stirred for 2 h at room temperature, then was quenched with sodium bicarbonate solution (2 mL) at 0 °C. The resulting mixture was extracted with di chloromethane (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-15% methanol / di chloromethane) to afford the title compound as a yellow oil (110 mg, 93.6% yield, mixture of oxide regioisomers). LCMS (ESI): m / z [M+H]+ calcd for CioH7BrN20: 250.97, found 250.95.

[0529] Step 3: Preparation of 5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)phenyl)pyridazine 1-oxide (Compound 87)

[0530] To a solution of Intermediate 3 (240 mg, 0.797 mmol, 1 equiv) in dioxane (5 mL) was added 5-(4-bromophenyl)pyridazine 1-oxide (200 mg, 0.797 mmol, 1 equiv), XPhos (37 mg, 0.080 mmol, 0.1 equiv), XPhos-Pd-G3 (68 mg, 0.080 mmol, 0.1 equiv) and cesium carbonate (778 mg, 2.39 mmol, 3 equiv). The mixture was stirred for 2 h at 100 °C under a nitrogen atmosphere, then was cooled to room temperature. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-10% methanol / di chloromethane) and further purified by preparative HPLC (Xselect CSH C18 OBD Column, 14-44% acetonitrile / water with 0.05% trifluoroacetic acid) to afford the title compound as a yellow solid (48.4 mg, 12.9% yield). LCMS (ESI): m / z [M+H]+ calcd for C26H29N7O2: 472.24, found 472.25. 'H NMR (300 MHz, DMSO-d6) δ 8.93 (d, J= 3.1 Hz, 1H), 8.53 (s, 2H), 8.28 (d, J= 6.8 Hz, 1H), 8.06 - 8.15 (m, 1H), 7.66 - 7.84 (m, 3H), 6.48 - 6.60 (m, 2H), 4.16 - 425 (m, 1H), 3.48 - 3.96 (m, 8H), 2.16 (t, J= 6.9 Hz, 2H), 1.82 - 1.95 (m, 2H), 1.68 (s, 3H), 1.41 - 1.62 (m, 4H).

[0531] Synthesis of Compound 90: (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(4-

[0532] (hydroxymethyl)pyridin-3-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone Step 1: Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(4-

[0533] (hydroxymethyl)pyridin-3-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone (Compound 90)

[0534] To a solution of Intermediate 6 (200 mg, 0.397 mmol, 1 equiv) in dioxane (4 mL) was added (3-bromopyridin-4-yl)methanol (112 mg, 0.596 mmol, 1.5 equiv), XPhos (18 mg, 0.040 mmol, 0.1 equiv), XPhos-Pd-G3 (34 mg, 0.040 mmol, 0.1 equiv) and cesium carbonate (388 mg, 1.191 mmol, 3 equiv). The mixture was stirred for 2 h at 90 °C under a nitrogen atmosphere, then was cooled to room temperature. The reaction was then quenched with water (10 mL) at 0 °C and the resulting mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-10% methanol / dichloromethane) and purified further by preparative HPLC (C18 OBD Column, 14- 44% acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as an off-white solid (115 mg, 59.7% yield). LCMS (ESI): m / z [M+H]+calcd for C28H23N6O2: 485.26, found 485.25. 'HNMR (500 MHz, DMSO-d6) δ 8.46 - 8.54 (m, 3H), 8.34 - 8.30 (m,

[0535] 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.54 (d, J= 5.0 Hz, 1H), 7.17 - 7.22 (m, 2H), 6.48 - 6.53 (m,

[0536] 2H), 5.36 (t, J= 5.3 Hz, 1H), 4.46 (d, J= 6.3 Hz, 2H), 4.16 - 4.26 (m, 1H), 3.77 - 3.89 (m,

[0537] 5H), 3.68 (s, 2H), 3.54 (s, 1H), 2.16 (t, J= 6.9 Hz, 2H), 1.84 - 1.92 (m, 2H), 1.66 - 1.70 (m,

[0538] 2H), 1.44 - 1.56 (m, 4H).

[0539] Synthesis of Compound 91: (2-(cyclopentylamino)pyrimidin-5-yl)(2-(3-fluoro-4- (pyrimidin-5-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone

[0540] Scheme 57

[0541] Step 1: Preparation of 5-(4-bromo-2-fluorophenyl)pyrimidine

[0542] To a solution of 4-bromo-2-fluorophenylboronic acid (500 mg, 2.29 mmol, 1 equiv) in dioxane (5 mL) and water (0.5 mL) was added 5-bromopyrimidine (726 mg, 4.57 mmol, 2.0 equiv), tetrakis(triphenylphosphine)palladium(0) (264 mg, 0.229 mmol, 0.1 equiv). The mixture was stirred for 2 h at 90 °C under a nitrogen atmosphere, then was cooled to room temperature. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-80% ethyl acetate / petroleum ether) to afford the title compound as a yellow solid (280 mg, 48.4% yield). LCMS (ESI): m / z [M+H]+calcd for CioH6BrFN2: 252.97, found 253.00.

[0543] Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(3-fluoro-4-(pyrimidin-5- yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone (Compound 91)

[0544] To a solution of 5-(4-bromo-2-fluorophenyl)pyrimidine (60 mg, 0.237 mmol, 1 equiv) in dioxane (3 mL) and water (0.3 mL) was added Intermediate 3 (142 mg, 0.474 mmol, 2.0 equiv), cesium carbonate (154 mg, 0.474 mmol, 2.0 equiv) and (SP-4-l)-[l,3-bis[2,6-bis(l- propylbutyl)phenyl]-4,5-dichloro-l,3-dihydro-2J / -imidazol-2-ylidene]dichloro(3- chloropyridine-KN)-Palladium (23 mg, 0.024 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 100 °C under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% methanol / dichloromethane) and further purified by preparative HPLC (XB ridge Prep Shield RP18 OBD column, 22-49% with 10 mM ammonium bicarbonate and 0.5% ammonia) to afford the title compound as a white solid (84.1 mg, 74.9% yield). LCMS (ESI): m / z [M+H]+calcd for C26H28FN7O: 474.24, found 474.25. 'H NMR (300 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.93 (s, 2H), 8.52 (s, 2H), 7.73 (d, J= 7.3 Hz, 1H), 7.50 (s, 1H), 6.39 (d, J = 9.4 Hz, 2H), 4.02 - 4.32 (m, 1H), 3.77 - 3.98 (m, 5H), 3.47 - 3.77 (m, 3H), 2.02 - 2.28 (m, 2H), 1.82 - 1.93 (m, 2H), 1.61 - 1.82 (m, 2H), 1.32 - 1.61 (m, 4H).19F NMR (282 MHz, DMSO-d6) δ -117.53.

[0545] Synthesis of Compound 92: (2-(cyclopentylamino)pyrimidin-5-yl)(2-(2-fluoro-4- (pyrimidin-5-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone

[0546] Scheme 58

[0547] Step 1: Preparation of 5-(4-bromo-3-fluorophenyl)pyrimidine

[0548] To a stirred solution of 4-bromo-3-fluorophenylboronic acid (826 mg, 3.77 mmol, 1 equiv) in 1,4-dioxane (10 mL) and water (1 mL) was added 5-bromopyrimidine (600 mg, 3.77 mmol, 1 equiv) and potassium carbonate (1.56 g, 11.3 mmol, 3 equiv), followed by tetrakis(triphenylphosphine)palladium(0) (436 mg, 0.377 mmol, 0.1 equiv). The reaction mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere, then was cooled to room temperature. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-15% methanol / di chloromethane) to afford the title compound as a light yellow solid (500 mg, 52.4% yield). LCMS (ESI): m / z [M+H]+calcd for CioH6BrFN2: 252.97, found 252.90.

[0549] Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(2-fluoro-4-(pyrimidin-5- yl)phenyl)-2,6-diazaspiro [3.4] octan-6-yl)methanone (Compound 92)

[0550] To a stirred solution of Intermediate 3 (200 mg, 0.664 mmol, 1 equiv) in anhydrous 1,4- dioxane (5 mL) was added 5-(4-bromo-3-fluorophenyl)pyrimidine (168 mg, 0.664 mmol, 1 equiv) and cesium carbonate (649 mg, 1.992 mmol, 3 equiv), followed by XPhos (32 mg, 0.066 mmol, 0.1 equiv) and XPhos-Pd-G3 (56 mg, 0.066 mmol, 0.1 equiv). The reaction mixture was stirred at 100 °C for 3 h under a nitrogen atmosphere, then was cooled to room temperature. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-15% methanol / di chloromethane) and purified further by preparative HPLC (Bridge Prep OBD Cl 8 column, 20-47% acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a white solid (59.7 mg, 19.0% yield). LCMS (ESI): m / z [M+H]+calcd for C26H28FN7O: 474.24, found 474.20.1HNMR (400 MHz, DMSO-d6) δ 9.09 (s, 3H), 8.49 - 8.51 (m, 2H), 7.74 (d, J = 7.1 Hz, 1H), 7.59 - 7.68 (m, 1H), 7.52 (d, J = 8.7 Hz, 1H), 6.66 (d, J = 10.5 Hz, 1H), 4.15 - 4.26 (m, 1H), 3.65 - 3.70 (m, 4H), 3.84 (s, 1H), 3.68 (s, 2H), 3.54 (s, 1H), 2.17 (t, J = 6.9 Hz, 2H), 1.88 (d, J= 8.9 Hz, 2H), 1.66 - 1.69 (m, 2H), 1.49 - 1.52 (m, 4H). Synthesis of Compound 93: (2-(cyclopentylamino)pyrimidin-5-yl)(2-(2-(hydroxymethyl)- 4-( LH-pyrazol-4-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone

[0551] Step 1: Preparation of methyl 2-bromo-5-( (tetr1:-ihydro-2 / / -pyran-2-yl)-l / / -pyrazol-4- yl)benzoate

[0552] To a solution of methyl 2-bromo-5-iodobenzoate (500 mg, 1.47 mmol, 1 equiv) and (oxan- 1- 2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (367 mg, 1.32 mmol, 0.90 equiv) in dioxane (10 mL) and water (2 mL) was added [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (107 mg, 0.146 mmol, 0.10 equiv) and potassium carbonate (608 mg, 4.399 mmol, 3.00 equiv). The reaction was heated at 100 °C for 2 h under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% methanol / dichloromethane) to afford the title compound as a yellow solid (400 mg, 74.6% yield). LCMS (ESI): m / z [M+H]+calcd for CieHnBrlShCh: 365.04, found 365.05. Step 2: Preparation of methyl 2-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)-5-( 1 -(t el rahydro-2 / / -py ran-2-yl )-l / / -pyrazol-4-yl (benzoate

[0553] To a solution of methyl 2-bromo-5-[l-(oxan-2-yl)pyrazol-4-yl]benzoate (370 mg, 1.01 mmol, 1 equiv) and Intermediate 3 (366 mg, 1.21 mmol, 1.20 equiv) in dioxane (10 mL) was added XPhos (48 mg, 0.101 mmol, 0.10 equiv), XPhos-Pd-G3 (85 mg, 0.100 mmol, 0.10 equiv) and cesium carbonate (990 mg, 3.04 mmol, 3.00 equiv). The mixture was stirred for 2 h at 100 °C under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% methanol / dichloromethane) to afford the title compound as a yellow solid (300 mg, 50.5% yield). LCMS (ESI): m / z [M+H]+calcd for C32H39N7O4: 586.31, found 586.30.

