Therapeutic compounds

Abstract

The present disclosure provides a compound of formula (I): The present invention relates to a compound of Formula (I), and pharmaceutically acceptable salts thereof, as well as compositions and uses thereof. The compounds are useful as inhibitors of the YAP:TEAD protein-protein interaction. Also included are pharmaceutical compositions comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and methods of using such compounds and salts in the treatment of various YAP:TEAD-mediated disorders, including cancer.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 941,515, filed November 27, 2019, and U.S. Provisional Patent Application No. 62 / 943,745, filed December 4, 2019, the contents of which are incorporated herein by reference in their entireties. [Background technology]

[0002] The Hippo signaling pathway regulates cell proliferation and cell death and determines organ size. This pathway is thought to act as a tumor suppressor in mammals, and disruptions of this pathway are often detected in human cancers. This pathway is involved in and / or can regulate the self-renewal and differentiation of stem and progenitor cells. In addition, the Hippo signaling pathway may be involved in wound healing and tissue regeneration. Furthermore, the Hippo signaling pathway crosstalks with other signaling pathways, such as Wnt, Notch, Hedgehog, and MAPK / ERK, which may affect a wide variety of biological events and whose dysfunction may be involved in many human diseases in addition to cancer.

[0003] The core of the Hippo signaling pathway consists of a cascade of kinases (Hippo-MST1-2, upstream of Lats1-2 and NDRI-2) that result in the phosphorylation of two transcriptional coactivators, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motifs or tafazzin). Unphosphorylated, activated YAP translocates to the cell nucleus, where its main target transcription factors are four proteins in the TEAD domain-containing family (TEAD1-TEAD4, collectively referred to as "TEAD"). YAP, together with other transcription factors such as Smad1, RUNX, ErbB4, and p73, has been shown to induce the expression of various genes, including connective tissue growth factor (CTGF), Gli2, Birc5, Birc2, fibroblast growth factor 1 (FGF1), and amphiregulin (AREG). Like YAP, unphosphorylated TAZ translocates to the cell nucleus, where it interacts with multiple DNA-binding transcription factors, including peroxisome proliferator-activated receptor gamma (PPARγ), thyroid transcription factor-1 (TTF-1), Pax3, TBX5, RUNX, TEAD1, and Smad2 / 3 / 4. Many of the genes activated by the YAP / TAZ-transcription factor complex mediate cell survival and proliferation. Thus, under some conditions, YAP and / or TAZ act as oncogenes, and the Hippo signaling pathway acts as a tumor suppressor.

[0004] The Hippo signaling pathway is a regulator of animal development, organ size, and stem cell regulation, and is therefore implicated in cancer development. In vitro, overexpression of YAP or TAZ in breast epithelial cells induces cell transformation through the interaction of both proteins with the TEAD family of transcription factors. Increased YAP / TAZ transcriptional activity has been shown to induce oncogenic characteristics, such as epithelial-mesenchymal transition, and confer stem cell properties to breast cancer cells. In vivo, overexpression of YAP or gene knockout of its upstream regulators MST1-2 in mouse liver leads to the development of hepatocellular carcinoma (HCC). Furthermore, when the tumor suppressor NF2 is inactivated in mouse liver, HCC development can be completely blocked by co-inactivation of YAP.

[0005] Deregulation of the Hippo tumor suppressor pathway is thought to be a key event in the development of a wide range of cancer types and malignancies.

[0006] Therefore, pharmacological targeting of the Hippo cascade through inhibition of YAP, TAZ, TEAD, and / or the YAP:TEAD protein-protein interaction may be a valuable approach for the treatment of cancers harboring functional alterations of this pathway. Summary of the Invention

[0007] The present disclosure provides a compound of formula (I) JPEG0007759877000001.jpg34170, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof, wherein: R 1 is C(O)N(R a )(R b ), C 6-20 Aryl, 5-20 membered heteroaryl, 5-20 membered heterocyclyl, and C 1-6 alkyl, wherein R 1 C 6-20Aryl, 5-20 membered heteroaryl and 5-20 membered heterocyclyl are independently selected from halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, and C 6-10 aryl, and R 1 C 1-6 Alkyl is halogen, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, and C 6-10 optionally substituted with one or more substituents selected from the group consisting of aryl; R a and R b are each independently H or C 1-6 alkyl, where C 1-6 Alkyl is a group that can be substituted with halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 Optionally substituted with one or more substituents selected from the group consisting of alkoxy; Or, R a and R b together with the atom to which they are attached form a 3-10 membered heterocyclyl, where the 3-10 membered heterocyclyl is selected from halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with one or more substituents selected from the group consisting of alkoxy; L is absent or * -O-CH2- ** , * -CH2-O- ** or -O-, where ** is R 2 represents the point of attachment to the moiety, * represents the point of attachment to the rest of the molecule; R 2 is C2-12 Alkyl, C 2-12 Alkenyl, or C 6-10 aryl, where R 2 C 2-12 Alkyl, C 2-12 Alkenyl, and C 6-10 Aryl is independently halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 6-10 Aryl, and C 3-10 cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of C 1-6 Alkyl, C 1-6 Alkoxy, and C 3-10 Cycloalkyl may independently include one or more halo, C 1-6 Haloalkyl, C 6-10 Aryl, or C 3-10 optionally further substituted with cycloalkyl; R 3 and R 4 are each independently H or C 1-6 alkyl, where C 1-6 Alkyl is a group that can be substituted with halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 Optionally substituted with one or more substituents selected from the group consisting of alkoxy; Or, R 3 and R 4 together with the atom to which they are attached form a 3-10 membered heterocyclyl, where the 3-10 membered heterocyclyl is selected from halo, OH, cyano, and C 1-6 alkyl, wherein C 1-6 Alkyl is a group that can be substituted with halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6and optionally further substituted with one or more substituents selected from the group consisting of alkoxy. Some other embodiments provide pharmaceutical compositions comprising the compound described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0008] Some other embodiments provide pharmaceutical compositions comprising the above-described compound and a therapeutically inert carrier.

[0009] Some other embodiments provide the above-described compound, or a pharmaceutically acceptable salt thereof, for use in medical therapy. Some other embodiments provide the above-described compound, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0010] Some other embodiments provide the above-mentioned compound, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of cancer.

[0011] Some other embodiments provide the above-described compound, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of cancer.

[0012] Some other embodiments provide methods for treating cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of the above-described compound, or a pharmaceutically acceptable salt thereof.

[0013] Some other embodiments provide the above-described compound, or a pharmaceutically acceptable salt thereof, for modulating YAP:TEAD protein-protein interaction.

[0014] Some other embodiments provide the above-described compound, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of a disease or condition mediated by YAP:TEAD activity.

[0015] Some other embodiments provide the use of the above-described compound, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of a disease or condition mediated by YAP:TEAD activity.

[0016] Some other embodiments provide methods for modulating YAP:TEAD activity, comprising contacting YAP:TEAD with a compound described above, or a pharmaceutically acceptable salt thereof.

[0017] Some other embodiments provide methods for treating a disease or condition mediated by YAP:TEAD activity in a mammal, comprising administering to the mammal a therapeutically effective amount of the above-described compound, or a pharmaceutically acceptable salt thereof.

[0018] Also provided are methods of making a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated compound thereof. Also provided are kits comprising a compound detailed herein, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated compound thereof, and optionally instructions for use. DETAILED DESCRIPTION OF THE INVENTION

[0019] I. Definition Unless otherwise indicated, the following specific terms and phrases used in the description and claims are defined as follows:

[0020] The terms "moiety" and "substituent" refer to an atom or a set of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds, thereby forming a part of the molecule.

[0021] The term "substituted" refers to the replacement of at least one of a compound or moiety's hydrogen atoms with another substituent or moiety. Examples of such substituents include, but are not limited to, halogen, -OH, -CN, oxo, alkoxy, alkyl, aryl, heteroaryl, haloalkyl, haloalkoxy, cycloalkyl, and heterocycle. For example, the term "alkyl substituted by halogen" refers to the fact that one or more hydrogen atoms of an alkyl (defined below) have been replaced with one or more halogen atoms (e.g., trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, etc.).

[0022] The term "alkyl," unless otherwise specified, refers to an aliphatic, straight- or branched-chain saturated hydrocarbon moiety having 1 to 20 carbon atoms. For example, in certain embodiments, an alkyl has 1 to 10 carbon atoms. In certain embodiments, an alkyl has 1 to 6 carbon atoms. Alkyl groups may be independently substituted with one or more substituents described herein.

[0023] The term "alkoxy" refers to a group of the formula -O-R', where R' is an alkyl group. The alkoxy group may be optionally substituted independently with one or more substituents described herein. Examples of alkoxy moieties include methoxy, ethoxy, isopropoxy, and tert-butoxy.

[0024] "Aryl," unless otherwise specified, refers to a cyclic aromatic hydrocarbon moiety having a monocyclic, bicyclic, or tricyclic aromatic ring of 5 to 16 carbon ring atoms. For example, in certain embodiments, an aryl has 6 to 10 carbon atoms. Bicyclic aryl ring systems include fused bicyclic rings having two fused 5-membered aryl rings (designated 5-5), fused 6-membered aryl rings (designated 5-6 and 6-5), and fused 6-membered aryl rings (designated 6-6). Aryl groups may be substituted as defined herein. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, and the like. The term "aryl" also includes partially hydrogenated derivatives of cyclic aromatic hydrocarbon moieties, provided that at least one ring of the cyclic aromatic hydrocarbon moiety is aromatic and each ring is optionally substituted.

[0025] The term "heteroaryl," unless otherwise specified, refers to an aromatic heterocyclic monocyclic, bicyclic, or tricyclic ring system of 5 to 16 ring atoms containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. For example, in some embodiments, a monocyclic heteroaryl ring can be 5-6 membered. In some embodiments, a heteroaryl ring can contain 5 to 10 carbon atoms. Bicyclic heteroaryl ring systems include fused bicyclic rings having two fused 5-membered heteroaryl rings (designated 5-5), having a 6-membered heteroaryl ring fused to a 5-membered heteroaryl ring (designated 5-6 and 6-5), and having two fused 6-membered heteroaryl rings (designated 6-6). Heteroaryl groups may be optionally substituted as defined herein. Examples of heteroaryl moieties include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl.

[0026] The terms "halo," "halogen," and "halide" may be used interchangeably and refer to a substituent fluoro, chloro, bromo, or iodo.

[0027] The term "haloalkyl" refers to an alkyl group in which one or more of the alkyl group's hydrogen atoms have been replaced by the same or different halogen atoms, in particular fluoro atoms. Examples of haloalkyl include monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, difluoromethyl or trifluoromethyl.

[0028] "Cycloalkyl," unless otherwise specified, refers to a saturated or partially unsaturated carbocyclic moiety having a monocyclic, bicyclic (including bridged bicyclic), or tricyclic ring and having 3 to 10 carbon atoms in the ring. For example, in certain embodiments, a cycloalkyl contains 3 to 8 carbon atoms (i.e., (C3-C8)cycloalkyl). In other particular embodiments, a cycloalkyl contains 3 to 6 carbon atoms (i.e., (C3-C6)cycloalkyl). Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and their partially unsaturated (cycloalkenyl) derivatives (e.g., cyclopentenyl, cyclohexenyl, and cycloheptenyl), bicyclo[3.1.0]hexanyl, bicyclo[3.1.0]hexenyl, bicyclo[3.1.1]heptanyl, and bicyclo[3.1.1]heptenyl. A cycloalkyl moiety is also referred to as "spirocyclopropyl." They may be attached in a "spirocycloakyl" fashion, such as JPEG0007759877000002.jpg17170. The cycloalkyl moiety may be substituted with one or more substituents.

[0029] "Heterocycle" or "heterocyclyl," unless otherwise indicated, refers to a 3-, 4-, 5-, 6-, and 7-membered monocyclic, 7-, 8-, 9-, and 10-membered bicyclic (including bridged bicyclic), or 10-, 11-, 12-, 13-, 14-, and 15-membered bicyclic, saturated or partially unsaturated heterocyclic moiety having one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from oxygen, nitrogen, and sulfur in the ring, with the remaining ring atoms being carbon. For example, in certain embodiments, heterocycle or heterocyclyl refers to a 4-, 5-, 6-, or 7-membered heterocycle. In some aspects, the heterocycle is a heterocycloalkyl. When used in reference to a ring atom of a heterocycle, the nitrogen or sulfur may be in an oxidized form, and the nitrogen may be substituted with one or more groups, such as C1-C6 alkyl. A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocycle ring atoms Any of these may be substituted with one or more substituents described herein. Examples of such saturated or partially unsaturated heterocycles include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The term heterocycle also includes groups in which a heterocycle is fused to one or more aryl, heteroaryl, or cycloalkyl rings, such as indolinyl, 3H-indolyl, chromanyl, azabicyclo[2.2.1]heptanyl, azabicyclo[3.1.0]hexanyl, azabicyclo[3.1.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl.

[0030] The term "fused bicyclic" refers to a ring system containing two fused rings, including bridged cycloalkyl and bridged heterocycloalkyl, as defined elsewhere herein. The rings are each independently aryl, heteroaryl, cycloalkyl, and heterocycle. In some embodiments, the rings are each independently C 5-6 Aryl, 5-6 membered heteroaryl, C3-6 cycloalkyl, and 4-6 membered heterocycles. Non-limiting examples of fused bicyclic ring systems include C 5-6 Aryl-C 5-6 Aryl, C 5-6 aryl-4-6 membered heteroaryl, and C 5-6 Aryl-C 5-6 Cycloalkyl is included.

[0031] Unless otherwise indicated, the term "hydrogen" or "hydro" refers to a hydrogen atom (-H) moiety and not to H2.

[0032] In the description herein, when the stereochemistry of a structure or portion of a structure is not indicated, for example, with a bold wedge or a dotted line, the structure or portion of the structure is intended to encompass all of its stereoisomers. However, in some cases where multiple chiral centers are present, the structure and name may be represented as a single enantiomer to aid in describing the relative stereochemistry.

[0033] Unless otherwise indicated, the term "a compound of the formula" or "a compound of formula" or "compounds of the formula" or "compounds of formula" refers to any compound selected from the genus of compounds defined by that formula (including, unless otherwise specified, any pharmaceutically acceptable salt or ester of any such compound).

[0034] The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the free base or free acid, but are not biologically or otherwise undesirable. As used herein, "pharmaceutically acceptable" refers to carriers, diluents, or excipients that are compatible with other ingredients of the formulation and not deleterious to the recipient thereof. Salts can be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, preferably hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, N-acetylcysteine, and the like. Additionally, salts can be prepared by the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts, etc. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins, and the like.

[0035] The compounds of the present invention can exist in the form of pharmaceutically acceptable salts. Another embodiment provides non-pharmaceutically acceptable salts of compounds of formula (I), which may be useful as intermediates for isolating or purifying compounds of formula (I). The compounds of the present invention can also exist in the form of pharmaceutically acceptable esters (e.g., methyl and ethyl esters of the acids of formula (I) used as prodrugs). The compounds of the present invention can also be solvated, for example, hydrated. Solvation can occur during the manufacturing process or as a result of the hygroscopic properties of the initial anhydrous compound of formula (I), for example.

[0036] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Diastereomers are stereoisomers with opposite configurations of one or more chiral centers that are not enantiomers. Stereoisomers that possess one or more asymmetric centers that are non-superimposable mirror images of each other are called "enantiomers." For example, when a compound possesses an asymmetric center, a pair of enantiomers is possible if the carbon atoms are bonded to four different groups. Enantiomers can be characterized by the absolute configuration of their asymmetric center or centers and are described by the Cahn-Ingold-Prelog R- and S-ordering rules or by the way the molecule rotates the plane of polarized light and are designated as dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture." In some embodiments, the compound is at least about 90% enriched by weight in a single diastereomer or enantiomer. In other embodiments, the compound is at least about 95%, 98%, or 99% enriched by weight in a single diastereomer or enantiomer.

[0037] Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, positional isomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention.

[0038] The compounds of the present invention may contain asymmetric or chiral centers and therefore may exist in various stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers, as well as mixtures thereof (e.g., racemic mixtures), are intended to form part of the present invention. In some cases, the stereochemistry has not been determined or has been tentatively assigned. Many organic compounds exist in optically active forms, i.e., they are capable of rotating the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its one or more chiral centers. The prefixes d and l, or (+) and (-), are used to denote the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer is also referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. Enantiomers can be separated from racemic mixtures by chiral separation techniques such as supercritical fluid chromatography (SFC). Assignments of configurations at chiral centers in separated enantiomers are tentative and are shown for illustrative purposes in compounds (l), (m), and (n), while stereochemistry is definitively established, for example, from X-ray crystallographic data.

[0039] The term "therapeutically effective amount" of a compound refers to an amount of compound effective to prevent, alleviate, or ameliorate symptoms of disease or prolong the survival of the treated subject. Determining a therapeutically effective amount is within the skill of the art. The therapeutically effective amount or dosage of a compound according to the present invention varies within wide limits and can be determined by methods known in the art. Such dosages will be tailored to the individual requirements of each particular case, including the particular compound administered, the route of administration, the condition being treated, and the patient being treated. Generally, for oral or parenteral administration to an adult weighing approximately 70 kg, a daily dose of about 0.1 mg to about 5,000 mg, 1 mg to about 1,000 mg, or 1 mg to 100 mg may be appropriate, although the lower and upper limits may be exceeded if indicated. The daily dose can be administered as a single dose, in divided doses, or, for parenteral administration, as a continuous infusion.

[0040] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable carrier, adjuvant, or vehicle," or "therapeutically inert carrier" can be used interchangeably throughout and are intended to include all substances compatible with drug administration, including solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other substances and compounds compatible with drug administration. However, use of any conventional media or agent in the compositions of the present invention is contemplated, provided that it is compatible with the active compound. Supplementary active compounds can also be incorporated into the compositions.

[0041] Pharmaceutically acceptable carriers useful for preparing the compositions herein can be solid, liquid, or gaseous; thus, the compositions can take the form of tablets, pills, capsules, suppositories, powders, enteric-coated or other protective preparations (e.g., bound to ion exchange resins or packaging in lipid-protein vesicles), sustained-release preparations, solutions, suspensions, elixirs, aerosols, and the like. Carriers can be selected from various oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly for injectable solutions (when isotonic with blood). For example, formulations for intravenous administration include sterile aqueous solutions of one or more active ingredients, prepared by dissolving one or more solid active ingredients in water to produce an aqueous solution and sterilizing the solution. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, wheat flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, nonfat dry milk, glycerol, propylene glycol, water, ethanol, and the like. The compositions may be subjected to conventional pharmaceutical excipients such as preservatives, stabilizers, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers, and the like. Suitable pharmaceutical carriers and their formulation are described in Remington's Pharmaceutical Sciences by E.W. Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable carrier to prepare the appropriate dosage form for proper administration to the recipient.

[0042] As used herein, the term "patient" or "individual" refers to an animal, e.g., a mammal such as a human. In one embodiment, a patient or individual refers to a human.

[0043] In practicing the methods of the present invention, a therapeutically effective amount of any one of the compounds of the present invention or any combination of the compounds of the present invention, or pharmaceutically acceptable salts or esters thereof, is administered alone or in combination via any of the useful and acceptable methods known in the art. Thus, the compounds or compositions can be administered orally (e.g., buccal), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., by suppository or lavage), transdermally (e.g., by skin electroporation), or by inhalation (e.g., by aerosol), and in the form of solid, liquid, or gaseous preparations, including tablets and suspensions. Administration can be carried out in a single unit dosage form using continuous therapy, or in a single-dose therapy, as appropriate. Therapeutic compositions can also be in the form of oil emulsions or dispersions in combination with lipophilic salts such as pamoic acid, or in the form of biodegradable sustained-release compositions for subcutaneous or intramuscular administration.

[0044] II. General and Partial General Formulas of the Disclosed Compounds In one embodiment, provided is a compound of formula (I): JPEG0007759877000003.jpg42170, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated compound thereof, wherein: R 1 is C(O)N(R a )(R b ), C 6-20 Aryl, 5-20 membered heteroaryl, 5-20 membered heterocyclyl, and C 1-6 alkyl, wherein R 1 C 6-20 Aryl, 5-20 membered heteroaryl and 5-20 membered heterocyclyl are independently selected from halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, and C 6-10aryl, and R 1 C 1-6 Alkyl is halogen, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, and C 6-10 optionally substituted with one or more substituents selected from the group consisting of aryl; R a and R b are each independently H or C 1-6 alkyl, where C 1-6 Alkyl is a group that can be substituted with halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 Optionally substituted with one or more substituents selected from the group consisting of alkoxy; Or, R a and R b together with the atom to which they are attached form a 3-10 membered heterocyclyl, where the 3-10 membered heterocyclyl is selected from halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with one or more substituents selected from the group consisting of alkoxy; L is absent or * -O-CH2- ** , * -CH2-O- ** or -O-, where ** is R 2 represents the point of attachment to the moiety, * represents the point of attachment to the rest of the molecule; R 2 is C 2-12 Alkyl, C 2-12 Alkenyl, or C 6-10 aryl, where R 2 C 2-12 Alkyl, C 2-12 Alkenyl, and C 6-10Aryl is independently halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 6-10 Aryl, and C 3-10 cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of C 1-6 Alkyl, C 1-6 Alkoxy, and C 3-10 Cycloalkyl may independently include one or more halo, C 1-6 Haloalkyl, C 6-10 Aryl, or C 3-10 may be further substituted with cycloalkyl; R 3 and R 4 are each independently H or C 1-6 alkyl, where C 1-6 Alkyl is a group that can be substituted with halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 Optionally substituted with one or more substituents selected from the group consisting of alkoxy; Or, R 3 and R 4 together with the atom to which they are attached form a 3-10 membered heterocyclyl, where the 3-10 membered heterocyclyl is selected from halo, OH, cyano, and C 1-6 alkyl, wherein C 1-6 Alkyl is a group that can be substituted with halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 It may be further substituted with one or more substituents selected from the group consisting of alkoxy.

[0045] The disclosed compounds are provided as set forth in the following embodiments.

[0046] In some embodiments, the compound of Formula (I) is a deuterated compound.

[0047] In some embodiments, R 1 is C(O)N(R a )(R b ), where R a and R b are each independently H or C 1-6 alkyl, where C 1-6 Alkyl is a group that can be substituted with halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 It may be optionally substituted with one or more substituents selected from the group consisting of alkoxy.

[0048] In some embodiments, R 1 is C(O)N(R a )(R b ), where R a and R b are each methyl.

[0049] In some embodiments, R 1 is C(O)N(R a )(R b ), wherein R a and R b together with the atom to which they are attached form a 4-membered heterocyclyl, where the 4-membered heterocyclyl is selected from halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 It may be optionally substituted with one or more substituents selected from the group consisting of alkoxy.

[0050] In some embodiments, R 1 Halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, and C 6-10 and aryl. 5-6 membered heteroaryl optionally substituted with one or more substituents selected from the group consisting of: aryl.

[0051] In some embodiments, R 1 is a 6-membered heteroaryl.

[0052] In some embodiments, R 1 Halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, and C 6-10 and aryl.

[0053] In some embodiments, R 1 is halogen, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, and C 6-10 C optionally substituted with one or more substituents selected from the group consisting of aryl 1-6 It is alkyl.

[0054] In some embodiments, L is absent.

[0055] In some embodiments, R 2 Halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 6-10 Aryl, and C 3-10 phenyl optionally substituted with one or more substituents selected from the group consisting of cycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, and C 3-10 Cycloalkyl may independently include one or more deuterium, halo, C 1-6 Haloalkyl, C 6-10 Aryl, or C 3-10 It may be further substituted with cycloalkyl.

[0056] In some embodiments, R 2 is one or more deuterium, halo, C 1-6 Haloalkyl, C 6-10 Aryl, or C 3-10 C optionally further substituted with cycloalkyl 5-6 It is a phenyl substituted with a cycloalkyl.

[0057] In some embodiments, R 2 is a phenyl substituted with a methylene substituted with a C5 cycloalkyl.

[0058] In some embodiments, R 3 and R 4 together with the atom to which they are attached form a 3-10 membered heterocyclyl, where the 3-10 membered heterocyclyl is selected from halo, OH, cyano and C 1-6 alkyl, wherein C 1-6 Alkyl is a group that can be substituted with halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 It may be further substituted with one or more substituents selected from the group consisting of alkoxy.

[0059] In some embodiments, R 3 and R 4 Halo, OH, cyano, and C, along with the atoms to which they are attached 1-6 and forming a 4-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkyl, wherein C 1-6 Alkyl is a group that can be substituted with halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 It may be further substituted with one or more substituents selected from the group consisting of alkoxy.

[0060] In an embodiment, R 1 is C(O)N(R a )(R b ), C6-20 Aryl, 5-20 membered heteroaryl, 5-20 membered heterocyclyl, and C 1-6 alkyl, wherein R 1 C 6-20 Aryl, 5-20 membered heteroaryl and 5-20 membered heterocyclyl are independently selected from cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; R 1 C 1-6 The alkyl may be substituted with one or more substituents selected from the group consisting of halogen and OH; R a and R b are each independently, C 1-6 alkyl or R a and R b together with the atom to which they are attached form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is selected from one or more C 1-6 L is absent or is -O- or * -O-CH2- ** where: ** is R 2 represents the point of attachment to the moiety, * represents the point of attachment to the rest of the molecule; R 2 is C 2-12 Alkyl, C 2-12 Alkenyl, or C 6-10 aryl, where R 2 C 2-12 Alkyl, C 2-12 Alkenyl, and C 6-10 Aryl is independently selected from halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 Aryl, and C 3-10 cycloalkyl, wherein C 1-6 Alkyl, C 1-6 Alkoxy, and C 3-10Cycloalkyl may independently include one or more halo, C 6-10 Aryl, or C 3-10 may be further substituted with cycloalkyl; R 3 and R 4 together with the atom to which they are attached form a 3-10 membered heterocyclyl, where the 3-10 membered heterocyclyl is selected from the group consisting of cyano, and C 1-6 alkyl, wherein C 1-6 The alkyl may be further substituted with one or more halo.

[0061] In some embodiments, L is absent and the compound of Formula (I) has the formula (IA): JPEG0007759877000004.jpg40170, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof.

[0062] In an embodiment, R 1 is C 1-6 It is a 5-20 membered heteroaryl optionally substituted with alkyl.

[0063] In an embodiment, R 1 is C 1-6 It is a 6-membered heteroaryl optionally substituted with alkyl.

[0064] In an embodiment, R 1 is pyrazinyl or pyrimidinyl optionally substituted with methyl.

[0065] In an embodiment, R 1 is pyrazinyl or pyrimidinyl optionally substituted with methyl.

[0066] In an embodiment, R 2 C may be substituted with one or more halo groups and may be further substituted with one or more halo groups. 5-6 It is a phenyl substituted with a cycloalkyl.

[0067] In an embodiment, R 2 is C 5-6 It is a phenyl substituted with a cycloalkyl.

[0068] In an embodiment, R 2 is phenyl substituted with cyclohexyl.

[0069] In an embodiment, R 2 is phenyl optionally substituted with one or more fluoro groups, C 5-6 It is substituted with cycloalkyl.

[0070] In an embodiment, R 2 is phenyl optionally substituted with one or more fluoro and substituted with cyclohexyl.

[0071] In an embodiment, R 2 is C 5-6 C optionally further substituted with cycloalkyl 1-6 It is phenyl substituted with alkyl.

[0072] In an embodiment, R 2 is phenyl substituted with methyl which may be further substituted with cyclopentyl.

[0073] In an embodiment, R 3 and R 4 together with the atom to which they are attached form a 4-membered heterocyclyl, where the heterocyclyl may contain one or more C 1-6 substituted with alkyl, wherein said C 1-6 At least one of the alkyls is further substituted with halo.

[0074] In an embodiment, R 3 and R 4 together with the atom to which they are attached form an azetidine, wherein the heterocyclyl is substituted with one or more methyl, where one methyl is further substituted with fluoro.

[0075] In an embodiment, R 2 C may be substituted with one or more halo groups and may be further substituted with one or more halo groups. 5-6 cycloalkyl-substituted phenyl; R 3 and R 4 together with the atom to which they are attached form a 4-membered heterocyclyl, where the heterocyclyl may contain one or more C 1-6 substituted with alkyl, wherein said C 1-6 At least one of the alkyls is further substituted with halo.

[0076] In an embodiment, R 2 is C 5-6 cycloalkyl-substituted phenyl; R 3 and R 4 together with the atom to which they are attached form a 4-membered heterocyclyl, where the heterocyclyl may contain one or more C 1-6 substituted with alkyl, 1-6 At least one of the alkyls is further substituted with halo.

[0077] In an embodiment, R 2 is phenyl substituted with cyclohexyl; R 3 and R 4 together with the atom to which they are attached form an azetidine, wherein the heterocyclyl is substituted with one or more methyl, where one methyl is further substituted with fluoro.

[0078] In an embodiment, R 2 is phenyl optionally substituted with one or more fluoro and substituted with cyclohexyl; R 3 and R 4 together with the atom to which they are attached form an azetidine, wherein the heterocyclyl is substituted with one or more methyl, where one methyl is further substituted with fluoro.

[0079] In an embodiment, R 2 is C5-6 C optionally further substituted with cycloalkyl 1-6 alkyl-substituted phenyl; R 3 and R 4 together with the atom to which they are attached form an azetidine, wherein the heterocyclyl is substituted with one or more methyl, where one methyl is further substituted with fluoro.

[0080] In an embodiment, R 2 is phenyl substituted with methyl which may be further substituted with cyclopentyl; R 3 and R 4 together with the atom to which they are attached form an azetidine, and the heterocyclyl is substituted with one or more methyl, where one methyl is further substituted with fluoro.

[0081] In an embodiment, R 1 is C 1-6 R is an optionally alkyl-substituted 5- to 20-membered heteroaryl; 2 C may be substituted with one or more halo groups and may be further substituted with one or more halo groups. 5-6 cycloalkyl-substituted phenyl; R 3 and R 4 together with the atom to which they are attached form a 4-membered heterocyclyl, where the heterocyclyl may contain one or more C 1-6 substituted with alkyl, wherein said C 1-6 At least one of the alkyls is further substituted with halo.

[0082] In an embodiment, R 1 is C 1-6 is an optionally alkyl-substituted 6-membered heteroaryl; R 2 is C 5-6 cycloalkyl-substituted phenyl; R 3 and R 4 together with the atom to which they are attached form a 4-membered heterocyclyl, where the heterocyclyl may contain one or more C 1-6 substituted with alkyl, wherein said C1-6 At least one of the alkyls is further substituted with halo.

[0083] In an embodiment, R 1 is pyrazinyl or pyrimidinyl optionally substituted by methyl; R 2 is phenyl substituted with cyclohexyl; R 3 and R 4 together with the atom to which they are attached form an azetidine, wherein the heterocyclyl is substituted with one or more methyl, where one methyl is further substituted with fluoro.

[0084] In an embodiment, R 1 is pyrazinyl or pyrimidinyl optionally substituted by methyl; R 2 is phenyl optionally substituted with one or more fluoro and substituted with cyclohexyl; R 3 and R 4 together with the atom to which they are attached form an azetidine, wherein the heterocyclyl is substituted with one or more methyl, where one methyl is further substituted with fluoro.

[0085] In an embodiment, R 1 is pyrazinyl or pyrimidinyl optionally substituted by methyl; R 2 is C 5-6 C optionally further substituted with cycloalkyl 1-6 alkyl-substituted phenyl; R 3 and R 4 together with the atom to which they are attached form an azetidine, wherein the heterocyclyl is substituted with one or more methyl, where one methyl is further substituted with fluoro.

[0086] In an embodiment, R 1 is pyrazinyl or pyrimidinyl optionally substituted by methyl; R 2 is phenyl substituted with methyl which may be further substituted with cyclopentyl; R 3 and R 4together with the atom to which they are attached form an azetidine, wherein the heterocyclyl is substituted with one or more methyl, where one methyl is further substituted with fluoro.

[0087] In some embodiments, the compound of Formula (I) has the formula (IB): JPEG0007759877000005.jpg37170, wherein R 5 H, halo, OH, cyano, and C 1-6 alkyl, wherein C 1-6 Alkyl can also be substituted with halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 It may be optionally substituted with one or more substituents selected from the group consisting of alkoxy.

[0088] In an embodiment, R 1 is C 1-6 It is a 5-20 membered heteroaryl optionally substituted with alkyl.

[0089] In an embodiment, R 1 is C 1-6 It is a 6-membered heteroaryl optionally substituted with alkyl.

[0090] In an embodiment, R 1 is pyrazinyl or pyrimidinyl optionally substituted with methyl.

[0091] In an embodiment, R 1 is pyrazinyl or pyrimidinyl optionally substituted with methyl.

[0092] In an embodiment, R 2 C may be substituted with one or more halo groups and may be further substituted with one or more halo groups. 5-6 It is a phenyl substituted with a cycloalkyl.

[0093] In an embodiment, R 2is C 5-6 It is a phenyl substituted with a cycloalkyl.

[0094] In an embodiment, R 2 is phenyl substituted with cyclohexyl.

[0095] In an embodiment, R 2 is phenyl optionally substituted with one or more fluoro groups, C 5-6 It is substituted with cycloalkyl.

[0096] In an embodiment, R 2 is phenyl optionally substituted with one or more fluoro and substituted with cyclohexyl.

[0097] In an embodiment, R 2 is C 5-6 C optionally further substituted with cycloalkyl 1-6 It is phenyl substituted with alkyl.

[0098] In an embodiment, R 2 is phenyl substituted with methyl which may be further substituted with cyclopentyl.

[0099] In an embodiment, R 1 is C 1-6 R is a 5- to 20-membered heteroaryl optionally substituted with alkyl; 2 C may be substituted with one or more halo groups and may be further substituted with one or more halo groups. 5-6 It is a phenyl substituted with a cycloalkyl.

[0100] In an embodiment, R 1 is C 1-6 a 6-membered heteroaryl optionally substituted with alkyl; R 2 is C 5-6 It is a phenyl substituted with a cycloalkyl.

[0101] In an embodiment, R1 is pyrazinyl or pyrimidinyl optionally substituted by methyl; R 2 is phenyl substituted with cyclohexyl.

[0102] In an embodiment, R 1 is pyrazinyl or pyrimidinyl optionally substituted by methyl; R 2 is phenyl optionally substituted with one or more fluoro and substituted with cyclohexyl.

[0103] In an embodiment, R 1 is pyrazinyl or pyrimidinyl optionally substituted by methyl; R 2 is C 5-6 C optionally further substituted with cycloalkyl 1-6 It is phenyl substituted with alkyl.

[0104] In an embodiment, R 1 is pyrazinyl or pyrimidinyl optionally substituted by methyl; R 2 is phenyl substituted with methyl which may be further substituted with cyclopentyl.

[0105] In an embodiment, R 1 is C 1-6 R is a 5- to 20-membered heteroaryl optionally substituted with alkyl; 2 C may be substituted with one or more halo groups and may be further substituted with one or more halo groups. 5-6 cycloalkyl-substituted phenyl; R 5 is hydrogen or methyl.

[0106] In an embodiment, R 1 is C 1-6 a 6-membered heteroaryl optionally substituted with alkyl; R 2 is C 5-6 cycloalkyl-substituted phenyl; R 5 is hydrogen or methyl.

[0107] In an embodiment, R 1 is pyrazinyl or pyrimidinyl optionally substituted by methyl; R 2 is phenyl substituted with cyclohexyl; R 5 is hydrogen or methyl.

[0108] In an embodiment, R 1 is pyrazinyl or pyrimidinyl optionally substituted by methyl; R 2 is phenyl optionally substituted with one or more fluoro and substituted with cyclohexyl; R 5 is hydrogen or methyl.

[0109] In an embodiment, R 1 is pyrazinyl or pyrimidinyl optionally substituted by methyl; R 2 is C 5-6 C optionally further substituted with cycloalkyl 1-6 alkyl-substituted phenyl; R 5 is hydrogen or methyl.

[0110] In an embodiment, R 1 is pyrazinyl or pyrimidinyl optionally substituted by methyl; R 2 is phenyl substituted with methyl which may be further substituted with cyclopentyl; R 5 is hydrogen or methyl; R 5 is hydrogen or methyl.

[0111] In some embodiments, R 5 is H and the compound of formula (IB) is JPEG0007759877000006.jpg34170, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof.

[0112] In some embodiments, R 5 is methyl and the compound of formula (IB) is JPEG0007759877000007.jpg42170, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof. In some embodiments, the compound of Formula (I) has the formula (IC): JPEG0007759877000008.jpg44170, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof.

[0113] In an embodiment, the compound of formula (IC) is: JPEG0007759877000009.jpg39170 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof, wherein: R 1 is C(O)N(R a )(R b ), C 6-20 Aryl, 5-20 membered heteroaryl, 5-20 membered heterocyclyl, and C 1-6 alkyl, wherein R 1 C 6-20 Aryl, 5-20 membered heteroaryl and 5-20 membered heterocyclyl are independently selected from halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, and C 6-10 aryl, and R 1 C 1-6 Alkyl is halogen, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, and C 6-10 optionally substituted with one or more substituents selected from the group consisting of aryl; R a and R b are each independently H or C 1-6 alkyl, where C 1-6Alkyl is a group that can be substituted with halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 substituted with one or more substituents selected from the group consisting of alkoxy; R a and R b together with the atom to which they are attached form a 3-10 membered heterocyclyl, where the 3-10 membered heterocyclyl is selected from halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 optionally substituted with one or more substituents selected from the group consisting of alkoxy; R 5 H, halo, OH, cyano, and C 1-6 alkyl, wherein C 1-6 Alkyl is a group that can be substituted with halo, OH, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 It may be further substituted with one or more substituents selected from the group consisting of alkoxy.

[0114] In an embodiment, R 1 is C(O)N(R a )(R b ), C 6-20 Aryl, 5-20 membered heteroaryl, 5-20 membered heterocyclyl, and C 1-6 alkyl, wherein R 1 C 6-20 Aryl, 5-20 membered heteroaryl and 5-20 membered heterocyclyl are independently selected from cyano, C 1-6 Alkyl and C 1-6 alkoxy; R 1 C 1-6 The alkyl may be substituted with one or more substituents selected from the group consisting of halogen and OH; R a and R b are each independently, C 1-6 alkyl or Ra and R b together with the atom to which they are attached form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is selected from one or more C 1-6 It may be substituted with alkyl.

[0115] In an embodiment, R 1 is C 1-6 It is a 5-20 membered heteroaryl optionally substituted with alkyl.

[0116] In an embodiment, R 1 is C 1-6 It is a 6-membered heteroaryl optionally substituted with alkyl.

[0117] In an embodiment, R 1 is pyrazinyl or pyrimidinyl optionally substituted with methyl.

[0118] In an embodiment, R 1 is pyrazinyl or pyrimidinyl optionally substituted with methyl.

[0119] In an embodiment, R 5 is H.

[0120] In an embodiment, R 5 is methyl.

[0121] In embodiments, compounds of Formula (I) include those listed in Table A, and stereoisomers thereof, tautomers thereof, and pharmaceutically acceptable salts thereof.

[0122] JPEG0007759877000010.jpg234170JPEG0007759877000011.jpg238170JPEG0007759877000012.jpg224170JPEG0007759877000013.j pg228170JPEG0007759877000014.jpg230170JPEG0007759877000015.jpg231170JPEG0007759877000016.jpg231170JPEG00077598770 00017.jpg228170JPEG0007759877000018.jpg235170JPEG0007759877000019.jpg223170JPEG0007759877000020.jpg218170JPEG000 7759877000021.jpg231170JPEG0007759877000022.jpg250170JPEG0007759877000023.jpg248170JPEG0007759877000024.jpg140170

[0123] In some embodiments, provided herein are: 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-N,N-dimethyl-7-oxo-4H-pyrazolo[1,5-a]pyrimidine-2-carboxamide; 5-[4-(cyclopentylmethyl)phenyl]-3-[3-(fluoromethyl)azetidine-1-carbonyl]-N,N-dimethyl-7-oxo-4H-pyrazolo[1,5-a]pyrimidine-2-carboxamide; 5-(4-cyclohexyl-3,5-difluoro-phenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-N,N-dimethyl-7-oxo-4H-pyrazolo[1,5-a]pyrimidine-2-carboxamide; 5-(4-Cyclohexyl-3-fluoro-phenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-N,N-dimethyl-7-oxo-4H-pyrazolo[1,5-a]pyrimidine-2-carboxamide; 5-(4-Cyclohexylphenyl)-N,N-dimethyl-7-oxo-3-[3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidine-2-carboxamide; 5-(4-Cyclohexylphenyl)-N,N-dimethyl-7-oxo-3-[3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidine-2-carboxamide; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-[3-(trifluoromethyl)pyrazin-2-yl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 3-[5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-7-oxo-4H-pyrazolo[1,5-a]pyrimidin-2-yl]pyrazine-2-carbonitrile; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-(4-methylpyrimidin-2-yl)-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-(4-isopropylpyrimidin-2-yl)-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-[4-(trifluoromethyl)pyrimidin-2-yl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-2-(4-ethylpyrimidin-2-yl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-(3-methoxypyrazin-2-yl)-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-(4-methoxypyrimidin-2-yl)-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-pyrimidin-2-yl-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-(2-pyridyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-pyrazin-2-yl-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-(4-methyl-2-pyridyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-oxazol-2-yl-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-N,N-dimethyl-2-(3-methylpyrazin-2-yl)-7-oxo-4H-pyrazolo[1,5-a]pyrimidine-3-carboxamide; 5-(4-cyclohexyl-3-fluoro-phenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-(3-methylpyrazin-2-yl)-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexyl-3-fluoro-phenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-pyrimidin-2-yl-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexyl-3-fluoro-phenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-pyrazin-2-yl-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-[4-(cyclopentylmethyl)phenyl]-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-pyrimidin-2-yl-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-[4-(cyclopentylmethyl)phenyl]-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-pyrazin-2-yl-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-(5-methylpyrazin-2-yl)-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-(3-methylpyrazin-2-yl)-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-(6-methylpyrazin-2-yl)-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-2-(3,4-dimethyl-2-pyridyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-2-(1,5-dimethylimidazol-4-yl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-2-(1-ethylimidazol-4-yl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-(1-methylimidazol-4-yl)-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-[2-methylazetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-[2-methylazetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-N-ethyl-3-[3-(fluoromethyl)azetidine-1-carbonyl]-N-methyl-7-oxo-4H-pyrazolo[1,5-a]pyrimidine-2-carboxamide; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-(pyrrolidine-1-carbonyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-(3-pyridyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-phenyl-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-oxazol-5-yl-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-2-pyrazin-2-yl-3-[3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-2-pyrazin-2-yl-3-[3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-2-pyrimidin-2-yl-3-[3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-2-pyrimidin-2-yl-3-[3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-2-(3-methylpyrazin-2-yl)-3-[3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-2-(3-methylpyrazin-2-yl)-3-[3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-[4-(cyclopentylmethyl)phenyl]-2-(3-methylpyrazin-2-yl)-3-[3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-[4-(cyclopentylmethyl)phenyl]-2-(3-methylpyrazin-2-yl)-3-[3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-[4-(cyclopentylmethyl)phenyl]-2-pyrimidin-2-yl-3-[3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-[4-(cyclopentylmethyl)phenyl]-2-pyrimidin-2-yl-3-[3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-[4-(cyclopentylmethyl)phenyl]-2-pyrazin-2-yl-3-[3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-[4-(cyclopentylmethyl)phenyl]-2-pyrazin-2-yl-3-[3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 3-[3-(fluoromethyl)azetidine-1-carbonyl]-5-[(4-isopropylphenyl)methoxy]-2-pyrazin-2-yl-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-[(4-tert-butylphenyl)methoxy]-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-pyrazin-2-yl-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-[(4-tert-butylphenyl)methoxy]-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-pyrimidin-2-yl-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-[4-(4,4-difluorocyclohexyl)phenyl]-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-(3-methylpyrazin-2-yl)-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-[4-[cyclopentyl(difluoro)methyl]phenyl]-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-(3-methylpyrazin-2-yl)-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-[4-(1-cyclopentylcyclopropyl)phenyl]-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-pyrimidin-2-yl-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-butylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-(3-methylpyrazin-2-yl)-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-[4-(1-fluorocyclohexyl)phenyl]-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-(3-methylpyrazin-2-yl)-4H-pyrazolo[1,5-a]pyrimidin-7-one; 3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-(3-methylpyrazin-2-yl)-5-(4-phenylphenyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one; 1-[5-(4-cyclohexylphenyl)-7-oxo-2-[2-hydroxy-1-methyl-ethyl]-4H-pyrazolo[1,5-a]pyrimidine-3-carbonyl]pyrrolidine-3-carbonitrile; 1-[5-(4-cyclohexylphenyl)-7-oxo-2-[2-hydroxy-1-methyl-ethyl]-4H-pyrazolo[1,5-a]pyrimidine-3-carbonyl]pyrrolidine-3-carbonitrile; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-[2-hydroxy-1-methyl-ethyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-[2-hydroxy-1-methyl-ethyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 2-(3-Methylpyrazin-2-yl)-3-[3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-5-[4-[2,2,2-trifluoro-1-phenyl-ethoxy]phenyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-(3-methylpyrazin-2-yl)-5-[4-[2,2,2-trifluoro-1-phenyl-ethoxy]phenyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 2-(3-Methylpyrazin-2-yl)-3-[3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-5-[4-[2,2,2-trifluoro-1-phenyl-ethoxy]phenyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-(3-methylpyrazin-2-yl)-5-[4-[2,2,2-trifluoro-1-phenyl-ethoxy]phenyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclopentylphenyl)-2-(3-methylpyrazin-2-yl)-3-[3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 2-(3-Methylpyrazin-2-yl)-3-[3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-5-[non-1-enyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 2-(3-methylpyrazin-2-yl)-5-nonyl-3-[3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 2-(3-methylpyrazin-2-yl)-3-[3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-5-[4-(1,2,2,3,3,4,4,5,5,6,6-undecadeuteriocyclohexyl)phenyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-[4-(2,2-dimethylpropyl)phenyl]-2-(3-methylpyrazin-2-yl)-3-[3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; 5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-[morpholin-2-yl]-4H-pyrazolo[1,5-a]pyrimidin-7-one; and 5-(4-Cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-[morpholin-2-yl]-4H-pyrazolo[1,5-a]pyrimidin-7-one or a pharmaceutically acceptable salt thereof. Further provided herein are, where appropriate, all stereoisomers of the compounds presented herein, including geometric isomers (e.g., cis / trans or E / Z isomers), enantiomers, diastereomers, or mixtures thereof in any ratio, including racemic mixtures.

[0124] In some embodiments, compounds of formula (I) are isotopically labeled by replacing one or more atoms therein with atoms having a different atomic mass or mass number. Such isotopically labeled (e.g., radiolabeled) compounds of formula (I) are considered to be within the scope of the present disclosure. Examples of isotopes that can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, including, but not limited to: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. Certain isotopically labeled compounds of formula (I), for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e. 14C are particularly useful for this purpose given their ease of incorporation and straightforward means of detection. For example, compounds of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0125] Deuterium, i.e. 2 Substitution with heavier isotopes such as H may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Any hydrogen (H) present in any of the compounds of formula (I) disclosed herein may be substituted with a heavier isotope such as H. 1 H) atoms and deuterium ( 2 It is understood that in any given compound of formula (I), any number of hydrogen atoms may be replaced by an equal number of deuterium atoms.

[0126] 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes such as N can be useful in positron emission tomography (PET) to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I) can be prepared by methods analogous to those described in the Examples below, or by conventional techniques known to those skilled in the art, typically using an appropriate isotopically labeled reagent in place of a previously used non-labeled reagent.

[0127] In addition to salt forms, the present disclosure provides compounds in prodrug form. As used herein, the term "prodrug" refers to a compound that easily undergoes chemical changes under physiological conditions to provide the compounds of the present disclosure. In addition, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with an appropriate enzyme or chemical reagent.

[0128] Prodrugs of the present disclosure may include phosphates, phosphate esters, alkyl phosphates, alkyl phosphate esters, acyl ethers, or other prodrug moieties as described below. In some embodiments, the prodrug moieties are as follows: JPEG0007759877000025.jpg53170

[0129] Additional types of prodrugs are also encompassed, for example, an amino acid residue, or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues, is covalently bonded to a free amino, hydroxy, or carboxylic acid group of a compound of the disclosure through an amide or ester bond. Amino acid residues include, but are not limited to, the 20 naturally occurring amino acids, commonly represented by their three-letter symbols, and also phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosin, isodemosin, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statin, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, and tert-butylglycine. Additional types of prodrugs are also encompassed. For example, free carboxyl groups of compounds of the present disclosure can be derivatized as amides or alkyl esters. As another example, compounds of the present disclosure containing free hydroxy groups can be derivatized as prodrugs by converting the hydroxy group to groups such as, but not limited to, phosphate esters, hemisuccinates, dimethylaminoacetates, or phosphoryloxymethyloxycarbonyl groups, as reviewed in Fleisher, D. et al. (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamate prodrugs of hydroxy and amino groups are also encompassed, as are carbonate prodrugs, sulfonate esters, and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl esters is also encompassed, where the acyl group can be, but is not limited to, an alkyl ester optionally substituted with ether, amine, and carboxylic acid functional groups, or the amino acid esters described above. This type of prodrug is described in J. Med. Chem., (1996), 39:10. More specific examples include prodrugs in which the hydrogen atom of the alcohol group is replaced with a (C 1-6 ) alkanoyloxymethyl, 1-((C 1-6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1-6 )alkanoyloxy)ethyl, (C 1-6 )alkoxycarbonyloxymethyl, N-(C 1-6 ) alkoxycarbonylaminomethyl, succinoyl, (C 1-6 ) alkanoyl, alpha-amino (C 1-4 )alkanoyl, arylacyl, and alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl groups, where each alpha-aminoacyl group independently represents a naturally occurring L-amino acid, P(O)(OH), -P(O)(O(C 1-6) alkyl) 2 or glycosyl (a radical obtained from removal of the hydroxyl group of the hemiacetal form of a carbohydrate).

[0130] For additional examples of prodrug derivatives, see, for example, a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs," by H. Bundgaard, pp. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988); and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), which are specifically incorporated herein by reference.

[0131] Additionally, the present disclosure provides metabolic products of the disclosed compounds. As used herein, "metabolite" refers to a product produced through metabolism in the body of a particular compound or salt thereof. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc., of the administered compound.

[0132] The metabolites are typically radiolabeled (e.g., 14 C or 3Identification of metabolites is accomplished by preparing a H isotope, parenterally administering it to animals such as rats, mice, guinea pigs, monkeys, or humans at a detectable dose (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating the conversion products from urine, blood, or other biological samples. Such products are easily isolated because they are labeled (otherwise isolated by using antibodies capable of binding to epitopes surviving in the metabolites). The structures of the metabolites are determined by conventional methods, such as MS, LC / MS, or NMR analysis. Metabolite analysis is generally performed in the same manner as conventional drug metabolism testing well known to those skilled in the art. Metabolites, unless otherwise found in vivo, are useful in diagnostic assays for therapeutic administration of the disclosed compounds.

[0133] Some compounds of the present disclosure can exist in unsolvated forms and solvated forms, including hydrated forms. Generally, solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Some compounds of the present disclosure can exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated in the present disclosure and are intended to be within the scope of the present disclosure.

[0134] III. Pharmaceutical Compositions and Administration Further disclosed are pharmaceutical compositions comprising at least one of the disclosed compounds and a therapeutically inert carrier. Another aspect includes a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the composition further comprises a pharmaceutically acceptable carrier, adjuvant, or vehicle. In another embodiment, the composition further comprises a therapeutically inert carrier. In another embodiment, the composition further comprises an amount of a compound effective to measurably disrupt YAP:TEAD protein-protein interaction. In some embodiments, the composition is formulated for administration to a patient in need thereof. In another embodiment, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to Formula (I) and a pharmaceutically acceptable carrier, diluent, and / or excipient.

[0135] Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acids, water, partial glyceride mixtures of salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0136] Compositions containing a compound of formula (I) or a salt thereof may be administered orally, parenterally, by inhalation spray, topically, transdermally, rectally, nasally, bucally, sublingually, vaginally, intraperitoneally, pulmonary, intradermally, epidurally or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

[0137] In one embodiment, the composition comprising the compound of formula (I) or a salt thereof is formulated as a solid dosage form for oral administration. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In some embodiments, the solid oral dosage form comprising the compound of formula (I) or a salt thereof comprises (i) an inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate; (ii) a filler or extender, such as starch, lactose, sucrose, glucose, mannitol, or silicic acid; (iii) a binder, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, or acacia; (iv) a humectant, such as glycerol; (v) a disintegrant, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, some silicates, or sodium carbonate; (vi) a solution retarder. (vii) an absorption enhancer, such as a quaternary ammonium salt; (viii) a wetting agent, such as cetyl alcohol or glycerol monostearate; (ix) an absorbent, such as kaolin or bentonite clay; and (x) a lubricant, such as one or more of talc, calcium stearate, magnesium stearate, polyethylene glycol, or sodium lauryl sulfate. In some embodiments, the solid oral dosage form is formulated as a capsule, tablet, or pill. In some embodiments, the solid oral dosage form further comprises a buffering agent. In some embodiments, such compositions for solid oral dosage forms may be formulated as fillers in soft and hard-filled gelatin capsules containing one or more excipients, such as lactose or milk sugar, polyethylene glycol, and the like.

[0138] In some embodiments, tablets, dragees, capsules, pills, and granules of compositions comprising a compound of Formula (I) or a salt thereof optionally comprise a coating or shell, such as an enteric coating. They may also optionally contain opacifying agents and can be of a composition that they release one or more active ingredients only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions include polymeric substances and waxes, which may be used as fillers in soft- and hard-filled gelatin capsules using such excipients as lactose or sugar milk, and high molecular weight polyethylene glycols, etc.

[0139] In another embodiment, a composition comprises a microencapsulated compound of formula (I) or a salt thereof, and optionally further comprises one or more additives.