[0554] Step 3: Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(2-(hydroxymethyl)-4-(l- (tetrahydro-2 / / -pyran-2-yl)-l / / -pyrazol-4-yl)phenyl)-2.6-diazaspiro|3.4|octan-6- yl)methanone

[0555] To a solution of methyl 2-{6-[2-(cyclopentylamino)pyrimidine-5-carbonyl]-2,6- diazaspiro[3.4]octan-2-yl}-5-[l-(oxan-2-yl)pyrazol-4-yl]benzoate (150 mg, 0.256 mmol, 1 equiv) in tetrahydrofuran (5 mL) was added lithium aluminum hydride (15 mg, 0.395 mmol, 1.54 equiv) at 0 °C. The resulting mixture was stirred for 1 hour at 0 °C. The reaction was quenched by addition of sodium sulfate solution at 0 °C and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-20% methanol / dichloromethane) to afford the title compound as a white solid (90 mg, 63.0% yield). LCMS (ESI): m / z [M+H]+calcd for C31H39N7O3: 558.31, found 558.25.

[0556] Step 4: Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(2-(hydroxymethyl)-4- (lZ7-pyrazol-4-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone (Compound 93)

[0557] To a stirred solution of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(2-(hydroxymethyl)-4-(l- (tetrahydro-2J / -pyran-2-yl)-U / -pyrazol-4-yl)phenyl)-2,6-diazaspiro[3.4]octan-6- yl)methanone (100 mg, 0.179 mmol, 1 equiv) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 1 h, then was concentrated to dryness. The residue was then purified by preparative HPLC (C 18 Column, 10-40% acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound (6.5 mg, 7.6% yield). LCMS (ESI): m / z [M+H]+calcd for C26H31N7O2: 474.26, found 474.30. 'HNMR (500 MHz, DMSO-d6) δ 12.76 (s, 1H), 8.51 (s, 2H), 7.68 - 8.05 (m, 3H), 7.44 - 7.48 (m, 1H), 7.30 - 7.34 (m, 1H), 6.39 - 6.44 (m, 1H), 4.94 - 5.02 (m, 1H), 4.36 - 4.44 (m, 2H), 4.16 - 4.24 (m, 1H), 3.75 - 3.89 (m, 5H), 3.62 - 3.67 (m, 2H), 3.52 (s, 1H), 2.14 (t, J= 6.9 Hz, 2H), 1.86 - 1.91 (m, 2H), 1.66 - 1.70 (m, 2H), 1.49- 1.53 (m, 4H). Synthesis of Compound 95: (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(5-

[0558] (hydroxymethyl)pyridin-3-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone

[0559] Step 1: Preparation of methyl 5-(4-bromophenyl)nicotinate

[0560] To a solution of b1r-omo-4-iodobenzene (4 g, 14.1 mmol, 1 equiv) and methyl 5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)nicotinate (3.7 g, 14.1 mmol, 1 equiv) in dioxane (60 mL) and water (6 mL) was added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1 g, 1.41 mmol, 0.1 equiv) and potassium carbonate (3.9 g, 28.3 mmol, 2 equiv). The mixture was stirred at 90 °C for 4 h under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a white solid (4 g, 96.8% yield). LCMS (ESI): m / z [M+H]+calcd for CnHioBrNCh: 291.99, found 291.90.

[0561] Step 2: Preparation of methyl 5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro [3.4] octan-2-yl)phenyl)nicotinate

[0562] To a solution of methyl 5-(4-bromophenyl)nicotinate (800 mg, 2.74 mmol, 1 equiv) and Intermediate 3 (825 mg, 2.74 mmol, 1 equiv) in dioxane (100 mL) was added XPhos-Pd-G3 (228 mg, 0.273 mmol, 0.1 equiv), XPhos (257 mg, 0.546 mmol, 0.2 equiv) and cesium carbonate (2.6 g, 8.21 mmol, 3 equiv). The mixture was stirred at 100 °C for 3 h under nitrogen, then was cooled to room temperature. The reaction mixture was then quenched with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% methanol / di chloromethane) to afford the title compound as a white solid (0.6 g, 42.8% yield). LCMS (ESI): m / z [M+H]+calcd for C29H32N6O3: 513.26, found 513.30. Step 3: Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(5-

[0563] (hydroxymethyl)pyridin-3-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone (Compound 95)

[0564] To a solution of methyl 5-(4-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)phenyl)nicotinate (0.59 g, 1.15 mmol, 1 equiv) in methanol (10 mL) was added sodium borohydride (88 mg, 2.30 mmol, 2.0 equiv) at 0 °C. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was then quenched with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% methanol / dichloromethane) and further purified by preparative HPLC (Cl 8 column, acetonitrile / water) to afford the title compound as a white solid (288.6 mg, 51.7% yield). LCMS (ESI): m / z [M+H]+calcd for C28H32N6O2: 485.26, found 485.25. 'H NMR (300 MHz, DMSO-cL) δ 8.69 (s, 1H), 8.52 (s, 2H), 8.40 (s, 1H), 7.88 (s, 1H), 7.73 (d, J= 7.1 Hz, 1H), 7.57 - 7.62 (m, 2H), 6.48 - 6.62 (m, 2H), 5.34 (t, J = 5.7 Hz, 1H), 4.58 (d, J = 5.7 Hz, 2H), 4.21 (d, J = 7.0 Hz, 1H), 3.83 (s, 5H), 3.55 - 3.68 (m, 3H), 2.16 (t, J = 6.8 Hz, 2H), 1.80 - 2.01 (m, 2H), 1.65 - 1.73 (m, 2H), 1.50 - 1.58 (m, 4H).

[0565] Synthesis of Compound 96: 2-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro [3.4] oct a n-2-y 1 )-5-( l / / -pyrazol-4-yl (benzonit rile

[0566] Step 1: Preparation of 2-(6-(2-(cyclopentylamino) pyrimidine-5-carbonyl)-2,6-diazaspiro [3.4] octan-2-yl)-5-( (te1t-rahydro-2 / / -pyran-2-yl)-l / / -pyrazol-4-yl)benzonitrile

[0567] To a solution of 2-chloro-5-[l-(oxan-2-yl) pyrazol-4-yl] benzonitrile (150 mg, 0.521 mmol, 1 equiv, prepared similarly to Compound 93, step 1) and Intermediate 3 (157 mg, 0.521 mmol, 1 equiv) in dioxane (5 mL) was added (SP-4-l)-[l,3-bis[2,6-bis(l-propylbutyl)phenyl]-4,5- dichloro l 3 dih dro 2J / imida ol 2 lidene]dichloro(3 chlorop ridine KN) Palladi m (50 mg, 0.052 mmol, 0.1 equiv) and cesium carbonate (509 mg, 1.563 mmol, 3 equiv). The mixture was stirred at 90 °C for 2 h under nitrogen, then was cooled to room temperature. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% methanol / dichloromethane) to afford the title compound (150 mg, 52.1% yield). LCMS (ESI): m / z [M+H]+calcd for CnEEeNsCh: 553.30, found 553.10.

[0568] Step 2: Preparation of 2-(6-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-2-yl)-5-( l / / -pyrazol-4-yl (benzonitrile (Compound 96)

[0569] To a stirred solution of 2-(6-(2-(cyclopentylamino) pyrimidine-5-carbonyl)-2,6-diazaspiro [3.4] octan-2-yl)-5-(l-(tetrahydro-2J / -pyran-2-yl)-17 / -pyrazol-4-yl) benzonitrile (100 mg, 0.181 mmol, 1 equiv) in di chloromethane (4 mL) was added trifluoroacetic acid (1 mL) . The reaction mixture was stirred at room temperature for 1 h, then was concentrated to dryness. The residue was purified by preparative HPLC (C18 column, acetonitrile / water with 0.1% formic acid) to afford the title compound as a white solid (29.6 mg, 34.5% yield). LCMS (ESI): m / z [M+H]+calcd for C26H28N8O: 469.24, found 469.25. 'H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.52 (s, 2H), 7.83 - 8.24 (m, 2H), 7.57 - 7.81 (m, 3H), 6.59 (s, 1H), 3.99 - 4.35 (m, 5H), 3.85 (s, 1H), 3.48 - 3.76 (m, 3H), 2.13 - 2.24 (m, 2H), 1.82 - 1.98 (m, 2H), 1.62 - 1.74 (m, 2H), 1.42 - 1.61 (m, 4H).

[0570] Synthesis of Compound 101: (2-(2-(lH-pyrazol-4-yl)pyrimidin-5-yl)-2,6- diazaspiro[3.4]octan-6-yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone

[0571] Step 1: Preparation of 5-Bromo-2-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4- yl)pyrimidine To a solution of 5-bromo-2-iodopyrimidine (819 mg, 2.876 mmol, 2.0 equiv) in dioxane (5 mL) and water (0.5 mL) was added (oxan1--2-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)pyrazole (400 mg, 1.438 mmol, 1.00 equiv), potassium carbonate (497 mg, 3.595 mmol, 2.5 equiv) and Pd(dppf)C12 (105 mg, 0.144 mmol, 0.1 equiv) at rt. The resulting mixture was stirred for 2h at 100°C under N2 atmosphere. The mixture was subsequently cooled to room temperature then diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-80% PEZEA) to afford 5-bromo-2- [l-(oxan-2-yl)pyrazol-4-yl]pyrimidine (400 mg, 81.0%) as a brown solid. LCMS (ESI): m / z [M+H]+calcd for Ci2Hi3BrN4O: 308.02 m / z, found 309.00.

[0572] Step 2: Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(2-(l-(tetrahydro-2H- pyran-2-yl)-lH-pyrazol-4-yl)pyrimidin-5-yl)-2,6-diazaspiro[3.4]octan-6-yl)methanone

[0573] To a solution of 5-bromo-2-[l-(oxan-2-yl)pyrazol-4-yl]pyrimidine (120 mg, 0.388 mmol, 1.00 equiv) in dioxane (3 mL) was added N-cyclopentyl-5-(2,6-diazaspiro[3.4]octane-6- carbonyl)pyrimidin-2-amine (117 mg, 0.388 mmol, 1.00 equiv), caesium carbonate (253 mg, 0.776 mmol, 2.0 equiv), RuPhos (183 mg, 0.039 mmol, 0.1 equiv) and RuPhos Pd G3 (32 mg, 0.039 mmol, 0.1 equiv) at rt. The resulting mixture was stirred for 2h at 100°C under N2. The mixture was subsequently cooled to room temperature then diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-20% DCM / MeOH) to afford N-cyclopentyl-5-(2-(2-[l-(oxan-2- yl)pyrazol-4-yl]pyrimidin-5-yl)-2,6-diazaspiro[3.4]octane-6-carbonyl)pyrimidin-2-amine (120 mg, 58.3%) as a white solid. LCMS (ESI): m / z [M+H]+calcd for C28H35N9O2: 529.15 m / z, found 530.35.

[0574] Step 3: Preparation of (2-(2-(lH-pyrazol-4-yl)pyrimidin-5-yl)-2,6-diazaspiro[3.4]octan-6- yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone (Compound 101)

[0575] To a solution of N-cyclopentyl-5-(2-{2-[l-(oxan-2-yl)pyrazol-4-yl]pyrimidin-5-yl}-2,6- diazaspiro[3.4]octane-6-carbonyl)pyrimidin-2-amine (90 mg, 0.170 mmol, 1 equiv) in DCM (2mL) was added TFA (1 mL). The resulting mixture was stirred for 2h at rt. The resulting mixture was concentrated under reduced pressure and the residue was purified by Prep-HPLC using a XBridge Prep Shield RP18 OBD 150 mm x 30 mm x 5 colum μnm (eluent: 14% to 44% (v / v) ACN and H2O with lOmmol / L NH4HC03+0.05%NH3H20) to afford N- cyclopentyl-5-(2-(2-(lH-pyrazol-4-yl)pyrimidin-5-yl)-2,6-diazaspiro[3.4]octane-6- carbonyl)pyrimidin-2-amine (22.8 mg, 30.1%) as a white solid. LCMS (ESI): m / z [M+H]+calcd for C23H27N9O: 445.20 m / z, found 446.20. 'H NMR (300 MHz, DMSO-d6) δ 13.00 (s, 1H), 8.51 (s, 2H), 7.91 - 8.22 (m, 4H), 7.73 (d, J = 7.3 Hz, 1H), 4.10 - 4.37 (m, 1H), 3.79 - 4.10 (m, 5H), 3.41 - 3.73 (m, 3H), 2.05 - 2.21 (m, 2H), 1.80 - 1.21 (m, 2H), 1.66 - 1.68 (m, 2H) 1 43 - 4 59 (m 4H) Synthesis of Compound 102: (2-(4-(4H-l,2,4-triazol-3-yl)phenyl)-2,6- diazaspiro[3.4]octan-6-yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone

[0576] Step 1: Preparation of (Z)-4-bromo-7V-((dimethylamino)methylene)benzamide

[0577] A mixture of 4-bromobenzamide (1 g, 4.999 mmol, 1 equiv) and 1,1 -dimethoxy -N,N- dimethylmethanamine (10 mL) was stirred at 90 °C for 15 minutes. The mixture was cooled to room temperature, and diethyl ether (30 mL) was added. The resulting crystals were filtered and dried to give (Z)-4-bromo-N-((dimethylamino)methylene)benzamide as a yellow solid (900 mg, 64.9% yield). LCMS (ESI): m / z [M+H]+calcd for CioHiiBrN20: 255.01, found 255.10.

[0578] Step 2: Preparation of 3-(4-bromophenyl)-4H-l,2,4-triazole

[0579] To a solution of (Z)-4-bromo-N-((dimethylamino) methyl ene)benzami de (800 mg, 3.14 mmol, 1 equiv) in acetic acid (10 mL) was added hydrazine hydrate (0.3 mL). The mixture was stirred for 2 h at 80 °C. The reaction was subsequently cooled to room temperature, and diethyl ether was added to precipitate the product. The precipitate was then collected and dried to afford the title compound (600 mg, 78.5% yield). LCMS (ESI): m / z [M+H]+calcd for CsELBrNs: 223.97, found 223.95.

[0580] Step 3: Preparation of 3-(4-bromophenyl)-4-(tetrahydro-2H-pyran-2-yl)-4H-l,2,4- triazole

[0581] To a solution of 3-(4-bromophenyl)-4H-l,2,4-triazole (400 mg, 1.79 mmol, 1 equiv) in tetrahydrofuran (5 mL) was added 3,4-dihydro-2H-pyran (225 mg, 2.68 mmol, 1.5 equiv) and methanesulfonic acid (17 mg, 0.178 mmol, 0.1 equiv). The mixture was stirred for 2 h at 75 °C, then was cooled to room temperature. The reaction was then quenched by addition of water (5 mL) and was extracted with ethyl acetate (10 mL x 3). The combined organic layers were was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to afford the title compound as a white solid (300 mg, 50.2% yield). LCMS (ESI): m / z [M+H]+calcd for Ci3Hi4BrN3O: 308.03, found 308.10.

[0582] Step 4: Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(4-(tetrahydro-2H- pyran-2-yl)-4H-l,2,4-triazol-3-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone

[0583] To a solution of (2-(cyclopentylamino)pyrimidin-5-yl)(2,6-diazaspiro[3.4]octan-6- yl)methanone (200 mg, 0.664 mmol, 1 equiv) and 3-(4-bromophenyl)-4-(tetrahydro-2H-pyran- 2-yl)-4H-l,2,4-triazole (224.95 mg, 0.730 mmol, 1.1 equiv) in dioxane (5 mL) was added XPhos (63 mg, 0.133 mmol, 0.2 equiv), XPhos-Pd-G3 (56 mg, 0.066 mmol, 0.1 equiv) and cesium carbonate (648 mg, 1.99 mmol, 3 equiv). The mixture was stirred at 100 °C for 2 h under nitrogen, then was cooled to room temperature. The mixture was then diluted with water (10 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-10% methanol / di chloromethane) to afford the title compound as a white solid (220 mg, 58.3% yield). LCMS (ESI): m / z [M+H]+calcd for C29H36N8O2: 529.30, found 529.25.

[0584] Step 5: Preparation of (2-(4-(4H-l,2,4-triazol-3-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl) (2-(cyclopentylamino)pyrimidin-5-yl)methanone (Compound 102)

[0585] To a stirred solution of 2-(cyclopentylamino) pyrimidin-5-yl)(2-(4-(4-(tetrahydro-2H-pyran-2- yl)-4H-l,2,4-triazol-3-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone (100 mg, 0.189 mmol, 1 equiv) in dichlorometahne (4 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Cl 8 column, acetonitrile / water with 0.1% formic acid) to afford the title compound as a white solid (58.4 mg, 60.0% yield). LCMS (ESI): m / z [M+H]+calcd for C24H28N8O: 445.24, found 445.25. 'H NMR (400 MHz, DMSO-d6) δ 12.7 - 14.8 (br, 1H), 8.52 (s, 2H), 8.16 (s, 1H), 7.76 - 7.91 (m, 2H), 7.65 - 7.75 (m, 1H), 6.52 (s, 2H), 4.21 (d, J = 6.7 Hz, 1H), 3.76 - 3.96 (m, 5H), 3.62 - 3.74 (m, 2H), 3.47 - 3.60 (m, 1H), 2.16 (t, J = 6.9 Hz, 2H), 1.82 - 1.98 (m, 2H), 1.61 - 1.77 (m, 2H), 1.42 - 1.59 (m, 4H).

[0586] Synthesis of Compound 105: (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(oxazol-5- yl)phenyl)-2,6-diazaspiro [3.4] octan-6-yl)methanone

[0587] Scheme 64

[0588] Intermediate 5

[0589] Step 1: Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(oxazol-5-yl)phenyl)- 2,6-diazaspiro[3.4]octan-6-yl)methanone (Compound 105)

[0590] To a solution of Intermediate 5 (100 mg, 0.219 mmol, 1.00 equiv) in dioxane (3 mL) and water (0.3 mL ) were added 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3-oxazole (85 mg, 0.438 mmol, 2 equiv), cesium carbonate (142.78 mg, 0.438 mmol, 2 equiv) and [1,1 - Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (16.03 mg, 0.022 mmol, 0.1 equiv). The mixture was stirred for 12 h at 100 °C under a nitrogen atmosphere. After the mixture was cooled to room temperature, the contents were diluted with water. The resulting mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue as then purified by silica gel chromatography (0-15% methanol / di chloromethane) and further purified by preparative HPLC (XB ridge Prep OBD C18 Column, 31-51% acetonitrile / water with 10 mM ammonium carbonate) to afford the title compound as a white solid (19.4 mg, 19.9% yield). LCMS (ESI): m / z [M+H]+calcd for C25H28N6O2: 445.23, found 445.20. 'H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 2H), 8.29 (s, 1H), 7.68 - 7.73 (m, 1H), 7.53 (s, 2H), 7.40 (s, 1H), 6.51 (s, 2H), 4.21 (d, J = 7.9 Hz, 1H), 3.52 - 3.84 (m, 8H), 2.10-2.22 (m, 2H), 1.87 - 1.91 (m, 2H), 1.53-1.73 (m, 2H), 1.49 - 1.54 (m, 4H).