[0140] In another embodiment, the composition comprises a liquid dosage form comprising a compound of Formula (I) or a salt thereof for oral administration, optionally further comprising one or more of pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In some embodiments, the liquid dosage form optionally further comprises one or more of an inert diluent, such as water or other solvent, a solubilizing agent, and an emulsifier, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol or fatty acid esters of sorbitan, and mixtures thereof. In some embodiments, the liquid oral composition optionally further comprises one or more adjuvants, such as wetting agents, suspending agents, sweeteners, flavoring agents, and fragrances.

[0141] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using appropriate dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally administrable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic aqueous sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil, including synthetic monoglycerides or diglycerides, can be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0142] Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0143] To prolong the effect of a compound of Formula (I), it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. In this case, the rate of absorption of the compound depends on its rate of dissolution, which, in turn, may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the compound-to-polymer ratio and the nature of the particular polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0144] In some embodiments, compositions for rectal or vaginal administration are prepared as suppositories, for example, which can be prepared by mixing a compound of Formula (I) or its salt with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax, which is solid at ordinary temperatures but liquid at body temperature and will therefore melt in the rectum or vaginal cavity and release the compound of Formula (I).

[0145] Exemplary dosage forms for topical or transdermal administration of a compound of Formula (I) include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The compound of Formula (I) or its salt is mixed under sterile conditions with a pharmaceutically acceptable carrier and, optionally, a preservative or buffer. Additional examples of formulations include ophthalmic formulations, ear drops, eye drops, and transdermal patches. Transdermal dosage forms can be made by dissolving or suspending the compound of Formula (I) or its salt in a vehicle such as ethanol or dimethyl sulfoxide. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0146] Nasal aerosol or inhalation formulations of the compounds of formula (I) or their salts may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other common solubilizing or dispersing agents.

[0147] In some embodiments, the pharmaceutical composition may or may not be administered with food. In some embodiments, the pharmaceutically acceptable composition is administered without food. In some embodiments, the pharmaceutically acceptable composition of the present invention is administered with food.

[0148] The specific administration and treatment regimen for any particular patient will depend on a variety of factors, including age, weight, general health, sex, diet, time of administration, rate of excretion, combination formulation, the judgment of the treating physician, and the severity of the particular disease being treated. The amount of compound of formula (I) or salt thereof provided in the composition will also depend on the particular compound in the composition.

[0149] In one embodiment, the therapeutically effective amount of a compound of the invention administered parenterally per dose ranges from about 0.01-100 mg / kg, alternatively about 0.1 to 20 mg / kg of patient body weight per day, with a typical initial range of the compound used being 0.3 to 15 mg / kg / day. In another embodiment, oral unit dosage forms, such as tablets and capsules, contain from about 5 to about 100 mg of a compound of the invention.

[0150] An example of an oral tablet dosage form contains about 2 mg, 5 mg, 25 mg, 50 mg, 100 mg, 250 mg, or 500 mg of the compound of Formula (I) or a salt thereof, and further contains about 5-30 mg of anhydrous lactose, about 5-40 mg of croscarmellose sodium, about 5-30 mg of polyvinylpyrrolidone (PVP) K30, and about 1-10 mg of magnesium stearate. A method for formulating tablets involves blending the powdered ingredients together and further blending with a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving about 2-500 mg of the compound of Formula (I) or a salt thereof in an appropriate buffer solution, such as phosphate buffer, and adding a tonicifier, e.g., sodium chloride, as needed. The solution can be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

[0151] IV. Indications and Combination Therapies In some embodiments, the disclosed compounds are inhibitors of the YAP:TEAD protein-protein interaction ("YAP:TEAD inhibitors") that bind to TEAD and disrupt the YAP:TEAD protein-protein interaction. In embodiments, the disclosed compounds are useful for treating cancer, including cancers characterized by solid tumors, through their ability to inhibit the YAP:TEAD protein-protein interaction. The disclosed compounds are small molecule YAP:TEAD inhibitors. Small molecule YAP:TEAD inhibitors are useful, for example, for diagnosing or treating cancer, including, but not limited to, lung cancer, breast cancer, head and neck cancer, colon cancer, ovarian cancer, liver cancer, brain cancer, and prostate cancer, mesothelioma, sarcoma, and / or leukemia. In other embodiments, small molecule YAP:TEAD inhibitors are useful for diagnosing or treating cancer characterized by solid tumors, including, but not limited to, lung cancer, liver cancer, ovarian cancer, breast cancer, and / or squamous cell carcinoma. In some embodiments, the solid tumor has YAP / TAZ amplification or Nf2 deletion / mutation.

[0152] In some embodiments, the disclosed compounds are for use as therapeutically active agents.

[0153] In some embodiments, the disclosed compounds and disclosed compositions are for the therapeutic and / or prophylactic treatment of cancer.

[0154] In some embodiments, the disclosed compounds are for the preparation of a medicament for the therapeutic treatment of cancer.

[0155] In some embodiments, the disclosed compounds are for use in the therapeutic treatment of cancer.

[0156] The present disclosure relates to methods for the therapeutic treatment of cancer in a subject, the methods comprising administering to the subject an effective amount of any one or more of the disclosed compounds.

[0157] In some embodiments, the cancer is a solid tumor.

[0158] In some embodiments, the cancer is selected from the group consisting of lung cancer, liver cancer, ovarian cancer, breast cancer, and squamous cell carcinoma.

[0159] In some embodiments, the present disclosure includes the use of any of the compounds of Formula (I) disclosed herein for the therapeutic and / or prophylactic treatment of cancer. In other embodiments, the present disclosure includes the use of any of the compounds of Formula (I) disclosed herein for the preparation of a medicament for the therapeutic and / or prophylactic treatment of cancer. In other embodiments, the present disclosure includes the compounds of Formula (I) disclosed herein for the therapeutic and / or prophylactic treatment of cancer.

[0160] In some embodiments, the present disclosure includes a method for the therapeutic and / or prophylactic treatment of cancer, the method comprising administering an effective amount of a compound of Formula (I) disclosed herein.

[0161] In some embodiments, the method of treatment involves co-administration of a compound of Formula (I), or a stereoisomer, tautomer, or deuterated analog thereof, or a pharmaceutically acceptable salt of any of them, with at least one mitogen-activated protein kinase (MAPK) inhibitor. In some embodiments, the method of treatment involves co-administration of a compound of Formula (I), or a stereoisomer, tautomer, or deuterated analog thereof, or a pharmaceutically acceptable salt of any of them, with at least one inhibitor of the RAS / MAPK pathway. In some embodiments, the method of treatment involves co-administration of a compound of Formula (I), or a stereoisomer, tautomer, or deuterated analog thereof, or a pharmaceutically acceptable salt of any of them, with at least one epidermal growth factor receptor (EGFR) inhibitor. In some embodiments, the inhibitor of the RAS / MAPK pathway is a KRAS inhibitor, a RAF inhibitor, such as a BRAF monomer or RAF dimer inhibitor, a MEK inhibitor, an ERK inhibitor, an EGFR inhibitor, or a MAPK inhibitor, or any combination thereof. In some embodiments, the inhibitor of the RAS / MAPK pathway is an EGFR inhibitor or a MAPK inhibitor, or a combination thereof.Examples of EGFR inhibitors, MAPK inhibitors, and / or RAS / MAPK pathway inhibitors are disclosed in Moore, A.R., Rosenberg, S.C., McCormick, F. et al. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov (2020), which is incorporated herein by reference, and include, but are not limited to: sotorasib (AMG 510, Amgen), MRTX849 (Mirati Therapeutics), JNJ-74699157 / ARS-3248 (J&J Wellspring Biosciences), LY3499446 (Eli Lilly), GDCBI 1701963 (Boehringer Ingelheim), mRNA-5671 (Moderna Therapeutics), G12D inhibitors (Mirati Therapeutics), RAS(ON) inhibitors (Revolution Medicines), BBP-454 (BridgeBio Pharma), SP600125, PLX4032, GW5074, AZD6244, PD98059, simvastatin, alisertib, teriflunomide, NSC95397, PD325901, PD98059, lovastatin, sorafenib (NEXAVAR®, Bayer Labs), vemurafenib (ZELBORAF®, Hoffman-La Roche Inc.), dabrafenib (TAFLINAR®, Novartis Pharmaceuticals Corporation), selumetinib (KOSELUGO). TM, AstraZeneca Pharmaceuticals LP), trametinib (MEKINIST®, Novartis Pharmaceuticals Corporation), ulixertinib, silymarin, sirolimus (RAPAMUNE®, PV Prism CV), lapatinib (TYKERB® / TYVERB®, GlaxoSmithKline), crizotinib (XALKORI®, PF Prism CV), CV), taselisib (Roche), PF-0491502, PF502, enterolactone, PLX4720, PD0325901, PD184352, SC-514, alistelib (MLN8237), SB415286, PLX4720, obtaoclax (GX15-070), pimasterib, venetoclax (ABT-199 / VENCLEXTA® / VENCLYXTO®), eprenetapopt (APR-246), gemcitabine (Gemzar®), virinapant (TL32711), pexmetinib (ARRY-614), afuresertib, ralimetinib (LY2228820, Eli Lilly), cobimetinib (COTELLIC®, Exelixis / Genentech), prexasertib (LY2606368), erlotinib (TARCEVA®, OSI Pharmaceuticals), bevacizumab (AVASTIN®, Genentech), belvarafenib (Hanmi Pharm. / Genentech, Inc.), and binimetinib (MEKTOVI®, Array Biopharma Inc.).

[0162] Breast cancer The compounds of the present disclosure can be administered alone or in combination therapy for the treatment of breast cancer. For example, combination therapy includes administering a compound of the present disclosure and administering at least one additional therapeutic agent (e.g., 1, 2, 3, 4, 5, or 6 additional therapeutic agents) for the treatment of breast cancer.

[0163] The standard of care for breast cancer is determined by both disease characteristics (tumor, stage, pace of disease, etc.) and patient characteristics (age, biomarker expression, and intrinsic phenotype). General guidance for treatment selection is provided in the NCCN Guidelines (e.g., NCCN Clinical Practice Guidelines in Oncology, Breast Cancer, version 2.2016, National Comprehensive Cancer Network, 2016, pp. 1-202) and the ESMO Guidelines (e.g., Senkuspp. E., et al. Primary Breast Cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Annals of Oncology 2015;26(Suppl. 5):v8-v30; and Cardoso F., et al. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Annals of Oncology 2012;23(Suppl. 7):vii11-vii19.).

[0164] In some embodiments, the compounds are for use in combination therapy for the treatment of breast cancer in combination with one or more other therapeutic agents. In further embodiments, the compounds are for use in combination therapy for the treatment of early stage breast cancer or locally advanced breast cancer. In further embodiments, the compounds are for use in combination therapy for the treatment of advanced breast cancer or metastatic breast cancer.

[0165] In particular, the compounds of the present disclosure can be used alone or in combination with standard treatment options for breast cancer, which generally include surgery, systemic chemotherapy (pre- or post-operative), and / or radiation therapy. Depending on tumor and patient characteristics, systemic chemotherapy can be administered as adjuvant (post-operative) therapy or as neoadjuvant (pre-operative) therapy.

[0166] Thus, in one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering at least one additional therapeutic agent such as doxorubicin, epirubicin, cyclophosphamide, docetaxel, paclitaxel, methotrexate, and / or 5-fluorouracil.

[0167] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering doxorubicin and cyclophosphamide (AC chemotherapy). In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering docetaxel, doxorubicin, and cyclophosphamide (TAC chemotherapy). In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering cyclophosphamide, methotrexate, and 5-fluorouracil (CMF chemotherapy). In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering epirubicin and cyclophosphamide (EC chemotherapy). In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering 5-fluorouracil, epirubicin, and cyclophosphamide (FEC chemotherapy). In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC chemotherapy). In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering a taxane, particularly docetaxel or paclitaxel.

[0168] In one embodiment, the compound of the present disclosure is for use in the treatment of metastatic breast cancer, and the combination therapy comprises administering a compound of the present disclosure and administering at least one additional therapeutic agent such as doxorubicin, pegylated liposomal doxorubicin, epirubicin, cyclophosphamide, carboplatin, cisplatin, docetaxel, paclitaxel, albumin-bound paclitaxel, capecitabine, gemcitabine, vinorelbine, eribulin, ixabepilone, methotrexate, and / or 5-fluorouracil (5-FU). In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering docetaxel and capecitabine for use in the treatment of metastatic breast cancer. In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering gemcitabine and paclitaxel for use in the treatment of metastatic breast cancer.

[0169] Breast cancer - hormone receptor positive (ER+ and / or PR+) In a further aspect, the present disclosure provides a method for treating hormone receptor positive (HR+) breast cancer (also called estrogen receptor positive (ER+) breast cancer or estrogen receptor positive and / or progesterone receptor positive (PR+) breast cancer) by administering an effective amount of a compound of the present disclosure. In a further aspect of the embodiment, the breast cancer is early stage or locally advanced hormone receptor positive (HR+) breast cancer, also called early stage or locally advanced ER+ breast cancer. In a further aspect, the breast cancer is advanced hormone receptor positive (HR+) breast cancer or metastatic hormone receptor positive (HR+) breast cancer, also called advanced ER+ breast cancer or metastatic ER+ breast cancer.

[0170] In some embodiments, the compounds are for use in combination therapy for the treatment of hormone receptor positive (HR+) breast cancer or estrogen receptor positive (ER+) breast cancer. In a further embodiment, the compounds are for use in combination therapy for the treatment of early stage or locally advanced hormone receptor positive (HR+) breast cancer, also referred to as early stage or locally advanced ER+ breast cancer. In a further aspect of the embodiment, the compounds are for use in combination therapy for the treatment of advanced hormone receptor positive (HR+) breast cancer or metastatic hormone receptor positive (HR+) breast cancer, also referred to as advanced ER+ breast cancer or metastatic ER+ breast cancer. In one embodiment, the method comprises administering to an individual with hormone receptor positive (HR+) breast cancer or estrogen receptor positive (ER+) breast cancer an effective amount of a compound of the present disclosure in combination with one or more other therapeutic agents.

[0171] In particular, the compounds of the present disclosure can be used alone or in combination with standard treatment options for hormone receptor positive (HR+) or estrogen receptor positive (ER+) breast cancer, which generally include surgery, systemic chemotherapy (pre- or post-operative), and / or radiation therapy. Depending on tumor and patient characteristics, systemic chemotherapy can be administered as adjuvant (post-operative) therapy or as neoadjuvant (pre-operative) therapy.

[0172] In one embodiment, a compound of the present disclosure is for use in treating hormone receptor positive (HR+) breast cancer or estrogen receptor positive (ER+) breast cancer in combination with endocrine therapy. In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering tamoxifen. In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering an aromatase inhibitor, such as anastrozole, letrozole, or exemestane, for use in treating hormone receptor positive (HR+) breast cancer or estrogen receptor positive (ER+) breast cancer. In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering at least one additional therapeutic agent, such as anastrozole, letrozole, exemestane and everolimus, palbociclib and letrozole, palbociclib and letrozole, fulvestrant, tamoxifen, toremifene, megestrol acetate, fluoxemesterone, and / or ethinyl estradiol for use in the treatment of hormone receptor positive (HR+) breast cancer or estrogen receptor positive (ER+) breast cancer.

[0173] In one embodiment, the compounds of the present disclosure are for use in the treatment of hormone receptor positive (HR+) breast cancer or estrogen receptor positive (ER+) breast cancer in combination with one or more chemotherapeutic agents. In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering at least one additional therapeutic agent, such as doxorubicin, epirubicin, cyclophosphamide, docetaxel, paclitaxel, methotrexate, and / or 5-fluorouracil, for use in the treatment of hormone receptor positive (HR+) breast cancer or estrogen receptor positive (ER+) breast cancer.

[0174] In one embodiment, the compound of the present disclosure is for use in combination with doxorubicin and cyclophosphamide (AC chemotherapy). In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering docetaxel, doxorubicin, and cyclophosphamide (TAC chemotherapy). In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering cyclophosphamide, methotrexate, and 5-fluorouracil (CMF chemotherapy). In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering epirubicin and cyclophosphamide (EC chemotherapy). In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering 5-fluorouracil, epirubicin, and cyclophosphamide (FEC chemotherapy). In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC chemotherapy). In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering a taxane, such as docetaxel or paclitaxel.

[0175] In one embodiment, the compound of the present disclosure is for use in the treatment of metastatic breast cancer. In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering doxorubicin, pegylated liposomal doxorubicin, epirubicin, cyclophosphamide, carboplatin, cisplatin, docetaxel, paclitaxel, albumin-bound paclitaxel, capecitabine, gemcitabine, vinorelbine, eribulin, ixabepilone, methotrexate, and 5-fluorouracil (5-FU) for use in the treatment of metastatic breast cancer. In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering docetaxel and capecitabine for use in the treatment of metastatic breast cancer. In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering gemcitabine and paclitaxel for use in the treatment of metastatic breast cancer.

[0176] Breast cancer - HER2+ In a further aspect, the present disclosure provides a method for treating Her2+ positive breast cancer by administering an effective amount of a compound of the present disclosure. In a further aspect of the embodiment, the breast cancer is early stage or locally advanced Her2+ positive breast cancer, also referred to as early stage or locally advanced Her2+ positive breast cancer. In a further aspect, the breast cancer is advanced breast cancer, also referred to as advanced Her2+ positive breast cancer or metastatic ER+ breast cancer.

[0177] In some aspects, the compounds are for use in combination therapy for the treatment of Her2+ positive breast cancer. In further aspects, the compounds are for use in combination therapy for the treatment of early stage or locally advanced Her2+ positive breast cancer, also referred to as early stage or locally advanced Her2+ positive breast cancer. In a further aspect of the embodiment, the compounds are for use in combination therapy for the treatment of advanced Her2+ positive breast cancer, also referred to as advanced Her2+ positive breast cancer or metastatic ER+ breast cancer. In one embodiment, the method comprises administering to an individual with Her2+ positive breast cancer an effective amount of a compound of the present disclosure in combination with one or more other therapeutic agents.

[0178] In particular, the compounds of the present disclosure can be used alone or in combination with standard treatment options for Her2+ positive breast cancer, which generally include surgery, systemic chemotherapy (pre- or post-operative), and / or radiation therapy. Depending on tumor and patient characteristics, systemic chemotherapy can be administered as adjuvant (post-operative) therapy or as neoadjuvant (pre-operative) therapy.

[0179] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering a Her2 antibody to treat Her2+ positive breast cancer. In one aspect, the combination therapy comprises administering a compound of the present disclosure and administering trastuzumab or pertuzumab to treat Her2+ positive breast cancer. In another aspect, the combination therapy comprises administering a compound of the present disclosure and administering chemotherapy to treat Her2+ positive breast cancer. In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering doxorubicin and cyclophosphamide, followed by trastuzumab, to treat Her2+ positive breast cancer. In a further embodiment, the compound of the present disclosure is for use in the treatment of Her2+ positive breast cancer in combination with chemotherapy, followed by taxane and trastuzumab to treat Her2+ positive breast cancer. In another aspect, the compounds of the present disclosure are for use in the treatment of Her2+ positive breast cancer in combination with trastuzumab (Herceptin) and pertuzumab (Perjeta) for the treatment of Her2+ positive breast cancer.

[0180] In another embodiment, the compounds of the present disclosure are used in combination with docetaxel, carboplatin, and trastuzumab (TCH chemotherapy). In a further embodiment, the compounds of the present disclosure are administered in combination with docetaxel, carboplatin, trastuzumab, and pertuzumab. In a further embodiment, the compounds of the present disclosure are administered in combination with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC chemotherapy), and pertuzumab, trastuzumab, and docetaxel or paclitaxel. In another embodiment, the compounds of the present disclosure are used in combination with paclitaxel and trastuzumab. In a further embodiment, the compounds of the present disclosure are administered in combination with pertuzumab, trastuzumab, and paclitaxel or docetaxel.

[0181] The compounds of the present disclosure, when they are for use in treating metastatic Her2+ positive breast cancer, can also be used in combination with one or more chemotherapeutic agents selected from the group consisting of doxorubicin (A) (Adriamycin), pegylated liposomal doxorubicin (Doxil), epirubicin (E) (Ellence), cyclophosphamide (C) (Cytoxan), carboplatin (Platinol), cisplatin (Paraplatin), docetaxel (T) (Taxotere), paclitaxel (Taxol), albumin-bound paclitaxel (Abraxane), capecitabine (Xeloda), gemcitabine (Cynzar), vinorelbine (Navelbine), eribulin (Halaven), and ixabepilone (Ixempra). In one embodiment, the compounds of the disclosure are for use in the treatment of metastatic Her2+ positive breast cancer in combination with trastuzumab emtansine (T-DM1).

[0182] In certain embodiments, the compounds of the present disclosure are for use in combination with trastuzumab and pertuzumab and a taxane to treat metastatic Her2+ positive breast cancer. In one embodiment, the taxane is docetaxel. In another embodiment, the taxane is paclitaxel.

[0183] Breast Cancer - Triple Negative The compounds of the present disclosure can be used alone or in combination therapy with standard treatment options for triple-negative breast cancer (TNBC), which generally include surgery, systemic chemotherapy (pre- or post-operative), and / or radiation therapy.

[0184] The standard of care for TNBC is determined by both disease (stage, pace, etc.) and patient (age, comorbidities, symptoms, etc.) characteristics. General guidance for treatment selection is provided in the NCCN Guidelines (e.g., NCCN Clinical Practice Guidelines in Oncology, Breast Cancer, version 2.2016, National Comprehensive Cancer Network, 2016, pp. 1-202) and the ESMO Guidelines (e.g., Senkus, E., et al. Primary Breast Cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Annals of Oncology 2015;26(Suppl.5):v8-v30; and Cardoso F., et al. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Annals of Oncology 2012;23(Suppl.7):vii11-vii19). See also Rodler, E, et al. Breast Disease. 2010 / 2011;32:99-122.

[0185] Metastatic TNBC Systemic chemotherapy is the standard of care for patients with metastatic TNBC, but no standard regimen or protocol exists. Single-agent cytotoxic chemotherapy agents listed in Table 1 are typically considered the first-line options for patients with metastatic TNBC; however, combination chemotherapy regimens, such as those listed in Table 2, may be used, for example, in the setting of aggressive disease and visceral involvement. Further details on available chemotherapy combinations are provided below in the section on early-stage and locally advanced treatment options. Treatment may involve the sequential use of different single-agent therapies. Appropriate palliative surgery and radiation may be utilized to manage local complications.

[0186] The methods provided herein include administering to a patient with metastatic TNBC a compound of the present disclosure in combination with one of the single agent chemotherapeutic agents listed in Table 1, or in combination with the sequential use of different chemotherapeutic agents listed in Table 1. Such methods can optionally be combined with surgery and / or radiation therapy.

[0187] Table 1. Single-agent chemotherapy regimens JPEG0007759877000026.jpg89170

[0188] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering an anthracycline, such as doxorubicin, pegylated liposomal doxorubicin, or epirubicin.

[0189] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering a taxane, such as paclitaxel, docetaxel, or albumin-bound paclitaxel (eg, nab-paclitaxel).

[0190] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering an antimetabolite, including, for example, capecitabine or gemcitabine.

[0191] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering a non-taxane microtubule inhibitor such as vinorelbine, eribulin, or ixabepilone.

[0192] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering a platinum compound, such as carboplatin or cisplatin.

[0193] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering an alkylating agent such as cyclophosphamide.

[0194] In some embodiments, the compounds of the present disclosure are administered with a combination of chemotherapeutic agents summarized in Table 2 below.

[0195] Further guidance for treating metastatic TNBC is provided in Jones SE, et al. J Clin Concol. 2006;24:5381-5387; Heemskerk-Gerritsen BAM, et al. Ann Surg. Oncol. 2007;14:3335-3344; and Kell MR, et al. MBJ. 2007;334:437-438.

[0196] Early and locally advanced TNBC Patients with early-stage, potentially resectable locally advanced TNBC (i.e., no distant metastatic disease) are managed with locoregional therapy (surgical resection with or without radiation therapy) with or without systemic chemotherapy.

[0197] Surgical treatment can be breast-conserving (e.g., lumpectomy, which focuses on removing the primary tumor at the margins) or more extensive (e.g., mastectomy, which aims to completely remove all breast tissue). Radiation therapy is typically administered to the breast / chest wall and / or regional lymph nodes after surgery, with the goal of killing microscopic cancer cells remaining after surgery. In breast-conserving surgery, radiation is administered to the remaining breast tissue and sometimes to the regional lymph nodes (including the axillary lymph nodes). In the case of mastectomy, radiation may also be administered if factors predicting a higher risk of local recurrence are present.

[0198] In one embodiment, a compound of the present disclosure is administered in combination with surgical treatment as neoadjuvant or adjuvant therapy. In another embodiment, a compound of the present disclosure is administered before or after radiation therapy. In yet another embodiment, a compound of the present disclosure is administered in combination with surgical treatment and radiation therapy.

[0199] Depending on tumor and patient characteristics, chemotherapy can be administered in an adjuvant (post-operative) or neoadjuvant (pre-operative) setting. Examples of adjuvant / neoadjuvant chemotherapy regimens used to treat TNBC recommended by current guidance are shown in Table 2. Compounds of the present disclosure can be combined with any of the regimens shown in Table 2.

[0200] Table 2. Combination chemotherapy regimens JPEG0007759877000027.jpg197170

[0201] In one embodiment, the combination therapy comprises administering a compound of the present disclosure with an anthracycline and an alkylating agent, optionally followed by a taxane. In one such embodiment, a compound of the present disclosure is administered with doxorubicin and cyclophosphamide, followed by a taxane (e.g., docetaxel or paclitaxel) (a chemotherapy regimen designated AC→T).

[0202] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering an anthracycline and an alkylating agent. For example, in one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering doxorubicin or liposomal doxorubicin and cyclophosphamide (AC). In another embodiment, the combination therapy comprises administering a compound of the present disclosure and administering epirubicin and cyclophosphamide (a chemotherapy regimen called EC).

[0203] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering a taxane, an anthracycline, and an alkylating agent. For example, in one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering docetaxel, doxorubicin, and cyclophosphamide (a chemotherapy regimen designated TAC).

[0204] In another embodiment, the combination therapy comprises administering a compound of the present disclosure and administering a taxane and an alkylating agent. In one such embodiment, the combination therapy comprises administering a compound of the present disclosure and administering docetaxel and cyclophosphamide (a chemotherapy regimen referred to as TC).

[0205] In another embodiment, the combination therapy comprises administering a compound of the present disclosure and administering a taxane and an alkylating agent. For example, in one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering docetaxel and cyclophosphamide (a chemotherapy regimen designated TC).

[0206] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering an alkylating agent, methotrexate, and an antimetabolite. As an example, in one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering an alkylating agent, methotrexate, and an antimetabolite. In one such embodiment, the combination therapy comprises administering a compound of the present disclosure and administering cyclophosphamide, methotrexate, and fluorouracil (a chemotherapy regimen called CMF).

[0207] In another embodiment, the combination therapy comprises administering a compound of the present disclosure and administering an antimetabolite, an anthracycline, and an alkylating agent. In one such embodiment, the combination therapy comprises administering a compound of the present disclosure and administering fluorouracil, doxorubicin, and cyclophosphamide (a chemotherapy regimen designated FAC). In another such embodiment, the combination therapy comprises administering a compound of the present disclosure and administering fluorouracil, epirubicin, and cyclophosphamide (a chemotherapy regimen designated FEC).

[0208] In another embodiment, the combination therapy comprises administering a compound of the present disclosure and an antimetabolite, an anthracycline, and an alkylating agent, followed by a taxane. As an example, in one embodiment, the combination therapy comprises administering a compound of the present disclosure and fluorouracil, epirubicin, and cyclophosphamide, followed by docetaxel or paclitaxel (a chemotherapy regimen designated FEC (or CEF)→T). In another embodiment, the combination therapy comprises administering a compound of the present disclosure and fluorouracil, doxorubicin, and cyclophosphamide, followed by paclitaxel (a chemotherapy regimen designated FAC→T).

[0209] In yet another embodiment, the combination therapy comprises administering a compound of the present disclosure and administering a taxane and an antimetabolite. As an example, in one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering docetaxel and capecitabine. In another example, the combination therapy comprises administering a compound of the present disclosure and administering paclitaxel and gemcitabine (a chemotherapy regimen called GT).

[0210] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering an antimetabolite and a platinum compound. For example, in one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering gemcitabine and carboplatin.

[0211] In another embodiment, the combination therapy comprises administering a compound of the present disclosure and administering an antimetabolite and a non-taxane microtubule inhibitor. In one such embodiment, the combination therapy comprises administering a compound of the present disclosure and administering capecitibine and vinorelbine. In another such embodiment, the combination therapy comprises administering a compound of the present disclosure and administering gemcitabine and vinorelbine.

[0212] In another embodiment, the combination therapy comprises administering a compound of the present disclosure and administering a taxane and a VEGF inhibitor (e.g., an anti-VEGF antibody). For example, in one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering paclitaxel and bevacizumab.

[0213] Further guidance for treating early and locally advanced TNBC is provided in Solin LJ., Clin Br Cancer. 2009;9:96-100; Freedman GM, et al. Cancer. 2009;115:946-951; Heemskerk-Gerritsen BAM, et al. Ann Surg Oncol. 2007;14:3335-3344; and Kell MR, et al. MBJ. 2007;334:437-438.

[0214] Non-small cell lung cancer (NSCLC) The compounds of the present disclosure can be administered alone or can be used in combination therapy, for example, combination therapy includes administering a compound of the present disclosure and at least one additional therapeutic agent (e.g., 1, 2, 3, 4, 5, or 6 additional therapeutic agents).

[0215] In some embodiments, the compounds are for use in combination therapy for the treatment of non-small cell lung cancer NSCLC, such as squamous cell carcinoma, adenocarcinoma, large cell carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, or a combination thereof.

[0216] In one embodiment, the NSCLC is in latent stage 0, I, II, III, or IV.

[0217] In one embodiment, the NSLCL is in latent stage 0, IA, IB, IIA, IIB, IIIA, IIIB, or IV.

[0218] The present disclosure relates to the use of the disclosed compounds for adjuvant or neoadjuvant therapy.

[0219] The present disclosure relates to the use of the disclosed compounds for first-line, second-line, or third-line treatment.

[0220] The present disclosure relates to the use of the disclosed compounds for monotherapy.

[0221] The present disclosure relates to the use of the disclosed compounds for the treatment of stage IV or recurrent disease.

[0222] The present disclosure relates to the use of the disclosed compounds for treatment in combination with surgery, radiation therapy, or a combination thereof.

[0223] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering at least one additional therapeutic agent such as cisplatin, carboplatin, paclitaxel, paclitaxel protein-bound, docetaxel, gemcitabine, vinorelbine, etoposide, nintedanib, vinblastine, and / or pemetrexed.

[0224] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering at least one additional therapeutic agent such as afatinib, bevacizumab, cabozantinib, ceritinib, crizotinib, erlotinib hydrochloride, osimertinib, ramucirumab, gefitinib, alectinib, trastuzumab, cetuximab, ipilimumab, trametinib, dabrafenib, vemurafenib, dacomitinib, tivantinib, and / or onartuzumab.

[0225] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering at least one additional therapeutic agent, such as afatinib, crizotinib, erlotinib hydrochloride, and / or gefitinib.

[0226] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering a checkpoint inhibitor, such as pembrolizumab, atezolizumab, and / or nivolumab.

[0227] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering at least one additional therapeutic agent such as cisplatin, carboplatin, paclitaxel, paclitaxel protein-bound, docetaxel, gemcitabine, vinorelbine, etoposide, nintedanib, vinblastine, pemetrexed, afatinib, bevacizumab, cabozantinib, ceritinib, crizotinib, erlotinib hydrochloride, osimertinib, ramucirumab, gefitinib, necitumumab, alectinib, trastuzumab, cetuximab, ipilimumab, trametinib, dabrafenib, vemurafenib, dacomitinib, tivantinib, onartuzumab, pembrolizumab, atezolizumab, and / or nivolumab.

[0228] Small cell lung cancer (SCLC) The compounds of the present disclosure can be administered alone or can be used in combination therapy, for example, combination therapy includes administering a compound of the present disclosure and at least one additional therapeutic agent (e.g., 1, 2, 3, 4, 5, or 6 additional therapeutic agents).

[0229] In some embodiments, the compounds are for use in combination therapy for the treatment of small cell lung cancer (SCLC).

[0230] In one embodiment, the SCLC is small cell carcinoma (oat cell carcinoma), mixed small cell / large cell carcinoma, or combined small cell carcinoma.

[0231] In one embodiment, the SCLC is in latent stage 0, I, II, III, or IV.

[0232] In one embodiment, the SLCL is in latent stage, stage 0, IA, IB, IIA, IIB, IIIA, IIIB, or IV.

[0233] In one embodiment, the SLCL is in stages I-III (extreme stage).

[0234] The present disclosure relates to the use of the disclosed compounds for first line treatment of Stage IV (extensive) disease.

[0235] The present disclosure relates to the use of the disclosed compounds for second line treatment of Stage IV (relapsed or refractory disease).

[0236] The present disclosure relates to the use of the disclosed compounds for third line treatment of Stage IV (relapsed or refractory disease).

[0237] In one embodiment, the compound of the present disclosure is administered with one or more additional therapeutic agents selected from etoposide, platinum compounds, irinotecan, topotecan, vinca alkaloids, alkylating agents, doxorubicin, taxanes, and gemcitabine. In another embodiment, the platinum compound is cisplatin or carboplatin. In another embodiment, the vinca alkaloid is vinblastine, vincristine, or vinorelbine. In another embodiment, the alkylating agent is cyclophosphamide or ifosfamide. In another embodiment, the taxane is docetaxel or paclitaxel.

[0238] ovarian cancer In a further aspect, the disclosure provides a method for treating ovarian cancer (e.g., epithelial ovarian cancer (EOC), ovarian germ cell tumor, or ovarian stromal tumor) by administering an effective amount of a compound of the disclosure. In a further aspect of the embodiment, the ovarian cancer is epithelial ovarian cancer (EOC). In a further aspect of the embodiment, the ovarian cancer is ovarian germ cell tumor. In a further aspect of the embodiment, the ovarian cancer is ovarian stromal cell tumor. In one embodiment, the method comprises administering to an individual with ovarian cancer an effective amount of a compound of the disclosure.

[0239] The compounds of the present disclosure can be administered alone or in combination therapy to treat ovarian cancer. For example, the combination therapy includes administering a compound of the present disclosure and administering at least one additional therapeutic agent (e.g., 1, 2, 3, 4, 5, or 6 additional therapeutic agents).

[0240] In some aspects, the compounds are for use in combination therapy for the treatment of ovarian cancer (e.g., epithelial ovarian cancer (EOC), ovarian germ cell tumor, or ovarian stromal tumor). In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering at least one additional therapeutic agent, such as a platinum compound (e.g., carboplatin, cisplatin, less frequently oxaliplatin or iproplatin), and / or a taxane (e.g., paclitaxel or docetaxel, or albumin-bound paclitaxel (nab-paclitaxel)). In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering carboplatin and a taxane (e.g., paclitaxel or docetaxel, or albumin-bound paclitaxel (nab-paclitaxel)).

[0241] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering at least one additional therapeutic agent such as albumin-bound paclitaxel (nab-paclitaxel), altretamine, capecitabine, cyclophosphamide, etoposide, gemcitabine, ifosfamide, irinotecan, liposomal doxorubicin, melphalan, pemetrexed, topotecan, vinorelbine, bevacizumab, platinum compounds (e.g., carboplatin, cisplatin, oxaliplatin, or iproplatin), and / or taxanes (e.g., paclitaxel or docetaxel, or albumin-bound paclitaxel (nab-paclitaxel)).

[0242] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering bevacizumab and a taxane (eg, paclitaxel or docetaxel, or albumin-bound paclitaxel (nab-paclitaxel)).

[0243] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering at least one additional therapeutic agent, such as cisplatin, etoposide, and / or bleomycin.

[0244] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering cisplatin (Platinol), etoposide, and bleomycin (PEB (or BEP)).

[0245] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering paclitaxel (Taxol), ifosfamide, and cisplatin (TIP).

[0246] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering vinblastine, ifosfamide, and cisplatin (VeIP).

[0247] In one embodiment, the combination therapy comprises administering a compound of the present disclosure and administering etoposide (VP-16), ifosfamide, and cisplatin (VIP).

[0248] V. Method of Manufacturing In another embodiment, methods for making the subject compounds are provided. The following synthetic reaction schemes, detailed in the general schemes and examples, are only illustrative of some of the ways in which compounds of the present disclosure (or one embodiment or aspect thereof) may be synthesized. Various modifications to these synthetic reaction schemes can be made and will be suggested to those skilled in the art in view of the present disclosure contained herein.

[0249] Starting materials and reagents commonly used in the preparation of these compounds are available from suppliers such as Aldrich Chemical Co. or are prepared by methods known to those skilled in the art according to procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40.

[0250] The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if necessary using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, etc. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0251] Intermediates and final compounds were purified by flash chromatography and / or by reverse phase preparative HPLC (high performance liquid chromatography) and / or by supercritical fluid chromatography (SFC).

[0252] Liquid chromatography mass spectrometry (LCMS) was performed using either (1) an Agilent Technology 6110 / 6120 / G1946 / G1925B Quadrupole in ESI+ mode, or (2) a Shimadzu Liquid Chromatography Mass Spectrometry (LCMS) 2010 mass spectrometer in ESI+ mode. Unless otherwise specified, mass spectrometry spectral data typically show parent ions only. (MS or HRMS data, when indicated, are provided for specific intermediates or compounds.)

[0253] Nuclear magnetic resonance spectroscopy (NMR) was performed using (1) a Bruker 400 NMR spectrometer or (2) a Varian 400 NMR spectrometer and referenced to tetramethylsilane. NMR data is provided for specific intermediates or compounds where indicated.

[0254] VI. General Schemes and Examples General Scheme The following generalized schemes are used to prepare the disclosed compounds, intermediates, and pharmaceutically acceptable salts thereof. The disclosed compounds and intermediates can be prepared from commercially available starting materials and reagents using standard organic synthesis techniques. It is understood that the synthetic procedures used to prepare the disclosed compounds and intermediates will depend on the specific substituents present in the compound or intermediate, and that various protection, deprotection, and transformation steps standard in organic synthesis may be required, which may not be shown according to the general schemes. It is also understood that any of the steps shown in any of the general schemes below can be used in any combination and in any order that is chemically feasible to arrive at the desired intermediate or disclosed compound. Furthermore, it is understood that the stereochemistry of a particular compound or intermediate, when not disclosed in any of the examples provided, can be determined by any means known to those skilled in the art.

[0255] Scheme 1 JPEG0007759877000028.jpg48170 Scheme 1 illustrates the use of tin compounds to convert halo moieties into hydroxy groups, as defined above for formula (I), as represented by R 1 This paper describes a general synthesis scheme for converting L, R moieties into 2 , R 3 , and R 4 is as defined above for formula (I). Halo refers to any halogen including, for example, chlorine, bromine, or iodine.

[0256] Scheme 2 JPEG0007759877000029.jpg30170 Scheme 2 illustrates a compound of formula (I) in which a halo (halogen) moiety is replaced by -LR 2 describes a general synthetic scheme for converting -LR 2 The part is -O-CH2-R 2 R 1 , R 3 , and R 4is as defined above for formula (I). Halo refers to any halogen including, for example, chlorine, bromine, or iodine.

[0257] Scheme 3 JPEG0007759877000030.jpg32170 Scheme 3 illustrates a compound comprising a halo (halogen) moiety, as defined above for formula (I), at position R 1 In -C(O)-NR a R b This paper describes a general synthesis scheme for converting R 2 , R 3 , R 4 , R a , and R b is as defined above for formula (I). Halo refers to any halogen including, for example, chlorine, bromine, or iodine.

[0258] Scheme 4 Scheme 4 illustrates a general synthetic scheme for producing compounds of formula (I). 1 , R 2 , R 3 , and R 4 is as defined above for formula (I). Halo refers to any halogen including, for example, chlorine, bromine, or iodine.

[0259] Scheme 5 JPEG0007759877000032.jpg135170 Scheme 5 illustrates the addition of a halogen (halo) moiety to a compound of formula (I) at position R 1 This paper describes a general synthetic scheme for converting the alkyl moiety in R 2 , R 3 , R 4 and L are as defined above for formula (I). Halo refers to any halogen, including, for example, chlorine, bromine, or iodine. TIPS is triisopropylsilyl. R' can be any suitable atom or group, including, for example, hydrogen. In some embodiments, in step (i), The two R' substituents in JPEG0007759877000033.jpg19170 can form a ring structure (together with the atoms to which they are attached). In some embodiments, The compound in JPEG0007759877000034.jpg18170 is JPEG0007759877000035.jpg25170. [Example]

[0260] The following are examples of the methods and compositions of the present disclosure. It is understood that various other embodiments can be implemented given the general description provided above. The present disclosure will be more fully understood by referring to the following examples. However, the scope of the claims should not be interpreted as being limited to the scope of the examples.

[0261] Intermediate A Preparation of 2-bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one The general reaction scheme was as follows: JPEG0007759877000036.jpg81170

[0262] Step 1: Ethyl 3-(4-cyclohexylphenyl)-3-oxopropanoate To a solution of 1-(4-cyclohexylphenyl)ethanone (40 g, 197 mmol) in THF (400 mL) was slowly added NaH (60% in mineral oil, 17.4 g, 435 mmol) at 0 °C, followed by the slow addition of diethyl carbonate (70 g, 593 mmol) and stirring for 5 h. The reaction solution was quenched with saturated aqueous NH4Cl (500 mL) and extracted with EtOAc (500 mL × 2). The combined organic layers were washed with brine (500 mL × 2) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-10% EtOAc in petroleum ether) to give the title compound (50 g, 92%, ketone / enol = 2.4:1) as a yellow oil. 1 H NMR (400 MHz, CDCl): δ 12.58 (s, 1H enol), 7.86 (d, J = 8.4 Hz, 2H ketone), 7.71 (d, J = 8.4 Hz, 2H enol), 7.32 (d, J = 8.4 Hz, 2H ketone), 7.26 (d, J = 8.4 Hz, 2H enol), 5.64 (s, 1H enol), 4.25-4.17 (m, 4H). , 3.92 (s, ketone 2H), 2.59-2.51 (m, 2H), 1.80-1.77 (m, 8H), 1.71-1.68 (m, 2H), 1.45-1.41 (m, 8H), 1.34 (t, J = 7.2 Hz, enol 3H), 1.32-1.29 (m, 2H), 1.27 (t, J = 7.2 Hz, ketone 3H).

[0263] Step 2: Ethyl 5-amino-3-bromo-1H-pyrazole-4-carboxylate To a solution of ethyl 5-amino-1H-pyrazole-4-carboxylate (50 g, 322 mmol) in acetonitrile (500 mL) was slowly added NBS (60 g, 337 mmol) at 15° C., followed by stirring for 16 hours. The reaction solution was poured into water (500 mL), extracted with EtOAc (300 mL×3), washed with brine (300 mL×2), and concentrated in vacuo to give the crude title compound (75 g, 79% purity) as a yellow solid, which was used directly without further purification. LCMS (ESI): m / z 234.0 (M+H) + .

[0264] Step 3: Ethyl 2-bromo-5-(4-cyclohexylphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate A mixture of the resulting crude ethyl 5-amino-3-bromo-1H-pyrazole-4-carboxylate (50 g), ethyl 3-(4-cyclohexylphenyl)-3-oxopropanoate (65 g, 236 mmol), p-TsOH·HO (3.6 g, 21 mmol) in n-BuOH (400 mL) was stirred at 130° C. for 5 hours. The reaction solution was filtered, and the filter cake was washed with EtOAc (100 mL) to give the title compound (60 g, 63% over two steps) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):δ 11.50(s,1H), 7.68(d,J=8.4Hz,2H), 7.44(d,J=8.4Hz,2H), 6.28(s,1H), 4.38(q,J=7.2Hz,2H) ), 2.69-2.51(m,1H), 1.80-1.77(m,4H), 1.71-1.68(m,1H), 1.48-1.19(m,8H).LCMS(ESI):m / z 443.9(M+H) + .

[0265] Step 4: 2-Bromo-5-(4-cyclohexylphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid A mixture of lithium hydroxide monohydrate (9.5 g, 225 mmol) and ethyl 2-bromo-5-(4-cyclohexylphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate (10 g, 22.5 mmol) in water (150 mL) and ethanol (150 mL) was stirred at 80 °C for 16 hours. The reaction solution was concentrated in vacuo, and the residue was dissolved in water (200 mL) and adjusted to pH 3 with 1 M aqueous HCl. The solid was filtered, washed with water (50 mL), and dried in vacuo to give the title compound (8 g, 90%) as a white solid, which was used directly without further purification. LCMS (ESI): m / z 416.1 (M+H) + .

[0266] Step 5: 2-Bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one To a solution of 2-bromo-5-(4-cyclohexylphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (13 g, 31.2 mmol) and DIPEA (15.5 mL, 93.7 mmol) in DMF (100 mL) was added HATU (18.2 g, 47.9 mmol), which was then stirred for 20 minutes. 3-(Fluoromethyl)azetidine 2,2,2-trifluoroacetate (16 g, 78.1 mmol) was added to the reaction mixture, and the reaction was stirred for 16 hours at room temperature. The reaction was then poured into brine (500 mL), and the pH was adjusted to 6 with 2 M aqueous HCl. The solid was filtered, washed with water (50 mL) and EtOAc (200 mL), and dried to give the title compound (12 g, 79%) as a white solid. 1H NMR(400MHz,DMSO-d6):δ 12.55(s,1H), 7.69(d,J=8.4Hz,2H), 7.43(d,J=8.4Hz,2H), 6.13(s,1H), 4.63(dd,J=47.2,6.0Hz,2H), 4.17-4.13(m,2H), 3.87-3.83(m ,2H), 3.11-2.94(m,1H), 2.61-2.59(m,1H), 1.81-1.78(m,4H), 1.71-1.69(m,1H), 1.52-1.32(m,4H), 1.31-1.17(m,1H);LCMS(ESI):m / z 487.0(M+H) + .

[0267] Intermediate B Preparation of 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid The general reaction scheme was as follows: JPEG0007759877000042.jpg101170

[0268] Step 1: 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxamide A mixture of 2-bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (Intermediate A, 2.5 g, 5.1 mmol), DMAP (1 g, 8.2 mmol), and Pd(dppf)Cl (375 mg, 0.51 mmol) in formamide (20 mL) was stirred at 120 °C for 16 h under a CO atmosphere (15 Psi). The reaction solution was poured into water (50 mL), extracted with EtOAc (50 mL × 2), dried, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% MeOH in DCM) to give the title compound (450 mg, 19%) as a yellow solid. 1H NMR (400MHz, DMSO-d6): δ 12.45(br s,1H), 8.11(br s,1H), 7.77(d,J=8.0Hz,2H), 7.71(br s,1H), 7.41(d,J=8.0Hz,2H), 6.11(s,1H), 4.58(dd,J=47.2,6.4Hz,2H), 4.12-4.06(m,2H), 3.80-3.77(m,2H), 2.98-2.8 8(m,1H), 2.61-2.56(m,1H), 1.80-1.78(m,4H), 1.71-1.68(m,1H), 1.49-1.34(m,4H), 1.30-1.20(m,1H);LCMS(ESI):m / z 452.2.

[0269] Step 2: 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid JPEG0007759877000044.jpg37170 A mixture of 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxamide (360 mg, 0.8 mmol) and KOH (1 g, 17.8 mmol) in ethanol (30 mL) was stirred at 90 °C for 16 h, and the mixture was then concentrated in vacuo. The crude organic residue was then dissolved in water (20 mL) and acidified to pH 5 with 1 M aqueous HCl. The aqueous layer was extracted with DCM (30 mL × 3). The organic layer was dried over NaSO and concentrated in vacuo to afford the title compound (220 mg, 61%) as a yellow solid, which was used directly in the next step without further purification. 1H NMR(400MHz,DMSO-d6):δ 7.76(d,J=8.4Hz,2H), 7.40(d,J=7.6Hz,2H), 6.15(s,1H), 4.61(dd,J=47.2,5.6Hz,2H), 4.44-3.81(m,4H), 3.06-2.92 (m,1H), 2.63-2.55(m,1H), 1.82-1.77(m,4H), 1.74-1.67(m,1H), 1.47-1.37(m,4H), 1.22-1.25(m,1H);LCMS(ESI):m / z 453.2(M+H) + .

[0270] Intermediate C Preparation of 2-bromo-5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one The general reaction scheme was as follows: JPEG0007759877000045.jpg114170

[0271] Step 1: Cyclopentyltriphenylphosphonium bromide A mixture of triphenylphosphine (79.2 g, 301.95 mmol) and bromocyclopentane (50.0 g, 335.5 mmol) was stirred at 140° C. for 6 hours under a nitrogen atmosphere. The suspension was filtered. The resulting filter cake was washed with toluene and dried to give the title compound (60.0 g, 48%) as a white solid. 1 H NMR(400MHz,D2O):δ 7.78-7.68(m,9H), 7.63-7.55(m,6H), 4.00-3.87(m,1H), 2.35-2.22(m,2H), 1.85-1.65(m,2H), 1.63-1.49(m,2H), 1.36-1.24(m,2H).

[0272] Step 2: 1-Bromo-4-(cyclopentylidenemethyl)benzene To a solution of cyclopentyltriphenylphosphonium bromide (50.0 g, 121.6 mmol) in toluene (150 mL), LiHMDS (130.5 mL, 130.5 mmol) was added at −78° C. under a nitrogen atmosphere, and the solution was stirred for 30 minutes. 4-Bromobenzaldehyde (15.0 g, 81.07 mmol) was then added to the mixture, which was then stirred at 120° C. for 16 hours. The reaction solution was poured into water (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layer was washed with brine (50 mL × 2). The organic layer was dried over anhydrous NaSO and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether to give the title compound (15.0 g, 78%) as a colorless oil. 1 H NMR(400MHz,CDCl3):? 7.42(d,J=8.4Hz,2H), 7.17(d,J=8.4Hz,2H), 6.30(s,1H), 2.55-2.44(m,4H), 1.85-1.74(m,2H), 1.71-1.64(m,2H).

[0273] Step 3: 1-Bromo-4-(cyclopentylmethyl)benzene To a mixture of 1-bromo-4-(cyclopentylidenemethyl)benzene (9.0 g, 37.95 mmol) in ethanol (900 mL) was added PtO (431.0 mg, 1.90 mmol). The reaction suspension was stirred at 30 °C under H (35 Psi) for 12 minutes. The suspension was filtered through a pad of Celite, and the filter cake was washed with EtOH (500 mL × 2). The filtrate was concentrated in vacuo to give the title compound (9.0 g, 99%) as a colorless oil. 1 H NMR(400MHz,CDCl3):δ 7.39(d,J=8.0Hz,2H), 7.05(d,J=8.0Hz,2H), 2.56(d,J=7.6Hz,2H), 2.09-2.0(m,1H), 1.74-1.62(m,4H), 1.54-1.51(m,2H), 1.22-1.12(m,2H).

[0274] Step 4: Ethyl 3-(4-(cyclopentylmethyl)phenyl)-3-oxopropanoate In a glove box under a nitrogen atmosphere, to a mixture of 1-bromo-4-(cyclopentylmethyl)benzene (16.0 g, 66.9 mmol) in dioxane (200 mL) was added ethyl 3-ethoxyacrylate (28.9 g, 200.71 mmol), N-cyclohexyl-N-methylcyclohexanamine (13.1 g, 66.9 mmol), and LiCl (8.5 g, 200.71 mmol), at which point the mixture was stirred at room temperature for 10 min. Pd(P t Bu3)2 (2.1 g, 4.01 mmol) was added, and the reaction mixture was removed from the glove box. The reaction mixture was then stirred at 110 °C for 16 h. The solution was quenched with brine (300 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was dissolved in 1,2-dichloroethane, and to this mixture was added 6 M HCl (60 mL). The mixture was stirred at room temperature for 3 h. The solution was adjusted to pH 8 with saturated aqueous NaHCO3 and extracted with CHCl2 (200 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-5% EtOAc in petroleum ether) to give the title compound (5.5 g, 30%, ketone / enol = 3:1) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 12.59 (s, 1H enol), 7.87 (d, J = 8.4 Hz, 2H ketone), 7.69 (d, J = 8.4 Hz, 2H enol), 7.28 (d, J = 8.4 Hz, 2H ketone), 7.23 (d, J = 8.4 Hz, 2H enol), 5.64 (s, 1H enol), 4.30-4.20 (m, 4H), 3.98 (s, 2H ketone), 2.69 -2.64 (m, 4H), 2.15-2.04 (m, 2H), 1.75-1.63 (m, 8H), 1.55-1.48 (m, 4H), 1.34 (t, J = 7.2 Hz, 3H enol), 1.27 (t, J = 7.2 Hz, 3H ketone), 1.23-1.15 (m, 4H).

[0275] Step 5: Ethyl 2-bromo-5-(4-(cyclopentylmethyl)phenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate A mixture of ethyl 3-(4-(cyclopentylmethyl)phenyl)-3-oxopropanoate (1.83 g, 6.67 mmol), 4-methyl benzenesulfonic acid monohydrate (104.0 mg, 0.55 mmol), and ethyl 5-amino-3-bromo-1H-pyrazole-4-carboxylate (1.30 g, 5.55 mmol) in n-BuOH (10 mL) was stirred at 120° C. for 16 hours. The reaction mixture was then evaporated to dryness. The residue was purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to afford the title compound (1.20 g, 40%) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 11.50(s,1H), 7.70(d,J=8.0Hz,2H), 7.42(d,J=8.0Hz,2H), 6.31(s,1H), 4.35(q,J=7.2Hz,2H), 2.67(d,J=7.2Hz,2H) ), 2.21-2.05(m,1H), 1.71-1.57(m,4H), 1.55-1.45(m,2H), 1.38(t,J=7.2Hz,3H), 1.26-1.18(m,2H);LCMS(ESI):m / z 444.1(M+H)+ .