[0591] Synthesis of Compound 107: (2-(4-(lH-l,2,3-triazol-5-yl)phenyl)-2,6- diazaspiro[3.4]octan-6-yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone

[0592] Scheme 65

[0593] Step 1: Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(2-(tetrahydro-2H- pyran-2-yl)-2H-l,2,3-triazol-4-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone

[0594] To a stirring solution Intermediate 5 (150 mg, 0.329 mmol, 1 equiv) in dioxane (2 mL) and water (0.2 mL) was added 2-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2H- 1,2, 3 -triazole (138 mg, 0.494 mmol, 1.5 equiv), tetrakis(triphenylphosphine)palladium(0) (76 mg, 0.066 mmol, 0.2 equiv) and potassium carbonate (91 mg, 0.658 mmol, 2 equiv). The mixture was stirred under a nitrogen atmosphere at 100 °C for 16 h. The mixture was subsequently cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% methanol / dichloromethane) to afford the title compound (130 mg, 74.8% yield). LCMS (ESI): m / z [M+H]+calcd for C29H36N8O2: 529.30, found 529.40.

[0595] Step 2: Preparation of (2-(4-(lH-l,2,3-triazol-5-yl)phenyl)-2,6-diazaspiro[3.4]octan-6- yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone (Compound 107)

[0596] To a stirred solution of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(2-(tetrahydro-2H-pyran- 2-yl)-2H-l,2,3-triazol-4-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone (170 mg, 0.322 mmol, 1 equiv) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was subsequently diluted with water (5 mL). The resulting solution was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0- 20% methanol / dichloromethane) and further purified by preparative HPLC (XBridge Prep OBD C18 Column, 29-46% acetonitrile / water with 10 mM ammonium bicarbonate and 0.05% ammonia) to afford the title compound as a white solid (50.2 mg, 35.1% yield). LCMS (ESI): m / z [M+H]+calcd for C24H28N8O: 445.24, found 445.20. 'H NMR (300 MHz, DMSO-d6) 5 8.52 (s, 2H), 8.10 (s, 1H), 7.60 - 7.77 (m, 3H), 6.49 (d, J = 8.4 Hz, 2H), 4.14 - 4.27 (m,lH), 3.71 - 3.88 (m, 5H), 3.68 (s, 2H), 3.54 (s, 1H), 2.15 (t, J= 6.9 Hz, 2H), 1.81 - 1.99 (m, 2H), 1.60 - 1.74 (m,2H), 1.41 - 1.58 (m, 4H). Synthesis of Compound 111: (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(pyrazin-2- yl)phenyl)-2,6-diazaspiro [3.4] octan-6-yl)methanone

[0597] Intermediate 5

[0598] Step 1: Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(pyrazin-2-yl)phenyl)- 2,6-diazaspiro[3.4]octan-6-yl) (Compound 111)

[0599] To a solution of Intermediate 5 (100 mg, 0.219 mmol, 1 equiv) in dioxane (3 mL) and water (0.3 mL ) was added pyrazin-2-ylboronic acid (81 mg, 0.657 mmol, 3 equiv), potassium carbonate (91 mg, 0.657 mmol, 3 equiv) and bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (20 mg, 0.022 mmol, 0.1 equiv). The mixture was stirred for 12 h at 100 °C under a nitrogen atmosphere. The reaction was subsequently cooled to room temperature, quenched with water (20 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-15% methanol / di chloromethane) and further purified by preparative HPLC (Cl 8 OBD Column, 50:50 acetonitrile / water) to afford the title compound as a yellow solid (20.1 mg, 20.1% yield). LCMS (ESI): m / z [M+H]+calcd for C26H29N7O: 456.25, found 456.20. 'HNMR (300 MHz, DMSO-d6) δ 9.57 (s, 1H), 9.10 (d, J = 5.6 Hz, 1H), 8.52 (s, 2H), 7.68 - 7.92 (m, 4H), 6.56 (s, 2H), 4.16 - 4.24 (m, 1H), 3.81 - 3.95 (m, 5H), 3.52 - 3.72 (m, 3H), 2.17 (t, J = 6.9 Hz, 2H), 1.85 - 1.91 (m, 2H), 1.65 - 1.72 (m, 2H), 1.45 - 1.58 (m, 4H).

[0600] Synthesis of Compound 112: (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(pyrimidin-5- yl)phenyl)-2,6-diazaspiro [3.4] octan-6-yl)methanone

[0601] Scheme 67

[0602] Intermediate 5

[0603] Step 1: Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(pyrimidin-5- yl)phenyl)-2,6-diazaspiro [3.4] octan-6-yl)methanone (Compound 112)

[0604] A mixture of 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (82 mg, 0.400 mmol, 1.82 equiv), Intermediate 5 (100 mg, 0.220 mmol, 1.00 equiv), and potassium carbonate (91 mg, 0.660 mmol, 3 equiv) were dissolved in dioxane (10 mL) and water (1 mL), then [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (18 mg, 0.022 mmol, 0.10 equiv) was added and the reaction was stirred at 100 °C for 3 h under nitrogen. The mixture was subsequently cooled to room temperature and diluted with water (10 mL). The aqueous layer was extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% methanol / dichloromethane) and further purified by preparative HPLC (XSelect CSH Fluoro Phenyl column, 33-55% acetonitrile / water with 0.1% formic acid) to afford the title compound as an off-white solid (12.3 mg, 11.2% yield). LCMS (ESI): m / z [M+H]+calcd for C26H29N7O: 456.25, found 456.30. *HNMR (300 MHz, DMSO- de) δ 8.98 (d, J = 2.9 Hz, 3H), 8.45 (s, 2H), 7.45 - 7.72 (m, 3H), 6.50 (s, 2H), 4.07 - 4.20 (m, 1H), 3.68 - 3.88 (m, 5H), 3.45 - 3.65 (m, 3H), 1.98 - 2.22 (m, 2H), 1.73 - 1.92 (m, 2H), 1.61 (s, 2H), 1.34 - 1.50 (m, 4H).

[0605] Synthesis of Compound 115: (2-(5-( lH-pyrazol-4-yl)pyrimidin-2-yl)-2,6- diazaspiro[3.4]octan-6-yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone

[0606] Scheme 68

[0607] Step 1: Preparation of tert-butyl 2-(5-bromopyrimidin-2-yl)-2,6-diazaspiro[3.4]octane-6- carboxylate

[0608] To a solution of tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (400 mg, 1.88 mmol, 1 equiv) in acetonitrile (5 mL) was added 5-bromo-2-fluoropyrimidine (500 mg, 2.83 mmol, 1.5 equiv) and triethylamine (572 mg, 5.65 mmol, 3.0 equiv). The resulting mixture was stirred for 2 h at 80 °C. The mixture was then cooled to room temperature, quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-60% ethyl acetate / petroleum ether) to afford the title compound as a white solid (640 mg, 91.9% yield). LCMS (ESI): m / z [M+H]+calcd for CisEEiBrlSUCh: 369.08, found 369.10.

[0609] Step 2: Preparation of 2-(5-bromopyrimidin-2-yl)-2,6-diazaspiro [3.4] octane

[0610] To a stirred solution of tert-butyl 2-(5-bromopyrimidin-2-yl)-2,6-diazaspiro[3.4]octane-6- carboxylate (200 mg, 0.542 mmol, 1 equiv) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 1 h. The mixture was subsequently concentrated to dryness under reduced pressure to provide the title compound as a white solid (130 mg), which was used without purification. LCMS (ESI): m / z [M+H]+calcd for CioHi3BrN4: 271.03, found: 271.05.

[0611] Step 3: Preparation of 5-[2-(5-bromopyrimidin-2-yl)-2,6-diazaspiro[3.4]octane-6- carbonyl|- \-cyclopentylpyriinidin-2-ainine

[0612] To a solution of 2-(5-bromopyrimidin-2-yl)-2,6-diazaspiro[3.4]octane (100 mg, 0.372 mmol, 1 equiv) in pyridine (3 mL) was added Intermediate 1 (92 mg, 0.446 mmol, 1.2 equiv) and 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide (288 mg, 1.86 mmol, 5.0 equiv). The resulting mixture was stirred for 2 h at room temperature. The mixture was subsequently diluted with water and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with water (3 x 5 mL) and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1 : 10 methanol / dichloromethane) to afford the title compound as a white solid (120 mg, 70.4% yield). LCMS (ESI): m / z [M+H]+calcd for C2oH24BrN70: 458.12, found 458.15.

[0613] Step 4: Preparation of (2-(5-(lH-pyrazol-4-yl)pyrimidin-2-yl)-2,6-diazaspiro[3.4]octan-6- yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone (Compound 115)

[0614] To a solution of 5-[2-(5-bromopyrimidin-2-yl)-2,6-diazaspiro[3.4]octane-6-carbonyl]-N- cyclopentylpyrimidin-2-amine (80 mg, 0.175 mmol, 1 equiv) in dioxane (3 mL) and water (0.3 mL) was added 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-17 / -pyrazole (41 mg, 0.210 mmol, 1.2 equiv), potassium carbonate (48 mg, 0.350 mmol, 2.0 equiv) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 100 °C. The mixture was subsequently cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% methanol / dichloromethane) and further purified by preparative HPLC (XBridge Prep OBD column, 15-45% acetonitrile / water with 10 mM ammonium bicarbonate and 0.05% ammonia) to afford the title compound as a white solid (17.8 mg, 21.8% yield). LCMS (ESI): m / z [M+H]+calcd for C23H27N9O: 446.24, found 446.25. 'H NMR (400 MHz, DMSO-d6) δ 12.93 (s, 1H), 8.51 - 8.69 (m, 2H), 8.51 (s, 2H), 7.8 - 8.29 (m, 2H), 7.72 (s, 1H), 4.11 - 4.27 (m, 1H), 3.90 - 4.11 m, 4H), 3.83 (s, 1H), 3.67 (s, 2H), 3.53 (s, 1H), 2.14 (t, .7= 6.9 Hz, 2H), 1.82 - 1.95 (m, 2H), 1.66 - 1.68 (m, 2H), 1.41 - 1.59 (m, 4H).