[0276] Step 6: 2-Bromo-5-(4-(cyclopentylmethyl)phenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid To a mixture of ethyl 2-bromo-5-(4-(cyclopentylmethyl)phenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate (1.20 g, 2.7 mmol) in water (15 mL) and EtOH (15 mL) was added lithium hydroxide monohydrate (1.13 g, 27.0 mmol). The mixture was stirred at 90° C. for 16 hours. The solution was adjusted to pH 4 by the addition of 1 M aqueous HCl. The resulting mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give the title compound (950 mg, 85%) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 11.29(s,1H), 7.70(d,J=8.0Hz,2H), 7.40(d,J=8.0Hz,2H), 6.29(s,1H), 2.67(d,J=7.2Hz,2H) ), 2.15-2.07(m,1H), 1.70-1.56(m,4H), 1.54-1.43(m,2H), 1.25-1.15(m,2H);LCMS(ESI):m / z 416.1(M+H) + .

[0277] Step 7: 2-Bromo-5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000052.jpg45170 The title compound (900 mg, 75%) was prepared from 2-bromo-5-(4-(cyclopentylmethyl)phenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.0 g, 2.4 mmol) and 3-(fluoromethyl)azetidine trifluoroacetate (1.31 g, 6.01 mmol) according to the procedure outlined in Intermediate A, Step 5 to provide a yellow solid. 1 H NMR(400MHz,DMSO-d6):δ 7.70(d,J=8.4Hz,2H), 7.40(d,J=8.4Hz,2H), 6.14(s,1H), 4.63(dd,J=47.2,6.0Hz,2H), 4.18-4.13(m,2H), 3.88-3.85(m,2H) , 3.03-2.98(m,1H), 2.68-2.66(m,2H), 2.15-2.08(m,1H), 1.68-1.58(m,4H), 1.53-1.45(m,2H), 1.23-1.19(m,2H);LCMS:m / z 487.1(M+H) + .

[0278] Intermediate D Preparation of ethyl 2-bromo-5-chloro-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate The general reaction scheme was as follows: JPEG0007759877000053.jpg97170

[0279] Step 1: Ethyl 2-bromo-5,7-dioxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate A mixture of ethyl 5-amino-3-bromo-1H-pyrazole-4-carboxylate (22.0 g, 94 mmol), t-BuONa (27.1 g, 281.99 mmol), and diethyl malonate (43.0 mL, 281.99 mmol) in n-BuOH (40.0 mL) was stirred at 120° C. for 3 hours. The reaction mixture was adjusted to pH 4 with 1 M aqueous HCl. The mixture was filtered, washed with petroleum ether (100 mL × 2), EtOAc (50 mL), and dried over NaSO to give the title compound (18 g, 64%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):5.10(s,1H), 4.31(q,J=7.2Hz,2H), 1.29(t,J=7.2Hz,3H);LCMS(ESI):m / z 302.0(M+H) + .

[0280] Step 2: Ethyl 2-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine-3-carboxylate To a three-neck flask charged with POCl3 (119.0 mL, 1.28 mol), ethyl 2-bromo-5,7-dioxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylate (30.0 g, 99.3 mmol) and N,N-diethylaniline (46.0 mL, 297.9 mmol) were added. The solution was stirred at 100 °C for 16 h, at which point the reaction mixture was concentrated to remove POCl3. The residue was quenched with water (200 mL) and extracted with EtOAc (200 mL × 2). The organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 0-20% EtOAc in petroleum ether) to give the title compound (10.67 g, 32%) as a light yellow solid. 1 H NMR (400MHz, CDCl3): δ 7.17(s,1H), 4.49(q,J=7.2Hz,2H), 1.47(t,J=7.2Hz,3H).

[0281] Step 3: Ethyl 2-bromo-5-chloro-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate To a mixture of ethyl 2-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine-3-carboxylate (25.0 g, 73.75 mmol) in THF (180 mL) was added 1 M aqueous NaOH (185.0 mL, 0.18 mol) at room temperature. The reaction was stirred at room temperature for 12 hours. The reaction was filtered, concentrated in vacuo, and then washed with ethyl acetate (80 mL × 2) to afford the title compound (19 g, 80%) as a white solid. 1 H NMR(CD3OD):5.86(s,1H), 4.38(q,J=7.2Hz,2H), 1.39(t,J=7.2Hz,3H);LCMS(ESI):m / z 319.7(M+H) + .

[0282] Intermediate E Preparation of 2-bromo-5-chloro-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one The general reaction scheme was as follows: JPEG0007759877000057.jpg38170

[0283] Step 1: 2-Bromo-5-chloro-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid A mixture of ethyl 2-bromo-5-chloro-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate (45.0 g, 140.39 mmol) and lithium hydroxide monohydrate (58.90 g, 1.40 mol) was dissolved in 1:1 water / ethanol (420 mL) and stirred at 80° C. for 16 hours. The reaction solution was concentrated, and the pH was adjusted to 4 with 4 M aqueous HCl. The precipitated solid was collected and dried in vacuo to give the title compound (40 g, 97%) as a white solid. 1H NMR(400MHz,DMSO-d6):5.30(s,1H);LCMS(ESI):m / z 291.7(M+H) + .

[0284] Step 2: 2-Bromo-5-chloro-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one To a solution of 2-bromo-5-chloro-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (16.7 g, 57.1 mmol) and HATU (32.6 g, 85.65 mmol) in DMF (70 mL) was added N,N-diisopropylethylamine (30.5 mL, 171.3 mmol). The mixture was stirred at room temperature for 20 minutes, and 3-(fluoromethyl)azetidine hydrochloride (10.8 g, 85.65 mmol) was added. The resulting reaction solution was stirred at room temperature for 16 hours. The reaction mixture was poured into water (200 mL), extracted with DCM (200 mL x 3), and washed with brine (200 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to dryness. The crude organics were purified by flash column chromatography (eluting with 0-10% methanol in dichloromethane) to give the title compound (12 g, 58%) as a light yellow solid. 1 H NMR (400MHz, DMSO-d6): δ 5.76(s,1H), 4.63(dd,J=47.2,5.6Hz,2H), 4.18-4.12(m,2H), 3.86-3.83(m,2H), 3.05-2.91(m,1H).

[0285] Intermediate F Preparation of 5-chloro-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one To a solution of 2-bromo-5-chloro-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (3.0 g, 7.43 mmol), 2-methyl-3-(tributylstannyl)pyrazine (2.85 g, 7.43 mmol) in DMF (60 mL) was added CsF (3.38 g, 22.28 mmol), CuI (110 mg, 1.11 mmol), and Pd(dppf)Cl (543 mg, 0.74 mmol). The reaction mixture was stirred at 110 °C under a nitrogen atmosphere for 3 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel eluting with DCM / MeOH (0 to 20%) to afford the title compound (600 mg, 21%) as a black solid. 1 H NMR(400MHz,CD3OD):δ 8.61-8.45(m,2H), 5.85(s,1H), 4.59(dd,J=47.2,5.6Hz,2H), 4.52-4.35(m,1H), 4. 25-4.05(m,2H), 3.98-4.84(m,1H), 3.06-2.94(m,1H), 2.64(s,3H);LCMS(ESI):m / z 377.1(M+H) + .

[0286] intermediate G Preparation of 5-chloro-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000061.jpg30170 The title compound (800 mg, 47%) was provided as a white solid from 2-bromo-5-chloro-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (Intermediate E, 2.0 g, 4.68 mmol) and 2-(tributylstannyl)pyrimidine (1.73 g, 4.68 mmol) following the procedure outlined for Intermediate F. 1H NMR(400MHz,DMSO-d6):δ 8.88(d,J=4.8Hz,2H), 7.47(t,J=4.8Hz,1H), 5.47(s,1H), 4.54(dd,J=47.2,6.0 Hz,2H), 4.09-3.95(m,2H), 3.80-3.70(m,2H), 2.97-2.84(m,1H).LCMS(ESI+)m / z 363.1(M+H) + .

[0287] Intermediate J Preparation of 5-chloro-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000062.jpg30170 The title compound was prepared from 2-bromo-5-chloro-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (Intermediate E, 500 mg, 1.17 mmol) and 2-(tributylstannyl)pyrazine (432 mg, 1.17 mmol) following the procedure outlined for Intermediate F. Purification by reverse-phase chromatography (0.225% FA in water / MeCN) provided the desired compound as a white solid (50 mg, 12%). 1 H NMR(400MHz,CD3OD):δ 9.38(s,1H), 8.77-8.69(m,1H), 8.66(d,J=2.0, 1H), 6.13(s,1H), 4.54(dd,J=47.2,5.2Hz,2H ), 4.38-4.17(m,1H), 4.15-3.90(m,2H), 3.86-3.66(m,1H), 3.07-2.91(m,1H);LCMS(ESI):m / z 363.0(M+H) + .

[0288] Intermediate K Preparation of 2-bromo-3-(3-(fluoromethyl)azetidine-1-carbonyl)-5-((4-isopropylbenzyl)oxy)pyrazolo[1,5-a]pyrimidin-7(4H)-one The general reaction scheme was as follows: JPEG0007759877000063.jpg75170

[0289] Step 1: Ethyl 7-(benzyloxy)-2-bromo-5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate To a mixture of ethyl 2-bromo-5,7-dichloropyrazolo[1,5-a]pyrimidine-3-carboxylate (10.0 g, 29.5 mmol) and benzyl alcohol (3.0 mL, 32.45 mmol) in acetonitrile (200 mL) was added DBU (9.0 g, 59.0 mmol) slowly at 0° C. The solution was then stirred at 0° C. for 1 hour, at which point the reaction mixture was filtered. The filter cake was washed with acetonitrile (10 mL×2) and dried to afford the title compound (4.7 g, 38%) as a light yellow solid. 1 H NMR (400MHz, DMSO-d6): δ 7.58-7.56(m,2H), 7.55-7.53(m,3H), 5.60(s,1H), 4.33-4.28(q,J=7.2Hz,2H), 1.33-1.26(t,J=7.2Hz,3H).

[0290] Step 2: 2-Bromo-5-((4-isopropylbenzyl)oxy)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid A mixture of ethyl 7-(benzyloxy)-2-bromo-5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (5.3 g, 12.91 mmol), (4-isopropylphenyl)methanol (5.8 g, 38.72 mmol), and t-BuONa (4.3 g, 45.17 mmol) in 1,4-dioxane (30 mL) was stirred at 90 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (60 mL × 2). The aqueous layer was then adjusted to pH 4 by the addition of 2 M aqueous HCl and then extracted with ethyl acetate (40 × 2 mL). The organic phase was washed with brine (30 mL) and concentrated to dryness. The crude was triturated with ethyl acetate (5 mL) and filtered to give the title compound (3.8 g, 72%) as a white solid. LCMS (ESI): m / z 405.8 (M+H) + .

[0291] Step 3: 2-Bromo-3-(3-(fluoromethyl)azetidine-1-carbonyl)-5-((4-isopropylbenzyl)oxy)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000066.jpg36170 The title compound (280 mg, 7%) was obtained as a white solid, which was prepared from 2-bromo-5-((4-isopropylbenzyl)oxy)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (3.30 g, 8.12 mmol) following the procedure outlined for Intermediate A, Step 5. 1 H NMR(400MHz,DMSO-d6):δ 7.33(d,J=7.6Hz,2H), 7.23(d,J=7.6Hz,2H), 5.26-5.24(m,2H), 5.11(br,s,1H), 4.53(dd,J=47.2,5.6 Hz,2H), 4.19-4.01(m,3H), 3.73-3.71(m,1H), 2.91-2.84(m,2H), 1.19(d,J=6.8Hz,6H);LCMS(ESI):m / z 477.0(M+H) + .

[0292] Intermediate L Preparation of 5-(4-cyclohexylphenyl)-2-(dimethylcarbamoyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid The general reaction scheme was as follows: JPEG0007759877000067.jpg147170

[0293] Step 1: 5-amino-3-bromo-1H-pyrazole-4-carbonitrile JPEG0007759877000068.jpg27170 To a solution of 5-amino-1H-pyrazole-4-carbonitrile (20 g, 185 mmol) in MeCN (500 mL) was added NBS (36 g, 203 mmol) slowly at 16 °C, followed by stirring for 3 hours. The reaction mixture was poured into water (100 mL), extracted with EtOAc (50 mL x 3), washed with brine (50 mL x 2), and concentrated to give the crude product. The crude material was purified by silica gel chromatography (0-5% methanol in dichloromethane) to give the title compound (10 g, 29%). LCMS (ESI): m / z 187.0 (M+H) + .

[0294] Step 2: 2-Bromo-5-(4-cyclohexylphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile A mixture of 5-amino-3-bromo-1H-pyrazole-4-carbonitrile (7 g, 37 mmol), ethyl 3-(4-cyclohexylphenyl)-3-oxopropanoate (12 g, 45 mmol), and TsOH·HO (644 mg, 3.74 mmol) in n-butanol (100 mL) was stirred at 120° C. for 5 h. The precipitated solid was collected by filtration, washed with EtOH (20 mL), and dried to give the title compound as a white solid (6 g, 40%). 1H NMR(400MHz,DMSO-d6):δ 11.10(s,1H), 7.75(d,J=8.4Hz,2H), 7.42(d,J=8.4Hz,2H), 6.26(s,1H), 2.62-2.50(m,1H), 1.82-1.79(m,4H), 1.76-1.69(m,1H), 1.46-1.40(m,4H), 1.39-1.20(m,1H);LCMS(ESI):m / z 396.9(M+H) + .

[0295] Step 3: Methyl 3-cyano-5-(4-cyclohexylphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate A mixture of 2-bromo-5-(4-cyclohexylphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (3.0 g, 7.55 mmol), triethylamine (8.4 mL, 60.41 mmol), and PdCl(dppf) (828 mg, 1.13 mmol) in 1:1 DMF / methanol (100 mL) was stirred at 80 °C under a carbon monoxide atmosphere at 50 psi for 48 hours. The reaction mixture was concentrated to remove methanol, diluted with water (100 mL), and extracted with EtOAc (100 mL × 3). The organics were then washed with brine (100 mL × 2) and concentrated to dryness. The residue was purified by column chromatography on silica gel (0-2% methanol in dichloromethane) to give the title compound as a brown solid (1.3 g, 45%). 1 H NMR(400MHz,DMSO-d6):δ 7.93(d,J=8.4Hz,2H), 7.31(d,J=8.4Hz,2H), 6.21(s,1H), 3.90(s,3H), 2.62-2.50(m,1H), 1.82-1.79(m,4H), 1.76-1.69(m,1H), 1.46-1.40(m,4H), 1.39-1.20(m,1H);LCMS(ESI):m / z 377.0(M+H) + .

[0296] Step 4: 3-cyano-5-(4-cyclohexylphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid A mixture of methyl 3-cyano-5-(4-cyclohexylphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylate (1 g, 2.66 mmol), NaOH (0.53 g, 13.28 mmol) in 1:1 methanol / water (40 mL) was stirred at room temperature for 5 hours. The reaction mixture was then concentrated to remove methanol and diluted with water (100 mL). The solution was adjusted to pH 3 with 2 M aqueous HCl, extracted with dichloromethane (100 mL x 3), and concentrated to dryness to give the title compound as a yellow solid (0.5 g, 52%). LCMS (ESI): m / z 363.0 (M+H) + .

[0297] Step 5: 3-cyano-5-(4-cyclohexylphenyl)-N,N-dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxamide 3-Cyano-5-(4-cyclohexylphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid (400 mg, 1.1 mmol), N,N-dimethylamine hydrochloride (270 mg, 3.31 mmol), and N,N-diisopropylethylamine (0.91 mL, 5.52 mmol) in DMF (20 mL) was added HATU (629 mg, 1.66 mmol), which was then stirred at room temperature for 2 hours. The reaction mixture was then poured into water (100 mL), extracted with EtOAc (200 mL × 3), washed with brine (200 mL × 2), and concentrated to dryness. The residue was purified by column chromatography on silica gel (0-2.5% methanol in dichloromethane) to give the title compound (400 mg, 93%). LCMS (ESI) m / z 390.1 (M+H) + .

[0298] Step 6: 5-(4-cyclohexylphenyl)-N 2 ,N 2 -Dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2,3-dicarboxamide JPEG0007759877000073.jpg351703-Cyano-5-(4-cyclohexylphenyl)-N,N-dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxamide (300 mg, 0.77 mmol) was added to a mixture of HCl (10 mL) and stirred at room temperature for 16 hours. The reaction mixture was poured into water (50 mL), extracted with EtOAc (50 mL x 3), and concentrated to give the title compound as a brown solid (300 mg, 80% purity), which was used directly without further purification. LCMS (ESI): m / z 408.1 (M+H) + .

[0299] Step 7: 5-(4-cyclohexylphenyl)-2-(dimethylcarbamoyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid JPEG0007759877000074.jpg38170 The crude 5-(4-cyclohexylphenyl)-N 2 ,N 2 To a solution of 200 mg of 4,7-dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2,3-dicarboxamide in 5 mL of sulfuric acid was added NaNO (135 mg, 1.96 mmol) in 5 mL of water at 0 °C and stirred for 1 h. The reaction mixture was poured into 50 mL of water, extracted with 3 portions of EtOAc (50 mL each), and concentrated to give the title compound as a brown solid (170 mg, 81% for two steps), which was used without further purification. 1H NMR(400MHz,DMSO-d6):δ 11.44(s,1H), 7.70(d,J=8.4Hz,2H), 7.45(d,J=8.4Hz,2H), 6.28(s,1H), 3.02(s,3H), 2.86(s,3H), 2.62- 2.50(m,1H), 1.82-1.79(m,4H), 1.76-1.69(m,1H), 1.47-1.40(m,4H), 1.39-1.20(m,1H);LCMS(ESI):m / z 409.1(M+H) + .

[0300] Intermediate M Preparation of 2-bromo-5-(4-cyclohexyl-3-fluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one The general reaction scheme was as follows: JPEG0007759877000075.jpg98170

[0301] Step 1: Methyl 2-fluoro-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylate JPEG0007759877000076.jpg30170 The title compound (7.5 g, 75%) was provided as a yellow oil prepared from methyl 4-bromo-3-fluorobenzoate (10 g, 42.9 mmol) and (cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.9 g, 47.5 mmol) according to the procedure outlined for Example 3, Step 2. 1 H NMR(400MHz,CDCl3):δ 7.73(dd,J=8.0, 1.6Hz,1H), 7.64(dd,J=11.2,1.6Hz,1H), 7.31-7.23(m,1H), 6.03(s,1H) , 3.89(s,3H), 2.36-2.35(m,2H), 2.24-2.16(m,2H), 1.79-1.71(m,2H), 1.70-1.63(m,2H).

[0302] Step 2: Methyl 4-cyclohexyl-3-fluorobenzoate JPEG0007759877000077.jpg31170 The title compound (7.3 g, 97%) was provided as a colorless oil prepared from methyl 2-fluoro-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylate (7.5 g, 32 mmol) according to the procedure outlined for Example 3, Step 3. 1 H NMR(400MHz,CDCl3):δ 7.74(dd,J=8.0, 1.6, 1H), 7.63(dd,J=10.8,1.6Hz,1H), 7.34-7.17(m,1H), 3.88(s,3H), 2.9 2-2.77(m,1H), 1.90-1.79(m,4H), 1.78-1.71(m,1H), 1.46-1.35(m,4H), 1.32-1.26(m,1H).

[0303] Step 3: Ethyl 3-(4-cyclohexyl-3-fluorophenyl)-3-oxopropanoate JPEG0007759877000078.jpg29170 The title compound (7 g, 78%, ketone / enol=2:1) ​​was provided as a yellow oil prepared from methyl 4-cyclohexyl-3-fluorobenzoate (7.3 g, 31 mmol) according to the procedure outlined for Example 3, Step 4. 1 H NMR (400 MHz, CDCl): δ 12.52 (s, 1H enol), 7.65 (d, J = 8.4 Hz, 1H ketone), 7.56 (dd, J = 10.8, 1.2 Hz, 1H ketone), 7.47 (d, J = 8.4 Hz, 1H enol), 7.40 (dd, J = 11.2, 1.2 Hz, 1H enol), 7.32 (t, J = 8.0 Hz, 1H ketone), 7.27-7.26 (m,1H enol), 5.60 (s,1H enol), 4.32-4.12 (m,4H), 3.92 (s,2H ketone), 2.92-2.87 (m,2H), 1.85-1.82 (m,8H), 1.77-1.74 (m,2H), 1.47-1.39 (m,8H), 1.34-1.30 (m,2H), 1.30-1.22 (m,6H).

[0304] Step 4: Ethyl 2-bromo-5-(4-cyclohexyl-3-fluorophenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate A mixture of ethyl 3-(4-cyclohexyl-3-fluorophenyl)-3-oxopropanoate (12 g, 41 mmol), p-TsOH·HO (1.7 g, 8.9 mmol), and ethyl 5-amino-3-bromo-1H-pyrazole-4-carboxylate (10 g, 34 mmol) in 1-butanol (90 mL) was stirred at 130° C. for 5 hours. The reaction solution was filtered to give the title compound (13 g, 82%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):δ 11.65(s,1H), 7.64-7.51(m,3H), 6.35(s,1H), 4.33(q,J=7.2Hz,2H), 2.9 1-2.85(m,1H), 1.86-1.73(m,5H), 1.56-1.39(m,4H), 1.37-1.34(m,4H).

[0305] Step 5: 2-Bromo-5-(4-cyclohexyl-3-fluorophenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid A mixture of lithium hydroxide monohydrate (11.8 g, 281 mmol) and ethyl 2-bromo-5-(4-cyclohexyl-3-fluoro-phenyl)-7-oxo-4H-pyrazolo[1,5-a]pyrimidine-3-carboxylate (13 g, 28 mmol) in water (50 mL) and ethanol (50 mL) was stirred at 80° C. for 16 hours. The reaction solution was concentrated, and the pH was adjusted to 6 with 1N aqueous HCl. The mixture was filtered and dried to give the title compound (9.5 g, 78%) as a white solid. LCMS (ESI): m / z 433.9 (M+H) + .

[0306] Step 6: 2-Bromo-5-(4-cyclohexyl-3-fluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one To a solution of DIPEA (3.81 mL, 23 mmol) and 2-bromo-5-(4-cyclohexyl-3-fluorophenyl)-7-oxo-4H-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2 g, 4.6 mmol) in DMF (10 mL) was added HATU (2.7 g, 6.91 mmol) and stirred for 20 minutes. 3-(Fluoromethyl)azetidine hydrochloride (1.2 g, 9.6 mmol) was added to the mixture and the reaction was stirred for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by chromatography on silica gel (0-10% MeOH in DCM) to afford the title compound (1 g, 43%) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 7.63-7.39(m,3H), 6.17(s,1H), 4.59(dd,J=47.2,6.0Hz,2H), 4.14-4.10(m,2H), 3.89-3.78(m, 2H), 3.04-2.93(m,1H), 2.87-2.81(m,1H), 1.83-1.64(m,5H), 1.54-1.21(m,5H).LCMS(ESI):m / z 505.1(M+H) + .

[0307] Intermediate N Preparation of cis-3-(fluoromethyl)-2-methylazetidine 2,2,2-trifluoroacetate The general reaction scheme was as follows: JPEG0007759877000082.jpg65170

[0308] Step 1: Tert-butyl (4-diazo-3-oxobutan-2-yl)carbamate A mixture of 2-(tert-butoxycarbonylamino)propanoic acid (30 g, 159 mmol), DIPEA (47 mL, 270 mmol), and isobutyl chloroformate (33 g, 238 mmol) in THF (300 mL) was stirred at 0 °C for 4 h. Acetonitrile (200 mL) and (diazomethyl)trimethylsilane (160 mL, 317 mmol) were added, and the reaction mixture was stirred at 0 °C for 3 h, warmed to room temperature, and stirred for an additional 16 h. The reaction mixture was then diluted with EtOAc (500 mL) and washed with brine (500 mL × 2). The organic layer was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (0-15% EtOAc in petroleum ether) to afford the title compound (15 g, 44%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6): δ 7.28(d,J=7.2Hz,1H), 6.02(s,1H), 3.99(q,J=7.6Hz,1H), 1.38(s,9H), 1.15(d,J=7.6Hz,3H).

[0309] Step 2: Tert-butyl 2-methyl-3-oxoazetidine-1-carboxylate A mixture of rhodium(II) acetate dimer (830 mg, 1.88 mmol), tert-butyl N-(3-diazo-1-methyl-2-oxopropyl)carbamate (20 g, 93.8 mmol), and TEA (0.12 mL, 0.9 mmol) in DCM (300 mL) was stirred at 0 °C for 16 h. The reaction mixture was diluted with EtOAc (150 mL) and washed with brine (150 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (0-10% EtOAc in petroleum ether) to afford the title compound (11.4 g, 66%) as a colorless liquid. 1 H NMR (400MHz, CDCl3): δ 4.98-4.88(m,1H), 4.77-4.49(m,2H), 1.49(s,9H), 1.46(d,J=7.2Hz,3H).

[0310] Step 3: Tert-butyl 2-methyl-3-methyleneazetidine-1-carboxylate To a solution of methyltriphenylphosphonium iodide (52 g, 129.58 mmol) in THF (300 mL) was added t-BuOK (15 g, 134.97 mmol) at 0 °C, and the reaction was stirred at 0 °C for 30 min. At this point, tert-butyl 2-methyl-3-oxo-azetidine-1-carboxylate (10 g, 53.99 mmol) was added and stirred for an additional 2 h. The reaction mixture was diluted with EtOAc (150 mL) and washed with brine (150 mL × 2). The organic layer was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (0-10% EtOAc in petroleum ether) to afford the title compound (6 g, 61%) as a colorless liquid. 1 H NMR (400MHz, CDCl3): δ 4.95(s,2H), 4.80-4.70(m,1H), 4.49-4.35(m,2H), 1.46(s,9H), 1.42(d,J=6.4Hz,3H).

[0311] Step 4: cis-tert-butyl 3-(hydroxymethyl)-2-methylazetidine-1-carboxylate To a solution of tert-butyl 2-methyl-3-methyleneazetidine-1-carboxylate (3.0 g, 16.37 mmol) in THF (30 mL) at 0° C. was added borane (1 M in THF, 24.6 mL, 24.6 mmol). The solution was stirred for 1 h, at which point the reaction was quenched with methanol (10 mL). 3 M aqueous NaOH (5 mL) and 30% hydrogen peroxide in water (4.1 mL, 40.9 mmol) were then added dropwise at 0° C. The reaction was stirred for 1 h and then diluted with water (50 mL). The mixture was extracted with EtOAc (50 mL × 2). The organic phase was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by silica gel chromatography (0-18% EtOAc in petroleum ether) to afford the title compound (1.6 g, 49%) as a colorless oil. 1 H NMR(400MHz,CDCl3):δ 4.42-4.28(m,1H), 3.90-3.78(m,2H), 3.74-3.66(m,1H), 3.54-3.47(m,1H), 2.71-2.62(m,1H), 1.40(s,9H), 1.35(d,J=6.8Hz,3H).

[0312] Step 5: cis-tert-butyl 3-(fluoromethyl)-2-methylazetidine-1-carboxylate To a solution of 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (2.7 g, 8.94 mmol) and cis-tert-butyl 3-(hydroxymethyl)-2-methylazetidine-1-carboxylate (1.2 g, 5.96 mmol) in THF (20 mL) was added BTPP (3.73 g, 11.92 mmol) at room temperature. The solution was stirred for 16 hours and poured into water (50 mL). The solution was extracted with EtOAc (50 mL × 2), washed with brine (30 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude was purified by silica gel chromatography (0-5% EtOAc in petroleum ether) to give the title compound (1.0 g, 83%) as a colorless oil.1 H NMR(400MHz,CDCl3):δ 4.74-4.48(m,2H), 4.47-4.40(m,1H), 3.98-3.90(m,1H), 3.60-3.52(m,1H), 2.94-2.78(m,1H), 1.44(s,9H), 1.37(d,J=6.8Hz,3H).

[0313] Step 6: cis-3-(fluoromethyl)-2-methylazetidine 2,2,2-trifluoroacetate JPEG0007759877000088.jpg19170 To a mixture of cis-tert-butyl 3-(fluoromethyl)-2-methylazetidine-1-carboxylate (1.0 g, 4.92 mmol) in DCM (5 mL) was added TFA (3.5 mL, 46.97 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hours, at which point the reaction was concentrated to afford the title compound (1 g, 93%) as a colorless oil. The crude material was used directly in the next step without further purification. 1 H NMR (400MHz, CDCl3): δ 4.89-4.73(m,2H), 4.70-4.64(m,1H), 4.30-4.18(m,1H), 3.99-3.86(m,1H), 3.23-3.07(m,1H), 1.63-1.58(m,3H).

[0314] Intermediate O Preparation of triisopropyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane The general reaction scheme was as follows: JPEG0007759877000089.jpg39170

[0315] Step 1: 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-ol A solution of cuprous chloride (936 mg, 9.45 mmol), t-BuONa (1.34 g, 14.18 mmol), bis(pinacolato)diboron (26.41 g, 104 mmol), and prop-2-yn-1-ol (5.30 g, 94.54 mmol) in toluene (50 mL) was charged into a vial. The vial was purged and backfilled with nitrogen. Tri-tert-butylphosphine (10% solution in toluene, 26.4 mL, 11.3 mmol) was added dropwise to the vial. Finally, methanol (7.6 mL, 189 mmol) was added to the solution, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with 4 M HCl in EtOAc and filtered. The filter cake was washed with DCM (100 mL) and concentrated to dryness. The residue was purified by silica gel column chromatography (0-17% EtOAc in petroleum ether) to afford the title compound (10 g, 57%) as a colorless oil. 1 H NMR (400MHz, CDCl3): 5.90(s,1H), 5.84(s,1H), 4.25(s,2H), 2.00-1.98(m,1H), 1.28(s,12H).

[0316] Step 2: Triisopropyl((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)oxy)silane To a solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-ol (1 g, 5.43 mmol) in DCM (30 mL) was added chlorotriisopropylsilane (2.1 g, 10.87 mmol) and imidazole (0.74 g, 10.87 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (50 mL), washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to afford the title compound (1.0 g, 54%) as a colorless liquid. 1H NMR (400MHz, CDCl3): δ 6.06(s,1H), 5.92-5.87(m,1H), 4.37(s,2H), 1.27(s,12H), 1.18-1.10(m,3H), 1.09-1.06(d,J=7.2Hz,18H).

[0317] Intermediate P Preparation of ethyl 5-chloro-2-(3-methylpyrazin-2-yl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate A mixture of ethyl 2-bromo-5-chloro-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate (10 g, 31.2 mmol), 2-methyl-3-(tributylstannyl)pyrazine (12 g, 31.2 mmol), CsF (14 g, 93.6 mmol), CuI (463 mg, 4.68 mmol), and Pd(dppf)Cl (2.3 g, 3.12 mmol) in DMF (200 mL) was stirred at 100° C. for 16 h under a nitrogen atmosphere. The reaction mixture was concentrated in vacuo and purified by flash chromatography on silica gel eluting with MeOH / DCM (0-40%) to give the title compound (3.9 g, 29%) as a black solid. 1 H NMR(400MHz,DMSO-d6):δ 8.53(d,J=2.4Hz,1H), 8.48(d,J=2.4Hz,1H), 5.67(s,1H), 3.91(q,J=7.2Hz,2H), 2.30(s,3H), 0.86(t,J=7.2Hz,3H);LCMS(ESI):m / z 333.9(M+H) + .

[0318] Intermediate Q Preparation of ethyl 2-(3-methylpyrazin-2-yl)-7-oxo-5-(4-(2,2,2-trifluoro-1-phenylethoxy)phenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate JPEG0007759877000093.jpg36170

[0319] Step 1: 2,2,2-trifluoro-1-phenylethyl trifluoromethanesulfonate To a solution of 2,2,2-trifluoro-1-phenylethanol (4.8 g, 27.25 mmol) in THF (50 mL) was added NaH (60% in mineral oil, 1.2 g, 29.98 mmol) at 0° C., and the mixture was stirred for 15 minutes. Trifluoromethanesulfonyl chloride (5.0 g, 29.98 mmol) was added dropwise at 0° C. After 15 minutes, the reaction solution was poured into water (60 mL), extracted with EtOAc (40 mL × 3), and washed with brine (40 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (8.4 g, 98%) as a brown oil. 1 H NMR(400MHz, CDCl3): δ 7.59-7.47(m,5H), 5.85(q,J=6.0Hz,1H).

[0320] Step 2: 4,4,5,5-tetramethyl-2-(4-(2,2,2-trifluoro-1-phenylethoxy)phenyl)-1,3,2-dioxaborolane A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (4.0 g, 18.18 mmol), CsCO (11.8 g, 36.35 mmol), and 2,2,2-trifluoro-1-phenylethyl trifluoromethanesulfonate (8.4 g, 27.26 mmol) in DMF (50 mL) was stirred at room temperature for 2 hours. The reaction solution was diluted with water (150 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-10% EtOAc in petroleum ether) to afford the title compound (3.4 g, 50%) as a colorless oil. 1H NMR (400MHz, CDCl3): δ 7.69(d,J=8.4Hz,2H), 7.51-7.37(m,5H), 6.89(d,J=8.4Hz,2H), 5.47(q,J=6.4Hz,1H), 1.31(s,12H).

[0321] Step 3: Ethyl 2-(3-methylpyrazin-2-yl)-7-oxo-5-(4-(2,2,2-trifluoro-1-phenylethoxy)phenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate A mixture of ethyl 5-chloro-2-(3-methylpyrazin-2-yl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate (700 mg, 2.1 mmol), 4,4,5,5-tetramethyl-2-(4-(2,2,2-trifluoro-1-phenylethoxy)phenyl)-1,3,2-dioxaborolane (1.58 g, 4.2 mmol), Na2CO3 (667 mg, 6.3 mmol), Xphos-Pd-G2 (165 mg, 0.21 mmol), and Xphos (100 mg, 0.21 mmol) in DMSO (20 mL) and water (2 mL) was stirred at 110 °C under a nitrogen atmosphere for 16 h. The reaction solution was poured into water (100 mL), extracted with EtOAc (50 mL x 3), washed with brine (50 mL x 2), and concentrated to dryness. The residue was purified by column chromatography on silica gel (0-5% MeOH in DCM) to give the crude title compound (500 mg, 80% purity) as a brown solid. LCMS (ESI): m / z 550.1 (M+H) + .

[0322] Example 1 Preparation of 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-N,N-dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxamide To a solution of 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid (Intermediate B, 40 mg, 0.09 mmol), N,N-dimethylamine hydrochloride (18 mg, 0.22 mmol), and DIPEA (0.12 mL, 0.74 mmol) in DMF (3 mL) was added HATU (50 mg, 0.13 mmol), and the reaction mixture was stirred for 3 h. The reaction mixture was diluted with EtOAc (40 mL) and washed with water (50 mL × 2). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by preparative HPLC (acetonitrile 0-45 / 0.1% FA in water, Xtimate C18 150 * 40mm * 10 μm) to give the title compound (8.4 mg, 20%) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 12.06(s,1H), 7.73(d,J=8.4Hz,2H), 7.45(d,J=8.4Hz,2H), 6.22(s,1H), 4.59(dd,J=47.2,5.6Hz,2H), 4.14-4.11(m,2H), 3.93-3.73(m ,2H), 3.01-2.99(m,7H), 2.69-2.54(m,1H), 1.82-1.79(m,4H), 1.73-1.70(m,1H), 1.52-1.33(m,4H), 1.32-1.17(m,1H);LCMS(ESI):m / z 480.2(M+H) + .

[0323] Example 2 Preparation of 5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-N,N-dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxamide The general reaction scheme was as follows: JPEG0007759877000098.jpg76170

[0324] Step 1: 5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxamide JPEG0007759877000099.jpg32170 The title compound (35 mg, 38%) was provided as a brown solid. The title compound was prepared from 2-bromo-5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (100 mg, 0.21 mmol) according to the procedure outlined for Intermediate B, Step 1. LCMS (ESI): m / z 452.2 (M+H) + .

[0325] Step 2: 5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid JPEG0007759877000100.jpg44170 The title compound (30 mg, 85%) was provided as a white solid. The title compound was prepared from 5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxamide (35 mg, 0.08 mmol) following the procedure outlined for Intermediate B, Step 2. LCMS (ESI): m / z 453.2 (M+H) + .

[0326] Step 3: 5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-N,N-dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxamide JPEG0007759877000101.jpg46170 The title compound (9.39 mg, 18%) was provided as a white solid. The title compound was prepared from 5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid (40 mg, 0.09 mmol) according to the procedure outlined for Example 1. 1 H NMR(400MHz,DMSO-d6):δ 7.95(d,J=8.0Hz,2H), 7.26(d,J=8.0Hz,2H), 6.10(s,1H), 4.60(dd,J=47.2,5.2Hz,2H), 4.33-4.02(m,4H), 2.95(s,3H), 2.80(s,3H) ), 2.62-2.60(m,2H), 2.18-2.04(m,1H), 2.00-1.96(m,1H), 1.66-1.62(m,4H), 1.51-1.46(m,2H), 1.21-1.13(m,2H);LCMS(ESI):m / z 480.3(M+H) + .

[0327] Example 3 Preparation of 5-(4-cyclohexyl-3,5-difluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-N,N-dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxamide The general reaction scheme was as follows: JPEG0007759877000102.jpg179170

[0328] Step 1: Methyl 4-bromo-3,5-difluorobenzoate A solution of 4-bromo-3,5-difluorobenzoic acid (25.0 g, 105.5 mmol) in MeOH (50 mL) was stirred at 0° C. for 15 minutes, and then SOCl (25.1 g, 210.95 mmol) was added. The mixture was stirred at 60° C. for 16 hours. The reaction mixture was then diluted with saturated aqueous NH Cl (500 mL) and extracted with ethyl acetate (500 mL × 2 mL). The organic layer was washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (24.4 g, 92%) as a yellow solid. 1 H NMR (400MHz, CDCl3): δ 7.62-7.58(m,2H), 3.92(s,3H).

[0329] Step 2: Methyl 2,6-difluoro-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylate A mixture of methyl 4-bromo-3,5-difluorobenzoate (22.5 g, 89.63 mmol), Na2CO3 (2.92 g, 275.9 mmol), 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (22.57 g, 108.46 mmol), and Pd(dppf)Cl2 (6.59 g, 8.96 mmol) in 1,4-dioxane (200 mL) was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered. The filtrate was collected, extracted with EtOAc (200 mL × 2), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (0-10% EtOAc in petroleum ether) to afford the title compound (21.6 g, 85.8 mmol, 96%) as a yellow oil. 1 H NMR (400MHz, CDCl3): 7.56-7.47(m,2H), 5.88(br s,1H), 3.92(s,3H), 2.31-2.16(m,4H), 1.82-1.68(m,4H).

[0330] Step 3: Methyl 4-cyclohexyl-3,5-difluorobenzoate To a mixture of methyl 2,6-difluoro-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylate (21.65 g, 85.82 mmol) in MeOH (150 mL) was added 10% Pd / C (1.83 g, 1.72 mmol). The mixture was stirred at 80°C under a hydrogen atmosphere (1 atm) for 16 hours. The reaction mixture was filtered and concentrated in vacuo to afford the title compound (18.82 g, 86%) as a white solid, which was used without further purification. 1 H NMR(400MHz,CDCl3):δ 7.45(d,J=8.8Hz,2H), 3.90(s,3H), 3.07-2.92(m,1H), 1.84-1.80(m,4H), 1.53-1.52(m,1H), 1.41-1.27(m,4H), 1.29-1.23(m,1H).

[0331] Step 4: Ethyl 3-(4-cyclohexyl-3,5-difluorophenyl)-3-oxopropanoate To a solution of ethyl acetate (10.85 mL, 111.02 mmol) in THF (100 mL) was added LiHMDS (111 mL, 111 mmol) dropwise at −40° C. Then, methyl 4-cyclohexyl-3,5-difluorobenzoate (18.82 g, 74.02 mmol) in THF (50 mL) was added dropwise to the reaction mixture at −40° C. The resulting solution was stirred for 2 hours, at which time the reaction was quenched with saturated aqueous NH4Cl. The resulting solution was extracted with EtOAc (100 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide the title compound (18.9 g, 82%, ketone / enol = 3:2) as a yellow oil, which was used directly without further purification. 1H NMR (400 MHz, CDCl): δ 12.51 (s, 1H enol), 7.40 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 10.0 Hz, 2H), 5.56 (s, 1H enol), 4.32-4.19 (m, 4H), 3.91 (s, 2H ketone), 3.12-2.93 (m, 2H), 1.89-1.80 (m, 8H), 1.79-1.64 (m, 8H), 1.61-1.57 (m, 2H), 1.45-1.38 (m, 2H), 1.34-1.32 (m, 6H).

[0332] Step 5: Ethyl 2-bromo-5-(4-cyclohexyl-3,5-difluorophenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate A mixture of ethyl 3-(4-cyclohexyl-3,5-difluorophenyl)-3-oxopropanoate (5.0 g, 16.11 mmol), p-TsOH·HO (833 mg, 4.83 mmol), and ethyl 5-amino-3-bromo-1H-pyrazole-4-carboxylate (4.71 g, 16.11 mmol) in acetonitrile (50 mL) was stirred at 100 °C for 16 h. The reaction was then concentrated, and water (50 mL) was added. The resulting solution was extracted with ethyl acetate (100 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (0-5% MeOH in DCM) to afford the title compound (3.14 g, 41%) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ 7.48(d,J=9.6Hz,2H), 6.36(s,1H), 4.30(q,J=7.2Hz,2H), 3.04-2.97(m,1H), 1.84-1.69(m,7H), 1.39-1.29(m,6H).

[0333] Step 6: 2-Bromo-5-(4-cyclohexyl-3,5-difluorophenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid A mixture of lithium hydroxide monohydrate (310 mg, 7.39 mmol) and ethyl 2-bromo-5-(4-cyclohexyl-3,5-difluorophenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate (355 mg, 0.74 mmol) in water (3 mL) and ethanol (3 mL) was stirred at 80° C. for 16 hours. The reaction solution was concentrated and adjusted to pH 4 by adding 4 M aqueous HCl. The mixture was extracted with EtOAc (60 mL × 2). The combined organics were dried over NaSO and concentrated to give the title compound (320 mg, 96%) as a white solid. 1 H NMR (400MHz, DMSO-d6): δ 7.47(d,J=9.6Hz,2H), 6.31(s,1H), 3.05-2.91(m,1H), 1.82-1.66(m,8H), 1.35-1.32(m,2H).

[0334] Step 7: 2-Bromo-5-(4-cyclohexyl-3,5-difluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one To a solution of 2-bromo-5-(4-cyclohexyl-3,5-difluorophenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2.0 g, 4.42 mmol) and DIPEA (3.65 mL, 22.11 mmol) in DMF (15 mL) was added HATU (2.52 g, 6.63 mmol). The solution was stirred for 20 minutes, and then 3-(fluoromethyl)azetidine 2,2,2-trifluoroacetate (1.16 g, 9.17 mmol) was added. The reaction mixture was stirred for 2 hours and quenched with water (50 mL). The mixture was extracted with EtOAc (50 mL × 3), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-10% MeOH in DCM) to afford the title compound (1.22 g, 53%) as a white solid. 1H NMR(400MHz,DMSO-d6):δ 7.70(d,J=10.8Hz,2H), 6.16(s,1H), 4.62(dd,J=47.2,5.6Hz,2H), 4.35-4.17(m,2H), 4.14-4.09( LCMS(ESI):m / z 523.1(M+H) + .

[0335] Step 8: 5-(4-cyclohexyl-3,5-difluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxamide A mixture of 2-bromo-5-(4-cyclohexyl-3,5-difluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (600.0 mg, 1.15 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (83.9 mg, 0.11 mmol), and 4-dimethylaminopyridine (223.5 mg, 1.83 mmol) in formamide (1.03 g, 23 mmol) was stirred at 120° C. under CO (15 psi) for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (50 mL × 2). The combined organics were dried over NaSO and concentrated to dryness. The residue was purified by flash chromatography on silica gel eluting with CH2Cl2 / MeOH (10:1) to give the title compound (188 mg, 34% yield) as a white solid. LCMS (ESI): m / z 488.2 (M+H). + .

[0336] Step 9: 5-(4-cyclohexyl-3,5-difluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid JPEG0007759877000111.jpg37170 The title compound (80 mg, 43%) was provided as a yellow solid prepared from 5-(4-cyclohexyl-3,5-difluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxamide (188 mg, 0.39 mmol) according to the procedure outlined for Intermediate B, Step 2. LCMS (ESI): m / z 489.2 (M+H) + .

[0337] Step 10: 5-(4-cyclohexyl-3,5-difluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-N,N-dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxamide JPEG0007759877000112.jpg45170 The title compound (10.9 mg, 13%) was provided as a white solid prepared from 5-(4-cyclohexyl-3,5-difluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid (80 mg, 0.16 mmol) according to the procedure outlined for Example 1. 1 H NMR(400MHz,DMSO-d6):δ 7.69(d,J=10.8Hz,2H), 6.16(s,1H), 4.60(dd,J=47.6,5.6Hz,2H), 4.42-3.61(m,4H), 3.00-2.9 0(m,5H), 2.79(s,3H), 1.84-1.76(m,4H), 1.75-1.70(m,1H), 1.39-1.20(m,5H);LCMS(ESI):m / z 516.2(M+H) + .

[0338] Example 4 Preparation of 5-(4-cyclohexyl-3-fluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-N,N-dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxamide The general reaction scheme was as follows: JPEG0007759877000113.jpg86170

[0339] Step 1: 5-(4-cyclohexyl-3-fluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxamide JPEG0007759877000114.jpg45170 The title compound (200 mg, 43%) was provided as a tan solid prepared from 2-bromo-5-(4-cyclohexyl-3-fluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (500 mg, 0.99 mmol) according to the procedure outlined for Intermediate B, Step 1. LCMS (ESI) m / z 470.2 (M+H) + .

[0340] Step 2: 5-(4-cyclohexyl-3-fluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid JPEG0007759877000115.jpg45170 The title compound (70 mg, 35%) was provided as a brown solid prepared from 5-(4-cyclohexyl-3-fluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxamide (200 mg, 0.43 mmol) according to the procedure outlined for Intermediate B, Step 2. LCMS (ESI) m / z 471.2 (M+H) + .

[0341] Step 3: 5-(4-cyclohexyl-3-fluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-N,N-dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxamide JPEG0007759877000116.jpg45170 The title compound (29.3 mg, 40%) was provided as a white solid prepared from 5-(4-cyclohexyl-3-fluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid (70 mg, 0.15 mmol) according to the procedure outlined for Example 1. 1 H NMR(400MHz,CD3OD):δ 7.80-7.72(m,2H), 7.40-7.36(m,1H), 6.40(s,1H), 4.63(dd,J=47.2,6.4Hz,2H), 4.60-4.42(m,2H), 4.28-4.25(m,1H), 4.01-3.98 (m,1H), 3.08(s,6H), 2.95-2.92(m,2H), 1.90-1.81(m,4H), 1.78-1.76(m,1H), 1.58-1.46(m,4H), 1.34-1.27(m,1H);LCMS(ESI)m / z 498.3(M+H) + .

[0342] Example 5 Preparation of 5-(4-cyclohexylphenyl)-3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-N,N-dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxamide To a solution of 5-(4-cyclohexylphenyl)-2-(dimethylcarbamoyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Intermediate K, 70 mg, 0.17 mmol) and DIPEA (0.3 mL, 1.71 mmol) in DMF (5 mL) was added HATU (97 mg, 0.26 mmol). The reaction mixture was stirred at room temperature for 10 minutes, and (2R,3R)-3-(fluoromethyl)-2-methyl-azetidine 2,2,2-trifluoroacetic acid (116 mg, 0.54 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, at which time it was poured into water (50 mL), extracted with EtOAc (50 mL x 2), washed with brine (50 mL), and concentrated in vacuo. The residue was purified by preparative TLC (5% methanol in dichloromethane) to afford the title compound (27.0 mg, 32%) as a gray solid. 1 H NMR(400MHz,DMSO-d6):δ 7.97-7.85(m,2H), 7.35-7.29(m,2H), 6.13(s,1H), 4.85-4.60(m,3H), 3.95-3.90(m,2H), 2.93-2.71 (m,6H), 2.53-2.50(m,2H), 1.85-1.80(m,4H), 1.73-1.70(m,1H), 1.46-1.19(m,8H);LCMS(ESI):m / z 494.1(M+H) + .

[0343] Example 6 Preparation of 5-(4-cyclohexylphenyl)-3-((2R,3R)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-N,N-dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxamide JPEG0007759877000118.jpg46170 The title compound (11.5 mg, 14%) was prepared from 5-(4-cyclohexylphenyl)-2-(dimethylcarbamoyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (70 mg, 0.17 mmol) and (2S,3S)-3-(fluoromethyl)-2-methylazetidine 2,2,2-trifluoroacetate (120 mg, 0.54 mmol) following the procedure outlined for Example 5. 1 H NMR(400MHz,DMSO-d6):δ 7.97-7.75(m,2H), 7.31-7.29(m,2H), 6.12(s,1H), 4.82-4.63(m,3H), 3.98-3.92(m,2H), 2.93-2.7 1(m,6H), 2.53-2.50(m,2H), 1.85-1.80(m,4H), 1.73-1.70(m,1H), 1.46-1.19(m,8H);LCMS(ESI)m / z 494.1(M+H) + .

[0344] Example 7 Preparation of 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-(trifluoromethyl)pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000119.jpg48170

[0345] Step 1: 2-(tributylstannyl)-3-(trifluoromethyl)pyrazine JPEG0007759877000120.jpg33170n-Bu6Sn2 (1.27 g, 2.12 mmol) and 2-chloro-3-(trifluoromethyl)pyrazine (0.2 g, 1.1 mmol) in 1,4-dioxane (10 mL) were treated with (A- taPhos)PdCl (116 mg, 0.16 mmol) was added. The mixture was stirred at 150 °C under N in a microwave for 30 minutes. The resulting solution was extracted with EtOAc (30 mL × 2) and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (5% EtOAc in petroleum ether) to give the title compound (50 mg, 10%) as a colorless liquid. 1 H NMR (400MHz, CDCl3): δ 8.88(d,J=2.0Hz,1H), 8.48(d,J=2.0Hz,1H), 1.55-1.46(m,6H), 1.41-1.28(m,12H), 0.86-0.91(m,9H).

[0346] Step 2: 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-(trifluoromethyl)pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one A mixture of 2-(tributylstannyl)-3-(trifluoromethyl)pyrazine (45 mg, 0.10 mmol), 2-bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (25 mg, 0.05 mmol), CuCl (0.76 mg, 0.01 mmol), CsF (23 mg, 0.15 mmol), and Pd(dppf)Cl (4 mg, 0.01 mmol) in DMAc (2 mL) was stirred in a microwave at 140 °C for 3 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with brine (50 mL × 2). The organic layer was purified by preparative TLC (5% MeOH in DCM) to give the title compound (1.36 mg, 5%) as a white solid. 1H NMR(400MHz,CD3OD):δ 9.00-8.85(m,1H), 8.84-8.78(m,1H), 7.96(d,J=7.2Hz,2H), 7.34(d,J=7.2Hz,2H), 6.33(s,1H), 4.70-4.50(m,2H), 4.52-3.85(m,4H) ), 3.10-2.95(m,1H), 2.65-2.55(m,1H), 1.95-1.85(m,4H), 1.83-1.75(m,1H), 1.58-1.42(m,4H), 1.35-1.30(m,1H);LCMS(ESI):m / z 555.1(M+H) + .

[0347] Example 8 Preparation of 3-(5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-2-yl)pyrazine-2-carbonitrile JPEG0007759877000122.jpg47170

[0348] Step 1: 3-(tributylstannyl)pyrazine-2-carbonitrile JPEG0007759877000123.jpg35170 The title compound (1.68 g, 40%) was prepared from 3-chloropyrazine-2-carbonitrile (1.5 g, 10.75 mmol) following the procedure outlined for Example 7, Step 1. 1 H NMR (400MHz, CDCl3): δ 8.85-8.82(m,1H), 8.50-8.46(m,1H), 1.70-1.58(m,6H), 1.36-1.31(m,12H), 0.93-0.89(m,9H).

[0349] Step 2: 3-(5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-2-yl)pyrazine-2-carbonitrile JPEG0007759877000124.jpg48170 The title compound (8.2 mg, 1%) was prepared from 3-(tributylstannyl)pyrazine-2-carbonitrile (1.68 g, 4.25 mmol) and 2-bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (600 mg, 1.23 mmol) following the procedure outlined for Example 7, Step 2. 1 H NMR(400MHz,CD3OD):δ 9.00-8.70(m,2H), 8.00-7.90(m,2H), 7.50-7.30(m,2H), 6.29(s,1H), 4.70-4.55(m,2H), 4.49-3.83(m,4H), 3.10-2.95 (m,1H), 2.70-2.55(m,1H), 1.95-1.85(m,4H), 1.85-1.75(m,1H), 1.57-1.45(m,4H), 1.39-1.32(m,1H);LCMS(ESI):m / z 512.1(M+H) + .

[0350] The following compounds were prepared from 2-bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (Intermediate A) and the corresponding stannane reagent according to the procedure outlined for Example 7, Step 2. The corresponding stannane reagent was prepared from an aryl chloride and (A-taPhos)PdCl according to the procedure outlined for Example 7, Step 1. JPEG0007759877000125.jpg227170JPEG0007759877000126.jpg233170JPEG0007759877000127.jpg245170

[0351] Example 15 Preparation of 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000128.jpgCompound 37170 (8.72 mg, 4%) was prepared from 2-bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (200.0 mg, 0.41 mmol)) and 2-(tributylstannyl)pyrimidine (303 mg, 0.82 mmol) following the procedure outlined for Example 7, Step 2. 1 H NMR(400MHz,CD3OD):δ 8.90-8.88(m,2H), 7.90(d,J=8.0Hz,2H), 7.50-7.48(m,1H), 7.35(d,J=8.0Hz ,2H), 6.29(s,1H), 4.62(dd,J=47.6,6.0Hz,2H), 4.33-4.30(m,2H), 4.13-4.11 (m,1H), 4.05-4.03(m,1H), 3.01-2.98(m,1H), 2.61-2.59(m,1H), 1.92-1.88(m ,4H), 1.80-1.78(m,1H), 1.57-1.43(m,4H), 1.37-1.28(m,1H);LCMS(ESI):m / z 487.2(M+H) + .