[0615] Synthesis of Compound 116: (2-(6-(lH-pyrazol-4-yl)pyridin-3-yl)-2,6- diazaspiro[3.4]octan-6-yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone Step 1: Preparation of tert-butyl 2-(6-bromopyridin-3-yl)-2,6-diazaspiro[3.4]octane-6- carboxylate

[0616] To a solution of tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (500 mg, 2.36 mmol, 1 equiv) and 2-bromo-5-fluoropyridine (414 mg, 2.36 mmol, 1 equiv) in dimethylsulfoxide (5 mL) was added N, / f-diisopropylethylamine (913 mg, 7.07 mmol, 3 equiv). The mixture was stirred for 2 h at 130 °C. The reaction was subsequently cooled to room temperature and diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-100% ethyl acetate / petr oleum ether) to afford the title compound as a white solid (350 mg, 40.3% yield). LCMS (ESI): m / z [M+H]+calcd for CielMrNsCh: 368.09, found 368.10.

[0617] Step 2: Preparation of 2-(6-bromopyridin-3-yl)-2,6-diazaspiro[3.4]octane

[0618] To a solution of tert-butyl 2-(6-bromopyridin-3-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate (350 mg, 0.950 mmol, 1 equiv) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL, 0.009 mmol, 0.01 equiv) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 2 h. The resulting mixture was concentrated under reduced pressure to afford the title compound as a yellow oil (600 mg, 40.3%). LCMS (ESI): m / z [M+H]+calcd for CnHwBrNs: 268.04, found 268.05.

[0619] Step 3: Preparation of (2-(6-bromopyridin-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)(2- (cyclopentylamino)pyrimidin-5-yl)methanone

[0620] To a solution of 2-(6-bromopyridin-3-yl)-2,6-diazaspiro[3.4]octane (500 mg, 1.87 mmol, 1 equiv), pyridine (10 mL) and Intermediate 1 (386 mg, 1.87 mmol, 1 equiv) was added 3-(3- dimethylaminopropyl)carbodiimide (1157 mg, 7.460 mmol, 4 equiv). The mixture was stirred for 2 h at room temperature and subsequently quenched with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-15% methanol / dichloromethane) to afford the title compound as a white solid (200 mg, 23.4% yield). LCMS (ESI): m / z [M+H]+calcd for C2iH25BrN6O: 457.13, found 457.20.

[0621] Step 4: Preparation of (2-(6-(lH-pyrazol-4-yl)pyridin-3-yl)-2,6-diazaspiro[3.4]octan-6- yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone (Compound 116)

[0622] To a mixture of (2-(6-bromopyridin-3-yl)-2,6-diazaspiro[3.4]octan-6-yl)(2- (cyclopentylamino)pyrimidin-5-yl)methanone (100 mg, 0.219 mmol, 1 equiv) in dioxane (3 mL) and water (0.3 mL) was added 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (84 mg, 0.438 mmol, 2 equiv), cesium carbonate (142 mg, 0.438 mmol, 2 equiv) and tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.044 mmol, 0.2 equiv) and the mixture was stirred for 12 h at 100 °C under a nitrogen atmosphere. The mixture was subsequently cooled to room temperature and diluted with water (10 mL) The resulting mixture was extracted with over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-15% methanol / di chloromethane) further purified by preparative HPLC (XBridge BEH Shield RP18 Column, 20-50% acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a white solid (9.5 mg, 9.77% yield). LCMS (ESI): m / z [M+H]+calcd for C24H28N8: 445.24, found 445.20. 'H NMR (400 MHz, DMSO-d6) δ 12.80 (br, 1H), 8.52 (s, 2H), 8.01 (s, 2H), 768 - 7.82 (m, 2H), 7.42 - 7.53 (m, 1H), 6.86 - 6.91 (m, 1H), 4.17 - 4.26 (m, 1H), 3.74 - 3.93 (m, 5H), 3.47 - 3.74 (m, 3H), 2.17 (t, J = 6.9 Hz, 2H), 1.81 - 1.91 (m, 2H), 1.65 - 1.71 (s, 2H), 1,45 - 1.55 (m, 4H).

[0623] Synthesis of Compound 117: (2-(5-(lH-pyrazol-4-yl)pyridin-2-yl)-2,6- diazaspiro[3.4]octan-6-yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone

[0624] Step 1: Preparation of tert-butyl 2-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.4]octane-6- carboxylate

[0625] A solution of tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (300 mg, 1.41 mmol, 1 equiv) in acetonitrile (5 mL) was added 5-bromo-2-fluoropyridine (373 mg, 2.12 mmol, 1.5 equiv) and triethylamine (429 mg, 4.24 mmol, 3.0 equiv). The resulting mixture was stirred for 2 h at 80 °C. The reaction mixture was cooled to room temperature then quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to afford the title compound as an off- white solid (400 mg, 76.8% yield). LCMS (ESI): m / z [M+H]+calcd for CieH22BrN3O2: 368.09, found 368.10.

[0626] Step 2: Preparation of 2-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.4]octane

[0627] To a stirred solution of tert-butyl 2-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.4]octane-6- carboxylate (150 mg, 0.407 mmol, 1 equiv) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated to dryness under reduced pressure to afford the title compound as a white solid (100 mg), which was used without purification. LCMS (ESI): m / z [M+H]+calcd for CnHwBrNs: 268.04, found 268.10.

[0628] Step 3: Preparation of (2-(5-bromopyridin-2-yl)-2,6-diazaspiro[3.4]octan-6-yl)(2- (cyclopentylamino)pyrimidin-5-yl)methanone

[0629] To a solution of 2-(5-bromopyri din-2 -yl)-2,6-diazaspiro[3.4]octane (60 mg, 0.224 mmol, 1 equiv) in pyridine (2 mL) was added Intermediate 1 (55.64 mg, 0.269 mmol, 1.2 equiv) and 3-(3-dimethylaminopropyl)carbodiimide (174 mg, 1.12 mmol, 5.0 equiv). The resulting mixture was stirred for 2 h at room temperature. The mixture was subsequently quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% methanol / dichloromethane) to afford the title compound as a white solid (90 mg, 87.9% yield). LCMS (ESI): m / z [M+H]+calcd for C2iH25BrNeO: 459.13, found 459.10.

[0630] Step 4: Preparation of (2-(5-(lZ7-pyrazol-4-yl)pyridin-2-yl)-2,6-diazaspiro[3.4]octan-6- yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone (Compound 117)

[0631] A solution of 5-[2-(5-bromopyri din-2 -yl)-2,6-diazaspiro[3.4]octane-6-carbonyl]-N- cyclopentylpyrimidin-2-amine (80 mg, 0.175 mmol, 1 equiv) in dioxane (5 mL) and water (0.5 mL) was added 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (40.73 mg, 0.210 mmol, 1.2 equiv), potassium carbonate (48 mg, 0.350 mmol, 2.0 equiv) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol, 0.1 equiv). The resulting mixture was stirred for 2 h at 100 °C under nitrogen. The mixture was subsequently cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% methanol / dichloromethane) and further purified by preparative HPLC (XB ridge Prep OBD column, 19-39% acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a white solid (15.7 mg, 20.5% yield). LCMS (ESI): m / z [M+H]+calcd for C23H28N10O: 445.24, found 445.25. 'H NMR (400 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.51 (s, 2H), 8.35 (s, 1H), 7.56 - 8.21 (m, 4H), 6.41 (s, 1H), 4.20 (d, J= 7.8 Hz, 1H), 3.75 - 4.07 (m, 5H), 3.67 (s, 2H), 3.51 - 1.53 (m, 1H), 2.14 (t, J= 6.8 Hz, 2H), 1.86 - 1.88 (m, 2H), 1.66 - 1.68 (m, 2H), 1.49 - 1.53 (m, 4H).

[0632] Synthesis of Compound 118 and Compound 119: (S)-(2-(cyclopentylamino)pyrimidin-5- yl)(2-(4-(tetrahydrofuran-3-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone and (R)- (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(tetrahydrofuran-3-yl)phenyl)-2,6- diazaspiro [3.4] octan-6-yl)methanone

[0633] Step 1: Preparation of 4-(4-bromophenyl)tetrahydrofuran-2-ol

[0634] To a stirred solution of bro1m-o-4-iodobenzene (2.0 g, 7.07 mmol, 1 equiv) in acetontrile (40 mL) was added (Z)-but-2-ene-l,4-diol (0.75 g, 8.48 mmol, 1.2 equiv) and sodium bicarbonate (1.19 g, 14.1 mmol, 2.0 equiv) followed by palladium(II) acetate (0.03 g, 0.141 mmol, 0.02 equiv) and tetrabutylammonium chloride (2.09 g, 7.07 mmol, 1.0 equiv). The reaction mixture was stirred at 60 °C for 5 h. The mixture was subsequently cooled to room temperature, diluted with water (30 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-10% methanol / dichloromethane) to afford the title compound as a yellow oil (1.5 g, 87.2% yield).

[0635] Step 2: Preparation of 3-(4-bromophenyl)tetrahydrofuran

[0636] To a stirred solution of 4-(4-bromophenyl)tetrahydrofuran-2-ol (1 g, 4.11 mmol, 1 equiv) in dichloromethane (20 mL) at 0 °C was added triethylsilane (0.53 g, 4.53 mmol, 1.1 equiv) and boron trifluoride diethyl etherate (0.64 g, 4.53 mmol, 1.1 equiv). The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction was subsequently quenched with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-50% ethyl acetate / petr oleum ether) to afford the title compound as a yellow oil (0.62 g, 66.3% yield).

[0637] Step 3: Preparation of tert-butyl 2-(4-(tetrahydrofuran-3-yl)phenyl)-2,6- To a stirred solution of 3-(4-bromophenyl)tetrahydrofuran (0.5 g, 2.20 mmol, 1 equiv) in dioxane (10 mL) was added tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (0.47 g, 2.20 mmol, 1 equiv), XPhos (0.21 g, 0.440 mmol, 0.2 equiv) and XPhos-Pd-G3 (0.19 g, 0.220 mmol, 0.1 equiv). The reaction mixture was stirred at 100 °C for 3 h under nitrogen. The mixture was subsequently cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to afford the title compound as a yellow solid (0.52 g, 65.8% yield). LCMS (ESI): m / z [M+H]+calcd for C21H30N2O3: 359.23, found 359.25.

[0638] Step 4: Preparation of 2-(4-(tetrahydrofuran-3-yl)phenyl)-2,6-diazaspiro [3.4] octane

[0639] To a stirred solution of tert-butyl 2-(4-(tetrahydrofuran-3-yl)phenyl)-2,6- diazaspiro[3.4]octane-6-carboxylate (0.4 g, 1.12 mmol, 1 equiv) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated to dryness and the residue was purified by preparative HPLC (Cl 8 column, 0-40% acetonitrile / water) to afford the title compound as a white solid (0.25 g, 86.7% yield). LCMS (ESI): m / z [M+H]+calcd for C16H22N2O: 259.18, found 259.20. Synthesis of (S)-(2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(tetrahydrofuran-3- yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone and ( / ?)-( 2-

[0640] (cyclopentylamino)pyrimidin-5-yl)(2-(4-(tetrahydrofuran-3-yl)phenyl)-2,6- diazaspiro[3.4]octan-6-yl)methanone (Compounds 118 and 119)

[0641] To a stirred solution of 2-[4-(oxolan-3-yl)phenyl]-2,6-diazaspiro[3.4]octane (160 mg, 0.619 mmol, 1 equiv) in pyridine (8 mL) was added 3-(3-dimethylaminopropyl)carbodiimide (288 mg, 1.86 mmol, 3 equiv) and Intermediate 1 (193 mg, 0.928 mmol, 1.5 equiv). The mixture was stirred overnight at ambient temperature. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (XB ridge Prep Shield RP18 OBD Column, 30-60% acetonitrile / water) to afford a racemic mixture of the two title compounds as a yellow solid (90 mg). The compounds were separated by chiral -HPLC (CHIRALPAK IF column, 90:5:5 methyl tertbutyl ether / methanol / dichloromethane with 0.5% 2 M ammonia solution) to afford the two title compounds.

[0642] Compound 118 was isolated as the first eluting peak (35.5 mg, 12.8% yield). LCMS (ESI): m / z [M+H]+calcd for C26H33N5O2: 448.27, found 448.25. 'H NMR (300 MHz, DMSO-d6) 5 8.51 (s, 2H), 7.71 (d, J = 7.3 Hz, 1H), 7.05 - 7.10 (m, 2H), 6.35 - 6.42 (m, 2H), 4.20 (q, J = 6.8 Hz, 1H), 3.84 - 4.02 (m, 2H), 3.47 - 3.82 (m, 10H), 3.18 - 3.29 (m, 1H), 2.18 - 2.27 (m, 1H), 2.06 - 2.16 (m, 2H), 1.74 - 1.92 (m, 3H), 1.65 - 1.71 (m, 2H), 1.43 - 1.56 (m, 4H).

[0643] Compound 119 was isolated as the second eluting peak (39 4 mg 14 2% yield) LCMS (ESI): 8.51 (s, 2H), 7.71 (d, J= 7.3 Hz, 1H), 7.05 - 7.10 (m, 2H), 6.35 - 6.42 (m, 2H), 4.20 (q, J = 6.8 Hz, 1H), 3.84 - 4.02 (m, 2H), 3.47 - 3.82 (m, 10H), 3.18 - 3.29 (m, 1H), 2.18 - 2.27 (m, 1H), 2.06 - 2.16 (m, 2H), 1.74 - 1.92 (m, 3H), 1.65 - 1.71 (m, 2H), 1.43 - 1.56 (m, 4H).

[0644] Synthesis of Compound 123: (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(oxetan-3- yl)phenyl)-2,6-diazaspiro [3.4] octan-6-yl)methanone

[0645] Step 1: Preparation of tert-butyl 2-(4-(oxetan-3-yl)phenyl)-2,6-diazaspiro[3.4]octane-6- carboxylate

[0646] To a stirring solution of tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (500 mg, 2.36 mmol, 1 equiv) in dioxane (15 mL) was added cesium carbonate (2.3 g, 7.07 mmol, 3 equiv), XPhos (112 mg, 0.236 mmol, 0.1 equiv), XPhos-Pd-G3 (174 mg, 0.236 mmol, 0.1 equiv) and 3-(4-bromophenyl)oxetane (602 mg, 2.83 mmol, 1.2 equiv). The mixture was stirred at 100 °C for 5 h under nitrogen. The mixture was subsequently cooled to room temperature, filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (680 mg, 74.4% yield). LCMS (ESI): m / z [M+H]+calcd for C20H28N2O3: 345.21, found 345.10.

[0647] Step 2: Preparation of 2-(4-(oxetan-3-yl)phenyl)-2,6-diazaspiro [3.4] octane

[0648] To a stirred solution of tert-butyl 2-[4-(oxetan-3-yl)phenyl]-2,6-diazaspiro[3.4]octane-6- carboxylate (400 mg, 1.16 mmol, 1 equiv) in di chloromethane (6 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then diluted with diethyl ether to precipitate the product, which was collected by filtration and dried to afford the title compound (90 mg, 54.2% yield). LCMS (ESI): m / z [M+H]+calcd for C15H20N2O: 245.16, found 245.05.

[0649] Step 3: Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(oxetan-3-yl)phenyl)- To a stirred solution of 2-[4-(oxetan-3-yl)phenyl]-2,6-diazaspiro[3.4]octane (200 mg, 0.819 mmol, 1 equiv) in N,N-dimethylformamide (5 mL) was added Intermediate 1 (169 mg, 0.819 mmol, 1 equiv), HATU (467 mg, 1.23 mmol, 1.5 equiv) and A,A-diisopropylethylamine (212 mg, 1.64 mmol, 2 equiv). The reaction was stirred at room temperature for 5 h. The reaction mixture was subsequently quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-60% ethyl acetate / petroleum ether) and further purified by preparative HPLC (XBridge Prep C18 OBD column, 31-56% acetonitrile / water with 10 mM ammonium bicarbonate) to afford the title compound as a white solid (32.1 mg, 9.04% yield). LCMS (ESI): m / z [M+H]+calcd for C25H31N5O2: 434.25, found 434.35. 'H NMR (400 MHz, DMSO-d6) 5 8.51 (s, 2H), 7.72 (s, 1H), 7.20 (d, J = 8.9 Hz, 2H), 6.41 - 6.44 (m, 2H), 4.87 (t, J= 6.7 Hz, 2H), 4.54 (s, 2H), 4.04 - 4.26 (m, 2H), 3.58 - 3.97 (m, 8H), 2.06 - 2.17 (m, 2H), 1.87 - 1.89 (m, 2H), 1.66 - 1.69 (m, 2H), 1.49 - 1.53 (m, 4H).

[0650] Synthesis of Compound 124: (2-(4-(lH-pyrazol-4-yl)phenyl)-2,6-diazaspiro[3.4]octan-6- yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone

[0651] Step 1: Preparation of tert-butyl 2-(4-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4- yl)phenyl)-2,6-diazaspiro [3.4] octane-6-carboxylate

[0652] To a mixture of 4-(4-bromophenyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole (300 mg, 0.977 mmol, 1 equiv), tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (230 mg, 1.08 mmol, 1.11 equiv), and cesium carbonate (700 mg, 2.149 mmol, 2.20 equiv) in 1,4-dioxane (10 mL) was added XPhos (45 mg, 0.095 mmol, 0.10 equiv) and XPhos-Pd-G3 (85 mg, 0.101 mmol, 0.10 equiv) and the reaction mixture was stirred at 100 °C for 4 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature and quenched by addition of water (50 mL). The resulting mixture was extracted with ethyl acetate (80 mL x 3). The combined organic residue was purified by silica gel chromatography (20-60% ethyl acetate / petroleum ether) to afford the title compound as a yellow oil (300 mg, 69.7% yield). LCMS (ESI): m / z [M+H]+calcd for C25H34N4O3: 439.27, found 439.20.

[0653] Step 2: Preparation of 2-(4-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)phenyl)-2,6- diazaspiro [3.4] octane

[0654] Into a 20 mL pressure tank reactor were added tert-butyl 2-(4-(l-(tetrahydro-2H-pyran-2-yl)- lH-pyrazol-4-yl)phenyl)-2,6-diazaspiro[3.4]octane-6-carboxylate (200 mg, 0.456 mmol, 1 equiv), IN sodium carbonate solution (1 mL) in propan-l-ol (2 mL). The reaction mixture heated using a microwave at 150 °C for 3 h. The mixture was allowed to cool to room temperature then was concentrated under reduced pressure to afford the title compound as a viscous brown oil which was used directly without purification. LCMS (ESI): m / z [M+H]+calcd for C20H26N4O: 339.21, found 339.05.

[0655] Step 3: Preparation of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(l-(tetrahydro-2H- pyran-2-yl)-lH-pyrazol-4-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone

[0656] To a stirred solution of 2-(4-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)phenyl)-2,6- diazaspiro[3.4]octane (100 mg, crude) in pyridine (70 mL) was added Intermediate 1 (74 mg, 0.354 mmol) and et1h-yl-3-(3-dimethylaminopropyl)carbodiimide (138 mg, 0.885 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was subsequently quenched by the addition of water (35 mL). The resulting mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-20% methanol / dichloromethane) to afford the title compound as a white solid (60 mg, 38.5%) yield.