[0352] The following title compounds were prepared from 2-bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and arylstannanes following the procedure outlined for Example 7, Step 2. The corresponding stannane reagents are commercially available. JPEG0007759877000129.jpg245170JPEG0007759877000130.jpg132170

[0353] Example 19 Preparation of 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(oxazol-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000131.jpg37170

[0354] Step 1: 2-(tributylstannyl)oxazole To a solution of oxazole (4 g, 57.92 mmol) in THF (40 mL) under a nitrogen atmosphere at −78° C. was added n-BuLi (26 mL, 63.71 mmol) dropwise. The reaction mixture was stirred for 15 minutes, and then n-Bu3SnCl (20 g, 61.81 mmol) was added slowly. The reaction mixture was stirred for 1 hour and then concentrated in vacuo to afford the title compound (20.7 g, 99%) as a dark pink oil, which was used directly without further purification. 1 H NMR (400MHz, CDCl3): δ 7.85(s,1H), 7.19(s,1H), 1.62-1.59(m,6H), 1.37-1.32(m,12H), 0.93-0.90(m,9H).

[0355] Step 2: 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(oxazol-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000133.jpg36170 The title compound (19.8 mg, 10%) was prepared from 2-(tributylstannyl)oxazole (294 mg, 0.82 mmol) and 2-bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (0.2 g, 0.41 mmol) following the procedure outlined for Example 7, Step 2. 1H NMR(400MHz,CD3OD):δ 8.11(s,1H)7.87-7.85(m,2H)7.50-7.36(m,3H), 6.28(s,1H), 4.62-4.48(m,2H), 4.39-4.14(m,2H), 4.08-3.98(m,2H), 3.01 -2.95(m,1H), 2.63-2.60(m,1H), 1.90-1.87(m,4H), 1.79-1.75(m,1H), 1.53-1.46(m,4H), 1.34-1.30(m,1H);LCMS(ESI):m / z 476.2(M+H) + .

[0356] Example 20 Preparation of 5-(4-cyclohexylphenyl)-N,N-dimethyl-2-(3-methylpyrazin-2-yl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamide JPEG0007759877000134.jpg36170

[0357] Step 1: 2-Bromo-5-(4-cyclohexylphenyl)-N,N-dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamide JPEG0007759877000135.jpg36170 The title compound (3.8 g, 71%) was prepared from 2-bromo-5-(4-cyclohexylphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (5.0 g, 12.01 mmol) and dimethylamine hydrochloride (1.9 g, 24.02 mmol) following the procedure outlined for Intermediate A, Step 5. LCMS (ESI): m / z 443.1 (M+H) + .

[0358] Step 2: 5-(4-cyclohexylphenyl)-N,N-dimethyl-2-(3-methylpyrazin-2-yl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamide JPEG0007759877000136.jpg37170 The title compound (12 mg, 8%) was prepared from 2-bromo-5-(4-cyclohexylphenyl)-N,N-dimethyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxamide (150 mg, 0.34 mmol) and 2-methyl-3-(tributylstannyl)pyrazine (194 mg, 0.51 mmol) following the procedure outlined for Example 7, Step 2. 1 H NMR(400MHz,DMSO-d6):δ 12.57(s,1H), 8.58-8.53(m,2H), 7.70(d,J=8.0Hz,2H), 7.44(d,J=8.0Hz,2H), 6.11(s,1H), 2.87(s,6H), 2.74(s,3 LCMS(ESI):m / z 457.2(M+H) + .

[0359] Example 21 Preparation of 5-(4-cyclohexyl-3-fluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000137.jpg45170 The title compound (26 mg, 17%) was prepared from 2-bromo-5-(4-cyclohexyl-3-fluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (150 mg, 0.30 mmol) and 2-methyl-3-(tributylstannyl)pyrazine (170 mg, 0.45 mmol) following the procedure outlined for Example 7, Step 2. 1H NMR(400MHz,DMSO-d6):δ 12.54(s,1H), 8.64-8.59(m,2H), 7.67-7.60(m,2H), 7.58-7.53(m,1H), 6.25(s,1H), 4.49(dd,J=47.2,5.6Hz,2H), 4.21-3.40(m,4H), 2.92-2.86(m,2H), 2.67(s,3H), 1.84 -1.81(m,4H), 1.78-1.72(m,1H), 1.56-1.32(m,5H);LCMS(ESI):m / z 519.3(M+H) + .

[0360] Example 22 Preparation of 5-(4-cyclohexyl-3-fluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000138.jpg46170 The title compound (18.1 mg, 18%) was prepared from 2-bromo-5-(4-cyclohexyl-3-fluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (100 mg, 0.20 mmol) and 2-(tributylstannyl)pyrimidine (109 mg, 0.30 mmol) following the procedure outlined for Example 7, Step 2. 1 H NMR(400MHz,DMSO-d6):δ 9.00-8.90(m,2H), 7.80-7.60(m,2H), 7.60-7.40(m,2H), 6.13(s,1H), 4.70-4.46(m,2H), 4.20-3.95(m,2H), 3.90-3.65 (m,2H),3.00-2.80(m,2H), 1.85-1.75(m,4H), 1.75-1.70(m,1H), 1.57-1.40(m,4H), 1.32-1.25(m,1H);LCMS(ESI):m / z 505.1(M+H) + .

[0361] Example 23 Preparation of 5-(4-cyclohexyl-3-fluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000139.jpg44170 The title compound (17 mg, 11%) was prepared from 2-bromo-5-(4-cyclohexyl-3-fluorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (150 mg, 0.31 mmol) and 2-(tributylstannyl)pyrazine (170 mg, 0.46 mmol) following the procedure outlined for Example 7, Step 2. 1 H NMR(400MHz,DMSO-d6):δ 9.08(s,1H), 8.74-8.58(m,2H), 7.80-7.70(m,2H), 7.45-7.37(m,1H), 6.13(s,1H), 4.61(dd,J=47.2,6.0Hz,2H), 4.24-3.67(m,4H) , 3.00-2.90(m,1H), 2.90-2.80(m,1H), 1.85-1.75(m,4H), 1.75-1.65(m,1H), 1.54-1.38(m,4H), 1.34-1.25(m,1H);LCMS(ESI):m / z 505.2(M+H) + .

[0362] Example 24 Preparation of 5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000140.jpg45170 The title compound (14.80 mg, 30%) was prepared from 2-bromo-5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (50.0 mg, 0.10 mmol) and 2-(tributylstannyl)pyrimidine (75.70 mg, 0.21 mmol) following the procedure outlined for Example 7, Step 2. 1H NMR(400MHz,DMSO-d6):δ 12.55(s,1H), 8.97(d,J=4.8Hz,2H), 7.72(d,J=8.4Hz,2H), 7.58(t,J=4.8Hz,1H ), 7.41(d,J=8.4Hz,2H), 6.13(s,1H), 4.53(dd,J=47.2,6.0Hz,2H), 4.16-3.74( m,2H), 3.55-3.40(m,2H), 2.98-2.86(m,1H), 2.68(d,J=7.2Hz,2H), 2.18-2.07( m,1H), 1.69-1.57(m,4H), 1.55-1.43(m,2H), 1.25-1.18(m,2H).LCMS(ESI):m / z 487.1(M+H) + .

[0363] Example 25 Preparation of 5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000141.jpg46170 The title compound (22.8 mg, 45%) was prepared from 2-bromo-5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (50.0 mg, 0.10 mmol) and 2-(tributylstannyl)pyrazine (75.0 mg, 0.21 mmol) following the procedure outlined for Example 7, Step 2. 1 H NMR(400MHz,DMSO-d6):δ 12.62(s,1H), 9.18(s,1H), 8.75-8.70(m,2H), 7.85-7.69(m,2H), 7.38 (d,J=6.8Hz,2H), 6.15(s,1H), 4.57(dd,J=47.2,6.0Hz,2H), 4.15-3.50 (m,4H), 2.94-2.86(m,1H), 2.68(d,J=7.2Hz,2H), 2.16-2.07(m,1H), 1.69-1.57(m,4H), 1.53-1.45(m,2H), 1.23-1.16(m,2H).LCMS(ESI):m / z 487.2(M+H) + .

[0364] Example 26 Preparation of 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(5-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000142.jpg46170

[0365] Step 1: 2-methyl-5-(tributylstannyl)pyrazine To a solution of 2-bromo-5-methyl-pyrazine (1 g, 5.78 mmol) and tributylchlorostannane (3.16 g, 9.71 mmol) in THF (15 mL) was added n-BuLi (2.8 mL, 7.0 mmol) dropwise at −78° C. and further at this temperature for 2 h. The reaction was quenched with water (50 mL) and extracted with hexane (50 mL × 2). The combined organics were dried over NaSO, filtered, and concentrated. The crude was purified by column chromatography (0–10% ethyl acetate in petroleum ether) to afford the title compound (600 mg, 27%) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ 8.62(s,1H), 8.42(s,1H), 2.51(s,3H), 1.59-1.49(m,6H), 1.36-1.30(m,6H), 1.15(t,J=8.0Hz,6H), 0.88(t,J=7.2Hz,9H).

[0366] Step 2: 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(5-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000144.jpg44170 The title compound (34 mg, 17%) was prepared from 2-bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (200 mg, 0.41 mmol) and 2-methyl-5-(tributylstannyl)pyrazine (314 mg, 0.82 mmol) following the procedure outlined for Example 7, Step 2. 1 H NMR (400 MHz, CDCl): δ 10.57(s,1H), 9.27(s,1H), 8.61(s,1H), 7.66(d,J=8.0Hz,2H), 7.40(d, J=8.0Hz,2H), 6.31(s,1H), 4.42(dd,J=46.8,4.8Hz,2H), 4.25-3.68(m,4 H), 2.82-2.79(m,1H), 2.70(s,3H), 2.63-2.58(m,1H), 1.93-1.89(m,4H) , 1.83-1.79(m,1H), 1.47-1.44(m,4H), 1.36-1.27(m,1H).LCMS(ESI)m / z 501.3(M+H) + .

[0367] The following compound was prepared from 2-bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and a stannane reagent according to the procedure outlined for Example 26, Step 2. The corresponding stannane reagent is prepared from an aryl bromide and n-BuLi according to the procedure outlined for Example 26, Step 1. JPEG0007759877000145.jpg227170JPEG0007759877000146.jpg157170

[0368] Example 30 Preparation of 5-(4-cyclohexylphenyl)-2-(1,5-dimethyl-1H-imidazol-4-yl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000147.jpg70170

[0369] Step 1: 4-iodo-1,5-dimethyl-1H-imidazole To a solution of 4-iodo-5-methyl-1H-imidazole (2.5 g, 12 mmol) in THF (25 mL) was added NaH (0.53 g, 13.2 mmol, 60 wt% in mineral oil) at 0 °C and stirred for 30 min. Methyl iodide (3.4 mL, 55 mmol) was added, and the reaction mixture was allowed to warm to room temperature and stirred for 4 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (100 mL × 2). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (50% ethyl acetate in petroleum ether) to afford the title compound (1.1 g, 41%) as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ 7.41(s,1H), 3.60(s,3H), 2.21(s,3H).

[0370] Step 2: 1,5-dimethyl-4-(tributylstannyl)-1H-imidazole JPEG0007759877000149.jpg181704-Iodo-1,5-dimethyl-1H-imidazole (500 mg, 2.2 mmol) in THF (5 mL) was added dropwise at 0 °C with isopropylmagnesium chloride (2 M in THF, 1.2 mL, 2.3 mmol). The reaction mixture was warmed to room temperature and stirred for 1.5 h. Tributylchlorostannane (1.48 g, 4.55 mmol) was added, and the reaction mixture was stirred for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl (50 mL x 2) and extracted with ethyl acetate (50 mL x 2). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound (0.85 g, 98%) as a colorless oil. LCMS (ESI) m / z 387.0 (M+H) + .

[0371] Step 3: 5-(4-cyclohexylphenyl)-2-(1,5-dimethyl-1H-imidazol-4-yl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one A suspension of Pd(t-BuP) (15 mg, 0.03 mmol), CsF (160 mg, 1.0 mmol), 2-bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (100 mg, 0.21 mmol), and 1,5-dimethyl-4-(tributylstannyl)-1H-imidazole (316 mg, 0.82 mmol) in DMA (4 mL) was stirred at 120 °C for 16 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (10 mL × 5). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude was purified by reverse-phase preparative HPLC (27%-57% gradient 0.2% FA / HO -MeCN, Xtimate C18 150 * 40mm * 10 μm) to give the title compound (27 mg, 27%) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 7.93-7.89(br s,2H), 7.30-7.25(m,3H), 6.12(s,1H), 4.59(d,J=47.6,5.6Hz,2H), 4.36-3.81(m,4H), 3.74(s,3H), 2.96-2.88(m,1H), 2. 62-2.57(m,1H), 2.54(s,3H), 1.82-1.80(m,4H), 1.73-1.70(m,1H), 1.47-1.40(m,4H), 1.30-1.24(m,1H);LCMS(ESI):m / z 503.3(M+H) + .

[0372] Example 31 Preparation of 5-(4-cyclohexylphenyl)-2-(1-ethyl-1H-imidazol-4-yl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000151.jpg46170 The title compound (70.3 mg, 34%) was prepared from 2-bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and 4-iodo-1H-imidazole following a similar procedure outlined for Example 30, steps 1-3. 1 H NMR(400MHz,DMSO-d6):δ 8.00-7.84(m,4H), 7.23-7.18(m,2H), 6.10(s,1H), 4.60(d,J=47.2,5.2Hz,2H), 4.10-4.10(m,4H), 3.89-3.80(m,2H), 2.98 -2.92(m,1H), 2.59-2.56(m,1H), 1.83-1.80(m,4H), 1.73-1.70(m,1H), 1.31-1.53(m,7H), 1.29-1.26(m,1H);LCMS(ESI)m / z 503.3(M+H) + .

[0373] Example 32 Preparation of 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(1-methyl-1H-imidazol-4-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000152.jpg45170 The title compound (40.7 mg, 10%) was prepared from 2-bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and 4-iodo-1-methyl-1H-imidazole following the procedure outlined for Example 30, steps 2-3. 1H NMR(400MHz,DMSO-d6):δ 12.40(br s,1H), 7.89-7.62(m,4H), 7.39-7.35(m,2H), 6.11(s,1H), 4.61(d,J=47.6,5.6Hz,2H), 4.15(s,2H), 3.88-3.83(m,5H), 3.01 -2.90(m,1H), 2.97-2.92(m,1H), 1.89-1.75(m,4H), 1.77-1.69(m,1H), 1.45-1.37(m,4H), 1.32-1.22(m,1H);LCMS(ESI):m / z 489.1(M+H) + .

[0374] Example 33 Preparation of (S)-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(2-methylazetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and (R)-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(2-methylazetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000153.jpg46170

[0375] Step 1: 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(2-methylazetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one To a solution of 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid (Intermediate B, 300 mg, 0.66 mmol) in DMF (5 mL) was added 2-methylazetidine hydrochloride (210 mg, 2.0 mmol) and DIPEA (0.32 mL, 1.95 mmol). To this reaction mixture was added PyBOP (520 mg, 0.99 mmol). The solution was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (25 mL), and the solution was adjusted to pH 6 by the addition of 1 M aqueous HCl. The mixture was extracted with ethyl acetate (50 mL × 3), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (10% MeOH in DCM) to give the title compound (300 mg, 42%) as a yellow solid. LCMS (ESI): m / z 506.3 (M+H) + .

[0376] Step 2: (S)-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(2-methylazetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and (R)-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(2-methylazetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000155.jpg461705-(4-Cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(2-methylazetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (150 mg, 0.3 mmol) was separated by SFC (Chiralpak AD, isocratic 25% MeOH w / 0.1% NH4OH) to give enantiomer A (first SFC peak, 19.3 mg, 13%) and enantiomer B (second SFC peak, 21.3 mg, 14%), both as white solids.

[0377] Enantiomer A: 1 H NMR(400MHz,CD3OD):δ 7.93-7.91(m,2H), 7.32(d,J=8.0Hz,2H), 6.31(s,1H), 4.48-4.50(m,4H), 4.49-3.83(m,5H) , 3.07-3.03(m,1H), 2.58-2.56(m,2H), 1.99-1.73(m,6H), 1.59-1.26(m,8H);LCMS(ESI):m / z 506.3(M+H) + .

[0378] Enantiomer B: 1 H NMR(400MHz,CD3OD):δ 7.86-7.83(m,2H), 7.39(d,J=7.2Hz,2H), 6.32(s,1H), 4.64-4.54(m,4H), 4.45-3.96(m,5H) , 3.03-2.98(m,1H), 2.61-2.58(m,2H), 1.92-1.77(m,6H), 1.59-1.26(m,8H);LCMS(ESI):m / z 506.2(M+H) + .

[0379] Example 34 Preparation of 5-(4-cyclohexylphenyl)-N-ethyl-3-(3-(fluoromethyl)azetidine-1-carbonyl)-N-methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxamide JPEG0007759877000156.jpg45170 The title compound (32.6 mg, 30%) was prepared from 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid (Intermediate B, 100 mg, 0.22 mmol) and N-ethyl-methylamine (39.2 mg, 0.66 mmol) following the procedure outlined for Example 33, Step 1. 1H NMR(400MHz,DMSO-d6):δ 7.92-7.82(m,2H), 7.38-7.26(m,2H), 6.05(s,1H), 4.60(d,J=47.6,5.6Hz,2H) , 4.06-3.82(m,2H), 3.80-3.72(m,2H), 3.46-3.40(m,1H), 3.18-3.13(m,1H), 2. 93(s,3H), 2.80-2.77(m,1H), 2.59-2.51(m,1H), 1.83-1.80(m,4H), 1.70-1.66( m,1H), 1.47-1.29(m,4H), 1.24-1.18(m,1H), 1.14-0.98(m,3H).LCMS(ESI):m / z 494.3(M+H) + .

[0380] Example 35 Preparation of 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(pyrrolidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000157.jpg38170 The title compound (40.01 mg, 35%) was prepared from 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-2-carboxylic acid (Intermediate B, 100 mg, 0.22 mmol) and pyrrolidine (47 mg, 0.66 mmol) following the procedure outlined for Example 33, Step 1. 1 H NMR(400MHz,DMSO-d6):δ 7.95-7.85(m,2H), 7.32(d,J=5.6Hz,2H), 6.09(s,1H), 4.59(dd,J=47.2,5.6Hz,2H), 4.49-3.49(m,4H), 3.47-3.42(m,4H), 3.0 5-2.85(m,1H), 2.59-2.55(m,1H), 1.87-1.76(m,8H), 1.75-1.67(m,1H), 1.46-1.34(m,4H), 1.30-1.23(m,1H);LCMS(ESI):m / z 506.3(M+H) + .

[0381] Example 36 Preparation of 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one To a solution of pyridin-3-ylboronic acid (101 mg, 0.82 mmol) in DMSO (4 mL) and water (0.4 mL) was added Xphos Pd G3 (34.7 mg, 0.04 mmol), Xphos (19.6 mg, 0.04 mmol), Cs2CO3 (402 mg, 1.23 mmol), and 2-bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (200 mg, 0.41 mmol). The reaction mixture was then stirred at 120 °C under a nitrogen atmosphere in a microwave oven for 2 h. Water (10 mL) was added to the reaction mixture, which was adjusted to pH 5 by the addition of 2 M aqueous HCl, extracted with ethyl acetate (10 mL × 3), dried over Na SO , filtered, and concentrated in vacuo. The crude was purified by preparative TLC (10% methanol in DCM) to give the title compound (78.1 mg, 39%) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 12.80-12.21(m,1H), 8.97(s,1H), 8.63(s,1H), 8.19(d,J=8.0Hz,1H), 7.81-7.75(m, 2H), 7.52-7.50(m,1H), 7.41(d,J=6.8Hz,2H), 6.13(s,1H), 4.59(dd,J=46.8,6.0Hz,2 H), 4.10-4.02(m,2H), 3.85-3.79(m,2H), 2.96-2.92(m,1H), 2.62-2.58(m,1H), 1.84- 1.80(m,4H), 1.74-1.71(m,1H), 1.52-1.34(m,4H), 1.31-1.22(m,1H);LCMS(ESI):m / z 486.3(M+H) + .

[0382] Example 37 Preparation of 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000159.jpg37170 The title compound (18.2 mg, 9.0%) was prepared from 2-bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (200.0 mg, 0.40 mmol) and phenylboronic acid (100 mg, 0.8 mmol) following the procedure outlined for Example 36. 1 H NMR(400MHz,DMSO-d6):δ 12.33(s,1H), 7.79(d,J=6.4Hz,2H), 7.73(d,J=8.0Hz,2H), 7.51-7.41(m,5H), 6.13(s,1H), 4.51(dd, J=46.8,6.0Hz,2H), 4.17-3.37(m,4H), 2.92-2.83(m,1H), 2.70-2.60(m,1H), 1.83-1.80(m,4H), 1.74 -1.71(m,1H), 1.52-1.36(m,4H), 1.32-1.24(m,1H);LCMS(ESI):m / z 485.1(M+H) + .

[0383] Example 38 Preparation of 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(oxazol-5-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000160.jpg44170 The title compound (43.0 mg, 22%) was prepared from 2-bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (200 mg, 0.41 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (161 mg, 0.82 mmol) following the procedure outlined for Example 36. 1H NMR(400MHz,DMSO-d6):δ 8.46(s,1H), 7.96-7.93(m,2H), 7.79(s,1H), 7.31(d,J=7.6Hz,2H), 6.09(s,1H), 4.62(dd,J=47.2,5.6Hz,2H), 4.37-4.03(m,3H), 3.84-3.8 2(m,1H), 2.97-2.94(m,1H), 2.58-2.55(m,1H), 1.82-1.80(m,4H), 1.73-1.70(m,1H), 1.48-1.34(m,4H), 1.30-1.21(m,1H);LCMS(ESI):m / z 476.2(M+H) + .

[0384] Example 39 Preparation of 5-(4-cyclohexylphenyl)-3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and 5-(4-cyclohexylphenyl)-3-((2R,3R)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one The general reaction scheme was as follows: JPEG0007759877000161.jpg159170

[0385] Step 1: cis-2-bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)-2-methylazetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000162.jpg45170 The title compound (700 mg, 64%) was prepared from 2-bromo-5-(4-cyclohexylphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (900 mg, 2.16 mmol) and cis-3-(fluoromethyl)-2-methylazetidine 2,2,2-trifluoroacetate (939 mg, 4.32 mmol) following the procedure outlined for Intermediate A, Step 5. 1H NMR(400MHz,DMSO-d6):δ 12.65(br s,1H), 7.69(d,J=8.4Hz,2H), 7.44(d,J=8.4Hz,2H), 6.13(m,1H), 4.82-4.57(m,3H), 4.05-3.97(m,1H), 3.88-3.79(m ,1H), 3.03-2.98(m,1H), 2.63-2.60(m,1H), 1.82-1.79(m,4H), 1.73-1.70(m,1H), 1.51-1.20(m,8H).LCMS(ESI):m / z 501.2(M+H) + .

[0386] Step 2: cis-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000163.jpg46170 The title compound (100 mg, 66%) was prepared from cis-2-bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)-2-methylazetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (150 mg, 0.30 mmol) and 2-(tributylstannyl)pyrazine (220 mg, 0.60 mmol) following the procedure outlined for Example 7, Step 2.

[0387] Step 3: 5-(4-cyclohexylphenyl)-3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and 5-(4-cyclohexylphenyl)-3-((2R,3R)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000164.jpg45170 cis-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one was purified by preparative SFC (conditions: DAICEL CHIRALPAK AD-H (250 mm * Separation using a 30 mm, 5 μm (0.1% NH₃H₂O / EtOH) afforded Isomer A (5-(4-cyclohexylphenyl)-3-[(2S,3S)-3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-2-pyrazin-2-yl-4H-pyrazolo[1,5-a]pyrimidin-7-one; 19 mg, 14%) and Isomer B (5-(4-cyclohexylphenyl)-3-((2R,3R)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 19 mg, 14%).

[0388] Isomer A, second peak in SFC; 1 H NMR (400MHz, DMSO-d6): δ 12.73(br s,1H), 9.20-9.19(m 1H), 8.77-8.68(m,2H), 7.77-7.74(m,2H), 7.41(br d,J=7.2Hz,2H), 6.12(s,1H), 4.75-4.48(m,3H), 4.20-3.62(m,2H), 2.98-2.94(m,1H), 2. 62-2.60(m,1H), 1.83-1.80(m,4H), 1.74-1.70(m,1H), 1.47-1.24(m,8H);LCMS(ESI):m / z 501.2(M+H) + .

[0389] Isomer B, the fourth peak in SFC; 1H NMR(400MHz,DMSO-d6):δ 12.73(br s,1H), 9.20-9.18(m,1H), 8.76-8.69(m,2H), 7.78-7.76(m,2H), 7.41(d,J=7.6Hz,2H), 6.12(s,1H), 4.72-4.54(m,3H), 4.19 -3.56(m,2H), 2.97-2.93(m,1H), 2.62-2.60(m,1H), 1.83-1.80(m,4H), 1.74-1.70(m,1H), 1.48-1.30(m,8H);LCMS(ESI):m / z 501.2(M+H) + .

[0390] Example 40 Preparation of 5-(4-cyclohexylphenyl)-3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and 5-(4-cyclohexylphenyl)-3-((2R,3R)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000165.jpg45170

[0391] Step 1: cis-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000166.jpg45170 The title compound (30 mg, 20%) was prepared from cis-2-bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)-2-methylazetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (from Example 39, 150 mg, 0.30 mmol) and 2-(tributylstannyl)pyrimidine (220 mg, 0.60 mmol) following the procedure outlined for Example 7, Step 2. LCMS (ESI): m / z 501.2 (M+H) + .

[0392] Step 2: 5-(4-cyclohexylphenyl)-3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and 5-(4-cyclohexylphenyl)-3-((2R,3R)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000167.jpg46170 cis-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one was purified by SFC (conditions: DAICEL CHIRALCEL OJ-H (250 mm * Separation by SFC (column: Phenomenex-Amylose-1 (250 mm, 5 μm), 0.1% NH3HO MeOH) gave isomer A (5-(4-cyclohexylphenyl)-3-((2R,3R)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; fourth peak in SFC, 4.6 mg, 11%) as a white solid and a crude second peak. * Further purification by HPLC using a 0.1% NH3HO / MeOH column (30 mm, 5 um); conditions: 0.1% NH3HO / MeOH) afforded isomer B (5-(4-cyclohexylphenyl)-3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 8.2 mg, 20%) as a white solid.