[0657] Step 4: Preparation of (2-(4-(lH-pyrazol-4-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)(2- (cyclopentylamino)pyrimidin-5-yl)methanone (Compound 124)

[0658] To a stirred solution of (2-(cyclopentylamino)pyrimidin-5-yl)(2-(4-(l-(tetrahydro-2H-pyran- 2-yl)-lH-pyrazol-4-yl)phenyl)-2,6-diazaspiro[3.4]octan-6-yl)methanone (50 mg, 0.095 mmol, 1 equiv) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (XBridge Prep OBD column 20-50% acetonitrile / water with 10 mM ammonium bicarbonate and 0.05% ammonia) to afford the title compound as a white solid (15.8 mg, 37.1% yield). LCMS (ESI): m / z [M+H]+calcd for C25H29N7O: 444.25, found 444.15. 'H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 2H), 7.87 (s, 2H), 7.70 (d, J = 7.2 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 6.44 (s, 2H), 4.21 (q, J= 7.0 Hz, 1H), 3.77 (d, J= 15.1 Hz, 5H), 3.52 (s, 4H), 2.14 (t, J= 6.9 Hz, 2H), 1.89 (d, J= 9.8 Hz, 2H), 1.66 - 1.68 (m, 2H), 1.49-1.52 (m, 4H).

[0659] Synthesis of Compound 184: (2-(((lR3^)-3-fluorocyclopentyl)amino)pyrimidin-5-yl)(6-

[0660] Step 1: Preparation of 3-(4-bromophenyl)-5-methanesulfonylpyridine

[0661] To a solution of 3-bromo-5-methanesulfonylpyridine (500 mg, 2.12 mmol, 1 equiv) in dioxane (15 mL) and water (1.5 mL) was added 4-bromophenylboric acid (425 mg, 2.12 mmol, 1 equiv), potassium carbonate (876 mg, 6.35 mmol, 1 equiv) and tetrakis(triphenylphosphine)palladium(0) (244 mg, 0.212 mmol, 0.1 equiv). The mixture was stirred for 3 h at 100 °C under nitrogen. The reaction mixture was cooled to room temperature, quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to afford the title compound as a white solid (250 mg, 37.8% yield). LCMS (ESI): m / z [M+H]+calcd for CnHioBrNCLS: 311.96, found: 311.95.

[0662] Step 2: Preparation of N- [(1R,3R)-3-fluorocyclopentyl]-5-{2-[4-(5- methanesulfonylpyridin-3-yl)phenyl]-2,6-diazaspiro[3.4]octane-6-carbonyl}pyrimidin-2- amine (Compound 184)

[0663] To a stirred solution of 3-(4-bromophenyl)-5-methanesulfonylpyridine (200 mg, 0.641 mmol, 1 equiv) in dioxane (5 mL) was added Intermediate 5 (204 mg, 0.641 mmol, 1 equiv), RuPhos (29 mg, 0.064 mmol, 0.1 equiv), RuPhos-Pd-G3 (53 mg, 0.064 mmol, 0.1 equiv) and cesium carbonate (417 mg, 1.28 mmol, 2 equiv). The reaction mixture was stirred for 3 h at 90 °C under nitrogen. The reaction mixture was cooled to room temperature and quenched by addition of water (10 mL). The aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was then purified by silica gel chromatography (0-10% methanol / dichloromethane) to afford the title compound as a white solid (42.3 mg, 11.9% (300 MHz, DMSO-c / J 5 9.16 (s, 1H), 8.91 (s, 1H), 8.49 - 8.61 (m, 2H), 8.42 (s, 1H), 7.66 - 7.87 (m, 3H), 6.53 - 6.63 (m, 2H), 5.10 - 5.35 (m, 1H), 4.46 (q, J = 13 Hz, 1H), 3.76 - 3.91 (m, 5H), 3.65 - 3.72 (m, 3H), 3.39 (s, 3H), 2.04 - 2.28 (m, 5H), 1.80 - 1.92 (m, 2H), 1.69 - 1.79 (m, 1H).

[0664] Synthesis of Compound 185: (6-(4-(5-(aminomethyl)pyridin-3-yl)-2-fluorophenyl)-2,6- diazaspiro[3.4]octan-2-yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone

[0665] Step 1: Synthesis of tert-butyl ((5-(4-bromo-3-fluorophenyl)pyridin-3- yl)methyl)carbamate

[0666] To a stirred solution of (4-bromo-3-fluorophenyl)boronic acid (267 mg, 1.220 mmol, 0.70 equiv) in anhydrous 1,4-dioxane (10 mL) and water (1 mL) was added tert-butyl ((5- bromopyridin-3-yl)methyl)carbamate (500 mg, 1.741 mmol, 1.00 equiv), potassium carbonate (722 mg, 5.224 mmol, 3.00 equiv) and Pd(dppf)C12 (145 mg, 0.178 mmol, 0.10 equiv) at room temperature. The reaction mixture was stirred at 60°C for 3h under nitrogen atmosphere. The mixture was subsequently cooled to room temperature, diluted with water (20 mL) and extracted with EA (3 x 40 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography (0-15% DCM / MeOH) to afford tert-butyl ((5-(4-bromo-3-fluorophenyl)pyridin-3-yl)methyl)carbamate (300 mg, 45.2% yield) as a yellow solid. LCMS (ESI): m / z [M+H]+calcd for CnHisBrFIShCh: 381.05, found 381.0.

[0667] Step 2: Synthesis of tert-butyl ((5-(4-(2-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-6-yl)-3-fluorophenyl)pyridin-3-yl)methyl)carbamate

[0668] To a stirred solution of (2-(cyclopentylamino)pyrimidin-5-yl)(2,6-diazaspiro[3.4]octan-2- yl)methanone (250 mg, 0.829 mmol, 1 equiv) in anhydrous 1,4-dioxane (10 mL) was added tert-butyl ((5-(4-bromo-3-fluorophenyl)pyridin-3-yl)methyl)carbamate (316 mg, 0.829 mmol, 1.00 equiv), Cs2CO3 (344 mg, 2.489 mmol, 3.00 equiv) followed by catalytic amount of Xantphos (48.00 mg, 0.083 mmol, 0.1 equiv) and Pd2(dba)3 (76 mg, 0.083 mmol, 0.10 equiv) at room temperature. The reaction mixture was stirred at 90°C for a period of 3h under nitrogen atmosphere. After cooled to room temperature, the reaction was diluted by water (20 mL) and extracted with EA (3 x 40 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography (0-15% DCM / MeOH) to afford tertbutyl ((5-(4-(2-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6-diazaspiro[3.4]octan-6-yl)- 3-fluorophenyl)pyridin-3-yl)methyl)carbamate (170 mg, 34.1%) as a yellow solid. LCMS (ESI): m / z [M+H]+calcd for C33H40FN7O3: 602.32, found 602.25.

[0669] Step 3: Synthesis of (6-(4-(5-(aminomethyl)pyridin-3-yl)-2-fluorophenyl)-2,6- diazaspiro [3.4] octan-2-yl)(2-(cyclopentylamino)pyrimidin-5-yl)methanone (Compound 185)

[0670] To a stirred solution of tert-butyl ((5-(4-(2-(2-(cyclopentylamino)pyrimidine-5-carbonyl)-2,6- diazaspiro[3.4]octan-6-yl)-3-fluorophenyl)pyridin-3-yl)methyl)carbamate (160 mg, 0.266 mmol, 1 equiv) in anhydrous DCM (3 mL) was added TFA (3 mL) at room temperature. The reaction mixture was stirred at room temperature for ...

Claims

1. CLAIMSWe claim:

1. A compound according to Formula (I):or a pharmaceutically acceptable salt thereof; wherein:Y is (C3-C8)cycloalkyl, or 4- to 7-membered heterocycloalkyl; wherein each (C3- C8)cycloalkyl, or 4- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents selected from halo, (C1-C6)alkyl, and (C1-C6)haloalkyl;A1is 6-membered aryl or 5- 6-membered heteroaryl; wherein the 6-membered aryl or 5- to 6-membered heteroaryl is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1- C6)aminoalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, and (C3- C8)cycloalkyl;A2is hydrogen, 6- to 10-membered aryl, 4- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein each 6- to 10-membered aryl, 4- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, C(O)R1a, C(0)2R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, S(O)(NH)R1a, NR1aR1b, S(O)2R1a, carb oximi dami de, (C1- C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, and 4- to 7-membered heterocycloalkyl; wherein (C1-C6)alkyl, 4- to 7-membered heterocycloalkyl, (C3-C8)cycloalkyl, and (C1-C6)alkoxy are optionally substituted with one or more substituents selected from halo, cyano, hydroxy, C(O)2R1a, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, S(O)(NH)R1a, NR1aR1b, S(O)2R1a, NR1aSO2R1b, carboximidamide, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1- C6)haloalkoxy, 6- to 10-membered aryl, 5- to 6-membered heteroaryl, (C3-C8)cycloalkyl, and 4- to 7- heterocyclyloalkyl;R1aand R1bare each independently hydrogen, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C3- C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, (C3-C8)cycloalkylalkyl, 4- to 7-membered heterocycloalkylalkyl (C1-C6)alkylNRaNRbor NRaNRbwherein (C3-C8)cycloalkyl and 4- to7-membered heterocycloalkyl are optionally substituted with one or more halo, cyano, hydroxy, C(O)Ra, C(O)2Ra, C(O)NRaRb, S(O)NRaRb, S(O)2NRaRb, S(O)(NH)Ra, NRaRb, S(O)2Ra, carboximidamide, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, or 4- to 7- membered heterocycloalkyl, wherein (C3-C8)cycloalkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with one or more halo, cyano, hydroxy, C(O)Ra, C(O)2Ra, C(O)NRaRb, S(O)NRaRb, S(O)2NRaRb, S(O)(NH)Ra, NRaRb, S(O)2Ra, carboximidamide, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, or 4- to 7-membered heterocycloalkyl; or R1aand R1btaken together with the nitrogen to which they are attached form a 3- to 7-membered heterocycloalkyl ring;Raand Rbare each independently hydrogen, (C1-C6)alkyl, (C1-C6)hydroxyalkyl, (C3- C8)cycloalkyl, 4- to 7-membered heterocycloalkyl, (C3-C8)cycloalkylalkyl, or 4- to 7- membered heterocycloalkylalkyl, or Raand Rbtaken together with the nitrogen to which they are attached form a 3- to 7-membered heterocycloalkyl ring; and m is 1 and n is 1; or m is 2 and n is 0.

2. The compound of claim 1, wherein A2is hydrogen, 6- to 10-membered aryl, 4- to 7- membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein each 6- to 10- membered aryl, 4- to 7-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, S(O)(NH)R1a, NR1aR1b, carboximidamide, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxy alkyl, (C1-C6)aminoalkyl, (C1-C6)amidoalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (C3- C8)cycloalkyl(C1-C6)alkyl, 4- to 7-membered heterocycloalkyl, and 4- to 7-membered heterocycloalkyl(C1-C6)alkyl, wherein (C3-C8)cycloalkyl is optionally substituted with one or more substituents selected from hydroxy, (C1-C6)alkoxy, halo, and (C1-C6)haloalkyl; andR1aand R1bare each independently hydrogen, (C1-C6)alkyl, or (C1-C6)hydroxyalkyl, or R1aand R1btaken together with the nitrogen to which they are attached form a 3- to 7- membered heterocycloalkyl ring.

3. The compound of claim 1 or 2, having the structure of Formula la:

4. The compound of claim 1 or 2, having the structure of Formula lb:or a pharmaceutically acceptable salt thereof.

5. The compound of claim 3, having the structure of Formula lai:(lai), or a pharmaceutically acceptable salt thereof; wherein each X is independently N or CRa1, wherein at least two X are CRa1; and Ra1is independently for each occurrence hydrogen, halo, cyano, hydroxy, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, (C1-C6)alkoxy(C1- C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or (C3-C8)cycloalkyl.

6. The compound of claim 4, having the structure of Formula (Ibi):or a pharmaceutically acceptable salt thereof; wherein each X is independently N or CRa1, wherein at least two X are CRa1; andRa1is independently for each occurrence hydrogen, halo, cyano, hydroxy, (C1- C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, (C1-C6)alkoxy(C1- C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or (C3-C8)cycloalkyl.

7. The compound of any one of claims 1-6, wherein Y is (C3-C8)cycloalkyl or 4- to 7- membered heterocycloalkyl, wherein each (C3-C8)cycloalkyl or 4- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents selected from halo and (C1-C6)alkyl.

8. The compound of claim 7, wherein Y is (C3-C8)cycloalkyl optionally substituted with one or more substituents selected from halo and (C1-C6)alkyl.

9. The compound of claim 8, wherein Y is cyclobutyl or cyclopentyl, each of which is optionally substituted with one or more substituents selected from halo and (C1-C6)alkyl.

10. The compound of claim 8, wherein Y is cyclopentyl optionally substituted with one or two fluorine atoms.

11. The compound of claim 10, wherein Y is cyclopentyl, 3 -fluorocyclopentyl, 2- fluorocyclopentyl, or 3, 3 -difluorocyclopentyl.

12. The compound of claim 11, wherein Y is:

13. The compound of claim 8, wherein Y is cyclobutyl optionally substituted with methyl.

14. The compound of claim 7, wherein Y is tetrahydropyranyl.

15. The compound of any one of claims 1-14, wherein A1is phenyl or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, cyano, (C3-C8)cycloalkyl, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, and (C1-C6)haloalkoxy(C1-C6)alkyl.

16. The compound of claim 14, wherein A1is phenyl or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents selected from cyano, fluoro, chloro, cyclopropyl, methyl, and difluoromethoxy.

17. The compound of any one of claims 1-15, wherein A1is phenyl, pyridyl, pyrimidyl, pyridazinyl, or pyrazinyl each of which is optionally substituted with one or more halo, (C1- C6)hydroxyalkyl, (C1-C6)aminoalkyl, or cyano.

18. The compound of any one of claims 1-16, wherein A1is phenyl, pyridyl, pyrimidyl, pyridazinyl, or pyrazinyl each of which is optionally substituted with one or more (C1- C6)hydroxy alkyl.

19. The compound of any one of claims 1-17, wherein A1is phenyl, pyridyl, pyrimidyl, pyridazinyl, or pyrazinyl each of which is optionally substituted with one or more (C1- C6)aminoalkyl.

20. The compound of any one of claims 1-17, wherein A1is phenyl optionally substituted with one or more (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, cyano, fluoro, or chloro.

21. The compound of any one of claims 1-17, wherein A1is pyridyl optionally substituted with one or more (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, cyano, fluoro, or chloro.

22. The compound of any one of claims 1-17, wherein A1is pyrimidyl optionally substituted with one or more (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, cyano, fluoro, or chloro.

23. The compound of any one of claims 1-17, wherein A1is pyrazinyl optionally substituted with one or more (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, cyano, fluoro, or chloro.

24. The compound of any one of claims 1-17, wherein A1is pyridazinyl optionally substituted with one or more (C1-C6)hydroxyalkyl, (C1-C6)aminoalkyl, cyano, fluoro, or chloro.

25. The compound of any one of claims 1-14, wherein A1is:; denotes the point of attachment to N; and denotes the point of attachment to A2.

26. The compound of any one of claims 1-14, wherein A1is:N; and denotes the point of attachment to A .

27. The compound of any one of claims 1-24, wherein A1is:denotes the point of attachment to N; and denotes the point of attachment to A2.

28. The compound of any one of claims 1-27, wherein A2is phenyl or 5- to 6-membered heteroaryl; each of which is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, S(O)(NH)R1a, NR1aR1b, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1- C6)aminoalkyl, (C1-C6)amidoalkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy, (C3- C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, 4- to 7-membered heterocycloalkyl, and 4- to 7-membered heterocycloalkyl(C1-C6)alkyl; wherein (C3-C8)cycloalkyl is optionally substituted with one or more substituents selected from hydroxy, (C1-C6)alkoxy, halo, and (C1-C6)haloalkyl.

29. The compound of any one of claims 1-27, wherein A2is 2-pyridyl, 3-pyridyl, or 4- pyridyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1- C6)alkylamine, (C1-C6)alkoxyalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, phenyl, 4- to 7- membered heterocycloalkyl, and 5- to 6-membered heteroaryl.

30. The compound of any one of claims 1-27, wherein A2is a 4- to 7-membered heterocycloalkyl, optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkylamine, (C1-C6)alkoxyalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl.

31. The compound of any one of claims 1-27, wherein A2is pyrazole, imidazole, tetrahydrofuran, oxazole, isoxazole, 1,2, 3 -triazole, or 1,2,4-triazole; each of which is optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(0)2NR1aR1b, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkylamine, (C1-C6)alkoxyalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6- membered heteroaryl.

32. The compound of any one of claims 1-27, wherein A2is an N-oxide selected from pyridyl N-oxide, pyrimidinyl N-oxide, pyrazinyl N-oxide, and pyridazinyl N-oxide; each of which is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(0)2NR1aR1b, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkylamine, (C1-C6)alkoxyalkyl, and (C1-C6)alkoxy.

33. The compound of any one of claims 1-27, wherein A2is pyridazinyl optionally substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkylamine, (C1-C6)alkoxyalkyl, and (C1- C6)alkoxy.

34. The compound of any one of claims 1-27, wherein A2is pyrimidyl optionally substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkylamine, (C1-C6)alkoxyalkyl, and(C1- C6)alkoxy.

35. The compound of any one of claims 1-27, wherein A2is pyrazinyl optionally substituted with one or more substituents selected from the group consisting of halo, cyano, hydroxy, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkylamine, (C1-C6)alkoxyalkyl, and (C1- C6)alkoxy.

36. The compound of any one of claims 1-27, wherein A2is:wherein R2is hydrogen or (C1-C6)alkyl, wherein (C1-C6)alkyl is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, C(0)2R1a, C(O)R1a, C(O)NR1aR1b, S(O)NR1aR1b, S(O)2NR1aR1b, S(O)(NH)R1a, NR1aR1b, S(O)2R1a, NR1aSO2R1b, carboximidamide, (C1-C6)alkoxy, 6- to 10-membered aryl, 5- to 6-membered heteroaryl, (C3- C8)cycloalkyl, and 4- to 7- heterocycloalkyl.

37. The compound of any one of claims 1 to 36, wherein R1aand R1bare each hydrogen.

38. The compound of any one of claims 1 to 36, wherein one of R1aand R1bis hydrogen; and the other of R1aand R1bis (C1-C6)alkyl.

39. The compound of any one of claims 1 to 36, wherein R1aand R1bare each (C1- C6)alkyl.

40. The compound of any one of claims 1-27, wherein A2isĊ41. A compound selected from the following table:or a pharmaceutically acceptable salt thereof.

42. A compound selected from the following table:or a pharmaceutically acceptable salt thereof.

43. A compound selected from the following table:or a pharmaceutically acceptable salt thereof.

44. A pharmaceutical composition, comprising a compound of any one of claims 1 to 43; and at least one pharmaceutically acceptable excipient.

45. A method of preventing or treating an MRGPRX2 -mediated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of any one of claims 1 to 43.

46. The method of claim 45, wherein the MRGPRX2 -mediated disease or disorder is selected from the group consisting of chronic spontaneous urticaria, prurigo nodularis, irritable bowel syndrome, chronic inducible urticaria, atopic dermatitis, osteoarthritis, rosacea, migraine, pseudo-analphylaxis, mast cell activation syndrome, mastocytosis, pruritus, neurodermatitis, contact urticaria, allergic rhinitis, asthma, acute contact dermatitis, ulcerative colitis, Crohn’s disease, idiopathic chronic cough, rheumatoid arthritis, multiple sclerosis, geographic atrophy, endometriosis, seborrheic dermatitis, psoriasis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, neuropathic itch, periodontitis, autism, abdominal aortic aneurysms, deep vein thrombosis, amyotrophic lateral sclerosis, interstitial cystitis, coronary artery disease, cancer, sickle cell disease, obesity, and ulcers.

47. The method of claim 45 or 46, wherein the MRGPRX2 -mediated disease or disorder is prevented.

48. The method of claim 45 or 46, wherein the MRGPRX2 -mediated disease or disorder is treated.

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