[0393] Isomer A, fourth peak in SFC; 1H NMR(400MHz,DMSO-d6):δ 8.86-8.83(m,2H), 7.97-7.95(m,2H), 7.44-7.42(m,1H), 7.30(d,J=7.6Hz,2H), 6 .06(s,1H), 4.79-4.56(m,3H), 4.22-3.95(m,2H), 2.99-2.96(m,1H), 2.52-2.50(m 1H), 1.84-1.80(m,4H), 1.74 -1.70(m,1H), 1.50-1.35(m,8H).LCMS(ESI):m / z 501.2(M+H) + .

[0394] Isomer B, second peak in SFC; 1 H NMR(400MHz,DMSO-d6):δ 8.87-8.85(m,2H), 7.97-7.96(m,2H), 7.48-7.46(m,1H), 7.33(d,J=7.2Hz,2H), 6.15(s,1H), 4.79-4.58(m,3H), 4.34-3.65(m,2H) , 3.01-2.98(m,1H), 2.62-2.56(m,1H), 1.85-1.82(m,4H), 1.74-1.70(m,1H), 1.52-1.30(m,7H), 1.29-1.27(m,1H).LCMS(ESI);m / z 501.3(M+H) + .

[0395] Example 41 Preparation of 5-(4-cyclohexylphenyl)-3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and 5-(4-cyclohexylphenyl)-3-((2R,3R)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000168.jpg45170

[0396] Step 1: cis-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000169.jpg46170 The title compound (140 mg, 54%) was prepared from cis-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (250 mg, 0.50 mmol) and 2-methyl-3-(tributylstannyl)pyrazine (286 mg, 0.75 mmol) following the procedure outlined for Example 7, Step 2. LCMS (ESI): m / z 515.2 (M+H) + .

[0397] Step 2: 5-(4-cyclohexylphenyl)-3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and 5-(4-cyclohexylphenyl)-3-((2R,3R)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000170.jpg46170 cis-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one was purified by SFC (column: DAICEL CHIRALPAK IG (250 mm) *30 mm, 10 μm; Conditions: 0.1% NH3H2O ​​ETOH to give isomer A (5-(4-cyclohexylphenyl)-3-((2R,3R)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; fourth peak in SFC, 23.7 mg, 24%) as a white solid and a crude second peak, which was purified by SFC (DAICEL CHIRALPAK AD (250 mm) * Further separation with 30 mm, 10 um), 0.1% NH3HO ETOH, 40%) afforded isomer B (5-(4-cyclohexylphenyl)-3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 19.0 mg, 19%) as a white solid.

[0398] Isomer A, fourth peak in SFC; 1 H NMR(400MHz,DMSO-d6):δ 8.48-8.45(m,2H), 7.96-7.64(m,2H), 7.33-7.28(m,2H), 6.11(s,1H), 4.89-4.39(m,3H), 3.90-3.86(m,2H) ), 2.97-2.58(m,2H), 2.53(s,3H), 1.80-1.76(m,4H), 1.71-1.68(m,1H), 1.49-1.11(m,8H).LCMS(ESI):m / z 515.3(M+H) + .

[0399] Isomer B, second peak in SFC; 1H NMR (400MHz, DMSO-d6): δ 12.40 (br s, 1H), 8.54-8.50 (m 2H), 7.79-7.77(m,2H), 7.38-7.36(m,2H), 6.10(s,1H), 4.75-4.27(m,3H), 3.86-3.84(m,2H), 2.87-2. 86(m,2H), 2.58-2.56(m,3H), 1.80-1.76(m,4H), 1.70-1.68(m,1H), 1.48-1.21(m,8H);LCMS(ESI):m / z 515.3(M+H) + .

[0400] Example 42 Preparation of 5-(4-(cyclopentylmethyl)phenyl)-3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and 5-(4-(cyclopentylmethyl)phenyl)-3-((2R,3R)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000171.jpg45170

[0401] Step 1: cis-5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000172.jpg44170 The title compound (250 mg, 70%) was prepared from cis-2-bromo-5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)-2-methylazetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (350.0 mg, 0.70 mmol) and 2-methyl-3-(tributylstannyl)pyrazine (401.0 mg, 1.05 mmol) following the procedure outlined for Example 7, Step 2.

[0402] Step 2: 5-(4-(cyclopentylmethyl)phenyl)-3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and 5-(4-(cyclopentylmethyl)phenyl)-3-((2R,3R)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000173.jpg45170 cis-5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one was purified by SFC (conditions: Phenomenex-Amylose-1 (250 mm * 30mm, 5um), Supercritical DAICEL CHIRALPAK IG (250mm * Separation by SFC (conditions: Phenomenex-Amylose-1 (250 mm, 10 μm) 0.1% NH3H2O ​​EtOH) gave isomer A (5-(4-(cyclopentylmethyl)phenyl)-3-((2R,3R)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; fourth peak by SFC, 23.6 mg, 11%) and crude second peak, which were separated by SFC (conditions: Phenomenex-Amylose-1 (250 mm * Further purification using a 30 mm, 5 μm column, Supercritical 0.1% NH3HO, EtOH afforded Isomer B (5-(4-(cyclopentylmethyl)phenyl)-3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 20.6 mg, 9%) as a white solid.

[0403] Isomer A, 1H NMR(400MHz,DMSO-d6):δ 12.41(s,1H), 8.66-8.48(m,2H), 7.90-7.70(m,2H), 7.45-7.31(m,2H), 6.17(s,1H), 4.74-4.49(m,4H), 3.91-3.83(m,1H), 2.9 8-2.86(m,1H), 2.73-2.62(m,5H), 2.17-2.12(m,1H), 1.73-1.59(m,4H), 1.55-1.46(m,2H), 1.33-1.13(m,5H);LCMS(ESI):m / z 515.2(M+H) + .

[0404] isomer B, 1 H NMR(400MHz,DMSO-d6):δ 12.48(s,1H), 8.65-8.54(m,2H), 7.80-7.70(m,2H), 7.39(d,J=7.6Hz,2H), 6.17(s,1H), 4.70-4.35(m,4H), 3.89-3.83(m,1H), 2 .95-2.86(m,1H), 2.76-2.60(m,5H), 2.14-2.09(m,1H), 1.71-1.57(m,4H), 1.54-1.44(m,2H), 1.33-1.17(m,5H);LCMS(ESI):m / z 515.1(M+H) + .

[0405] Example 43 Preparation of 5-(4-(cyclopentylmethyl)phenyl)-3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and 5-(4-(cyclopentylmethyl)phenyl)-3-((2R,3R)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000174.jpg45170

[0406] Step 1: cis-5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000175.jpg44170 The title compound (160 mg, 64%) was prepared from cis-2-bromo-5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)-2-methylazetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (250 mg, 0.50 mmol) and 2-(tributylstannyl)pyrimidine (369 mg, 1.0 mmol) following the procedure outlined for Example 7, Step 2.

[0407] Step 2: 5-(4-(cyclopentylmethyl)phenyl)-3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and 5-(4-(cyclopentylmethyl)phenyl)-3-((2R,3R)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000176.jpg45170 cis-5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one was purified by SFC (conditions: DAICEL CHIRALCEL OJ-H (250 mm * The resulting cis racemate (90 mg) was purified by preparative SFC (Phenomenex-Amylose-1 (250 mm, 5 μm), Supercritical Fluid 0.1% NH3H2O, MeOH) to remove trace amounts of the trans azetidine isomer (30 mg). *Further dissolution in 30 mm, 5 μm, Supercritical 0.1% NH3HO / MeOH afforded Isomer A (5-(4-(cyclopentylmethyl)phenyl)-3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; first peak by SFC, 12.8 mg, 14%) and Isomer B (5-(4-(cyclopentylmethyl)phenyl)-3-((2R,3R)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; second peak by SFC, 8.6 mg, 10%), both as white solids.

[0408] Isomer A, 1 H NMR (400 MHz, DMSO-d): δ 12.69(s,1H), 8.95(d,J=4.8Hz,2H), 7.80-7.64(m,2H), 7.58-7.50(m,1H), 7.38(d,J=7.6Hz,2H), 6.10(s,1H), 4.72-4.24(m,3H), 4.10-3.52(m,2H), 2 .98-2.85(m,1H), 2.67(d,J=7.6Hz,2H), 2.18-2.06(m,1H), 1.71-1.57(m,4 H), 1.56-1.43(m,3H), 1.27-1.13(m,3H), 1.09-0.91(m,1H);LCMS(ESI):m / z 501.3(M+H) + .

[0409] isomer B, 1H NMR (400 MHz, DMSO-d): δ 12.70(s,1H), 8.97-8.82(m,2H), 7.98-7.81(m,2H), 7.52-7.43(m,1H), 7 .36-7.24(m,2H), 6.08(s,1H), 4.89-4.57(m,3H), 4.10-3.83(m,2H), 2.99 -2.86(m,1H), 2.64(d,J=7.2Hz,2H), 2.12-2.06(m,1H), 1.64-1.57(m,4H) , 1.52-1.45(m,3H), 1.23-1.16(m,3H), 1.06-0.94(m,1H);LCMS(ESI):m / z 501.2(M+H) + .

[0410] Example 44 Preparation of 5-(4-(cyclopentylmethyl)phenyl)-3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and 5-(4-(cyclopentylmethyl)phenyl)-3-((2R,3R)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000177.jpg45170

[0411] Step 1: cis-5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000178.jpg45170 The title compound (100 mg, 50%) was prepared as a white solid from cis-2-bromo-5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)-2-methylazetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (200 mg, 0.40 mmol) and 2-(tributylstannyl)pyrazine (295 mg, 0.80 mmol) following the procedure outlined for Example 7, Step 2.

[0412] Step 2: 5-(4-(cyclopentylmethyl)phenyl)-3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and 5-(4-(cyclopentylmethyl)phenyl)-3-((2R,3R)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000179.jpg45170 cis-5-(4-(cyclopentylmethyl)phenyl)-3-(3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one was purified by preparative SFC (DAICEL CHIRALCEL OJ-H (250 mm * Separation by SFC (Phenomenex-Amylose-1 (250 mm, 5 μm), Supercritical Fluid 0.1% NH3H2O ​​MeOH) gave Isomer A (4th peak in SFC, 24.7 mg, 25%) as a white solid and the crude of the 2nd peak. * Further purification with 30 mm, 5 μm), 0.1% NH 3 H 2 O (EtOH) gave Isomer B (second peak in SFC, 25.2 mg, 25%) as a white solid.

[0413] Isomer A, the fourth peak in SFC (OJ). 1H NMR (400 MHz, DMSO-d): δ 12.78(s,1H), 9.22(s,1H), 8.86-8.64(m,2H), 7.73(d,J=7.2Hz,2H), 7.40 (d,J=7.6Hz,2H), 6.14(s,1H), 4.72-4.28(m,3H), 4.10-3.64(m,2H), 3.02 -2.87(m,1H), 2.67(d,J=7.6Hz,2H), 2.21-2.06(m,1H), 1.71-1.56(m,4H) , 1.56-1.41(m,3H), 1.26-1.15(m,3H), 1.05-1.85(m,1H).LCMS(ESI):m / z 501.3(M+H) + .

[0414] Isomer B, the second peak in SFC (OJ). 1 H NMR (400 MHz, DMSO-d): δ 12.74(s,1H), 9.22(s,1H), 8.87-8.63(m,2H), 7.73(d,J=7.6Hz,2H), 7.40 (d,J=7.6Hz,2H), 6.13(s,1H), 4.72-4.52(m,3H), 4.10-3.50(m,2H), 2.98 -2.89(m,1H), 2.67(d,J=7.6Hz,2H), 2.18-2.07(m,1H), 1.70-1.58(m,4H) , 1.54-1.43(m,3H), 1.24-1.17(m,2H), 1.08-0.84(m,1H).LCMS(ESI):m / z 501.2(M+H) + .

[0415] Example 45 Preparation of 3-(3-(fluoromethyl)azetidine-1-carbonyl)-5-((4-isopropylbenzyl)oxy)-2-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000180.jpg45170 The title compound (3 mg, 2%) was prepared from 2-bromo-3-(3-(fluoromethyl)azetidine-1-carbonyl)-5-((4-isopropylbenzyl)oxy)pyrazolo[1,5-a]pyrimidin-7(4H)-one (100 mg, 0.21 mmol) and 2-(tributylstannyl)pyrazine (154 mg, 0.42 mmol) following the procedure outlined for Example 7, Step 2. 1 H NMR(400MHz,CD3OD):δ 9.19(s,1H), 8.64-8.62(m,1H), 8.55-8.53(m,1H), 7.36(d,J=8.0Hz,2H), 7.23(d,J=8.0Hz,2H), 5.45-5.30(m,3H), 4.62-4. 49(m,2H), 4.30-4.25(m,2H), 4.21-4.12(m,1H), 3.99-3.97(m,1H), 3.03-2.83(m,2H), 1.24(d,J=7.2Hz,6H);LCMS(ESI):m / z 477.2(M+H) + .

[0416] Example 46 Preparation of 5-((4-(Tert-butyl)benzyl)oxy)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000181.jpg44170

[0417] Step 1: 2-Bromo-5-((4-(tert-butyl)benzyl)oxy)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one The title compound (100 mg, 21%) was prepared from ethyl 7-(benzyloxy)-2-bromo-5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (350 mg, 0.96 mmol) and (4-(tert-butyl)phenyl)methanol (240 mg, 1.44 mmol) following the procedure outlined for Intermediate J, steps 2-3. LCMS (ESI): m / z 490.9 (M+H) + .

[0418] Step 2: 5-((4-(Tert-butyl)benzyl)oxy)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(pyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000183.jpg46170 The title compound (20 mg, 16%) was prepared from 2-bromo-5-((4-(tert-butyl)benzyl)oxy)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (120 mg, 0.24 mmol) and 2-(tributylstannyl)pyrazine (180 mg, 0.49 mmol) following the procedure outlined for Example 7, Step 2. 1 H NMR(400MHz,DMSO-d6):δ 9.12(s,1H), 8.72-8.70(m,1H), 8.67(d,J=2.4Hz,1H), 7.45-7.43(m,4H), 5.47(br s,1H), 5.29(s,2H), 4.52(dd,J=47.2,5.6Hz,2H), 4.11-3.57(m,4H), 2.91-2.89(m,1H), 1.28(s,9H);LCMS(ESI):m / z 491.1(M+H) + .

[0419] Example 47 Preparation of 5-((4-(Tert-butyl)benzyl)oxy)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one To a mixture of 5-chloro-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (70 mg, 0.19 mmol) in 1,4-dioxane (7 mL) was added NaH (15 mg, 0.38 mmol, 60% in mineral oil). The mixture was stirred at room temperature for 15 minutes, then (4-(tert-butyl)phenyl)methanol (48 mg, 0.29 mmol) and t-BuONa (37 mg, 0.39 mmol). The mixture was stirred at 100° C. for 20 hours and then poured into water (50 mL). The mixture was adjusted to pH 6 by the addition of 1 M aqueous HCl. The aqueous phase was lyophilized and the mixture was analyzed by reversed-phase HPLC (isocratic, water modified with 0.04% NH3H2O ​​and 10 mM NH4HCO3-MeCN, Xtimate C18 10μ 250mm * Purification by 50 mm column) gave the title compound (5.6 mg, 6%) as a white solid. 1 H NMR(400MHz,CD3OD):δ 8.85-8.83(m,2H), 7.45-7.39(m,5H), 5.38-5.33(m,3H), 4.54(dd,J=47.2,5.6Hz,2H) , 4.30-4.09(m,2H), 4.01-3.95(m,2H), 3.03-2.88(m,1H), 1.33(s,9H).LCMS(ESI):m / z 491.3(M+H) + .

[0420] Example 48 Preparation of 5-(4-(4,4-difluorocyclohexyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000185.jpg46170

[0421] Step 1: 4'-chloro-4,4-difluoro-2,3,4,5-tetrahydro-1,1'-biphenyl A mixture of 2-(4,4-difluorocyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (702 mg, 2.87 mmol), 1-bromo-4-chlorobenzene (500 mg, 2.61 mmol), Na2CO3 (831 mg, 7.83 mmol), and Pd(dppf)Cl2 (191 mg, 0.26 mmol) in 1,4-dioxane (6 mL) was stirred at 100 °C for 16 h under a nitrogen atmosphere. The reaction mixture was then diluted with water (30 mL), and the resulting solution was extracted with EtOAc (30 mL × 2). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether to give the title compound (550 mg, 92%) as a white solid. 1 H NMR (400MHz, CDCl3): δ 7.31-7.29(m,4H), 5.92-5.90(m,1H), 2.78-2.65(m,4H), 2.25-2.14(m,2H).

[0422] Step 2: 2-(4',4'-difluoro-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A mixture of 4'-chloro-4,4-difluoro-2,3,4,5-tetrahydro-1,1'-biphenyl (550 mg, 2.41 mmol), Xphos Pd G3 (203 mg, 0.24 mmol), and Xphos (115 mg, 0.24 mmol), B2Pin2 (1.07 g, 4.2 mmol), and KOAc (709 mg, 7.23 mmol) in 1,4-dioxane was stirred at 100° C. for 16 hours. The resulting solution was quenched with water (30 mL), extracted with EtOAc (30 mL × 2), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / EtOAc (100:3) to give the title compound (500 mg, 65%) as a yellow solid. 1H NMR (400MHz, CDCl3): δ 7.78(d,J=8.0Hz,2H), 7.38(d,J=8.4Hz,2H), 5.97(s,1H), 2.76-2.71(m,4H), 2.24-2.12(m,2H), 1.35(s,12H).

[0423] Step 3: 2-(4-(4,4-difluorocyclohexyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a mixture of 2-(4',4'-difluoro-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg, 1.56 mmol) in methanol (10 mL) was added 10% Pd on carbon (333 mg, 0.31 mmol), and the mixture was stirred under a hydrogen atmosphere (1 atm) at 20° C. for 16 hours. The reaction mixture was filtered and concentrated to give the title compound (440 mg, 87%) as a white solid. 1 H NMR (400MHz, CDCl3): δ 7.77(d,J=8.0Hz,2H), 7.24(d,J=8.0Hz,2H), 2.65-2.53(m,1H), 2.28-2.16(m,2H), 1.97-1.79(m,6H), 1.34(s,12H).

[0424] Step 4: 5-(4-(4,4-difluorocyclohexyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one To a mixture of 5-chloro-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (100 mg, 0.28 mmol) in DMSO (5 mL) and water (0.5 mL) was added Xphos Pd G3 (24 mg, 0.03 mmol), Xphos (14 mg, 0.03 mmol), 2-[4-(1-cyclopentylcyclopropyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (130 mg, 0.41 mmol), and Na2CO3 (89 mg, 0.83 mmol), and the mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature and then adjusted to pH 4 with 1 M aqueous HCl. The solution was extracted with EtOAc (20 mL × 3) and washed with water (30 mL × 2). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (5% MeOH in DCM) to give the title compound (8.6 mg, 6%) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 12.35(s,1H), 8.58(d,J=7.2Hz,2H), 7.74(d,J=8.0Hz,2H), 7.45(d,J=8.0Hz,2H), 6.16(s,1H), 4.46(dd,J=46.8,5 .6Hz,2H), 4.00-3.59(m,4H), 2.82-2.78(m,2H), 2.63(s,3H), 2.11-1.91(m,6H), 1.74-1.68(m,2H);LCMS(ESI):m / z 537.1(M+H) + .

[0425] Example 49 Preparation of 5-(4-(cyclopentyldifluoromethyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one The general reaction scheme was as follows: JPEG0007759877000190.jpg137170

[0426] Step 1: Cyclopentanecarbonyl chloride To a stirred solution of cyclopentanecarboxylic acid (10.0 g, 87.6 mmol) in DCM (100 mL) was added SOCl (14.8 mL, 175.22 mmol). The mixture was stirred at 0 °C under a nitrogen atmosphere for 15 h. The reaction was concentrated to give the title compound (10 g, 86%) as a yellow oil, which was used without further purification.

[0427] Step 2: (4-Bromophenyl)(cyclopentyl)methanone To a solution of AlCl3 (10.0 g, 75.4 mmol) and bromobenzene (17.76 g, 113.13 mmol) was added cyclopentanecarbonyl chloride (10.0 g, 75.42 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 15 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (0-5% EtOAc in petroleum ether) to give the title compound (9.5 g, 73%) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ 7.83(d,J=8.8Hz,2H), 7.58(d,J=8.8Hz,2H), 3.68-3.60(m,1H), 1.91-1.88(m,4H), 1.70-1.64(m,4H).

[0428] Step 3: 2-(4-bromophenyl)-2-cyclopentyl-1,3-dithiolane To a stirred solution of 32170(4-bromophenyl)(cyclopentyl)methanone (1.0 g, 3.95 mmol) in DCM (15 mL) was added BF3·Et2O (1.4 mL, 11.1 mmol) and ethane-1,2-dithiol (655 mg, 6.95 mmol) and stirred at 20 °C for 16 h. The mixture was diluted with DCM (50 mL). The organic phase was then washed with 10% aqueous NaOH (40 mL), followed by water and brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with 0–5% EtOAc in petroleum ether) to afford the title compound (1.1 g, 85%) as a colorless oil. 1 H NMR(400MHz,CDCl3):δ 7.69(d,J=8.4Hz,2H), 7.42(d,J=8.4Hz,2H), 3.35-3.26(m,2H), 3.16-3.04(m,2H), 2.75-2.65(m,1H), 1.73-1.56(m,4H), 1.53-1.38(m,4H).

[0429] Step 4: 1-Bromo-4-(cyclopentyldifluoromethyl)benzene To a mixture of 2-(4-bromophenyl)-2-cyclopentyl-1,3-dithiolane (100 mg, 0.30 mmol) and NIS (137 mg, 0.61 mmol) in DCM (5 mL) at −70° C. was added 70% pyridine hydrofluoride in pyridine (0.11 mL, 1.21 mmol). After stirring at −70° C. for 15 min, the reaction mixture was filtered through Al2O3 and washed with hexane. The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether) to give the title compound (30 mg, 36%) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ 7.47(d,J=8.4Hz,2H), 7.26(d,J=8.4Hz,2H), 2.53-2.50(m,1H), 1.63-1.47(m,8H).

[0430] Step 5: 2-(4-(cyclopentyldifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane JPEG0007759877000195.jpg32170 The title compound (100 mg, 50%) was prepared from 1-bromo-4-(cyclopentyldifluoromethyl)benzene (170 mg, 0.62 mmol) following the procedure outlined for Example 48, Step 2. 1 H NMR (400MHz, CDCl3): δ 7.85(d,J=8.4Hz,2H), 7.47(d,J=8.4Hz,2H), 2.63-2.60(m,1H), 1.68-1.53(m,8H), 1.36(s,12H).

[0431] Step 6: 5-(4-(cyclopentyldifluoromethyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000196.jpg46170 The title compound (17 mg, 24%) was prepared from 2-(4-(cyclopentyldifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (43 mg, 0.13 mmol) and 5-chloro-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (50 mg, 0.13 mmol) following the procedure outlined for Example 48, Step 4. 1 H NMR(400MHz,DMSO-d6):δ 8.50-8.48(m,2H), 8.18(d,J=8.0Hz,2H), 7.58(d,J=8.0Hz,2H), 6.19(s,1H), 4.66(dd,J=47.2,5.2Hz,2H) , 4.49-4.14(m,2H), 4.12-3.64(m,2H), 3.03-2.75(m,2H), 2.42(s,3H), 1.73-1.52(m,8H);LCMS(ESI):m / z 537.2(M+H) + .

[0432] Example 50 Preparation of 5-(4-(1-cyclopentylcyclopropyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000197.jpg41170 The title compound (8.62 mg, 6%) was prepared from 5-chloro-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (100 mg, 0.28 mmol) and 2-(4-(1-cyclopentylcyclopropyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (129 mg, 0.41 mmol) following the procedure outlined for Step 4 of Example 48. 1 H NMR (400 MHz, DMSO-d): δ 8.90-8.80(m,2H), 8.00-7.80(m,2H), 7.50-7.40(m,1H), 7.36(d,J=7.6H z,2H), 6.05(s,1H), 4.67(dd,J=47.2,5.2Hz,2H), 4.22-3.59(m,4H), 3.0 0-2.80(m,2H), 1.95-1.80(m,1H), 1.70-1.55(m,2H), 1.50-1.35(m,4H), 1.21-1.09(m,2H), 0.73-0.71(m,2H), 0.67-0.65(m,2H);LCMS(ESI):m / z 513.2(M+H) + .

[0433] Example 51 Preparation of 5-(4-butylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000198.jpg45170 The title compound (3.68 mg, 6%) was prepared from 1-bromo-4-butylbenzene and 5-chloro-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one following the procedure outlined for Example 48, steps 2 and 4. 1 H NMR(400MHz,DMSO-d6):δ 12.30(s,1H), 8.60-8.55(m,2H), 7.88-7.78(m,2H), 7.39-7.33(m,2H), 6.16(s,1H), 4.59-4.47(m,2H), 3.99-3.72(m,4H), 2. 92-2.91(m,2H), 2.66(s,3H), 2.52-2.48(m,1H), 1.62-1.58(m,2H), 1.36-1.15(m,2H), 0.93(t,J=7.2Hz,3H);LCMS(ESI):m / z 475.2(M+H) + .

[0434] Example 52 Preparation of 5-(4-(1-fluorocyclohexyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one The general reaction scheme was as follows: JPEG0007759877000199.jpg115170

[0435] Step 1: 1-(4-bromophenyl)cyclohexanol A mixture of 1,4-dibromobenzene (5.00 g, 21.2 mmol) in THF (50 mL) was cooled to −78° C., and then n-BuLi (9.33 mL, 23.31 mmol) was added under a nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 1 hour, at which point cyclohexanone (2.29 g, 23.31 mmol) was added to the mixture. The reaction was then slowly warmed to 0° C. and stirred for an additional hour. The reaction mixture was then quenched with water (10 mL). The resulting solution was extracted with ethyl acetate (50 × 2 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to provide the title compound (1 g, 18%) as a colorless solid. 1 H NMR (400MHz, CDCl3): δ 7.47(d,J=8.4Hz,2H), 7.40(d,J=8.4Hz,2H), 1.82-1.64(m,9H), 1.37-1.23(m,1H).

[0436] Step 2: 1-Bromo-4-(1-fluorocyclohexyl)benzene JPEG0007759877000201.jpg251701-(4-Bromophenyl)cyclohexanol (2.00 g, 7.84 mmol) in dichloromethane (20 mL) was added DAST (3.79 g, 23.52 mmol) at −78° C. The mixture was stirred at −78° C. for 4 hours. The reaction was quenched by the addition of water (5 mL). The resulting solution was extracted with dichloromethane (50 mL), dried over NaSO, filtered, and concentrated in vacuo to give the crude title compound (2 g) as a colorless oil, which was used directly without further purification.

[0437] Step 3: 2-(4-(1-fluorocyclohexyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A mixture of 1-bromo-4-(1-fluorocyclohexyl)benzene (200.0 mg, 0.78 mmol), Pd(dppf)Cl, KOAc (229.0 mg, 2.33 mmol), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (395.0 mg, 1.56 mmol) in 1,4-dioxane (4 mL) was stirred at 100° C. for 16 hours under a nitrogen atmosphere. The resulting solution was extracted with EtOAc (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (30:1) to afford the title compound (140.0 mg, 59% over two steps) as a white solid.

[0438] Step 4: 5-(4-(1-fluorocyclohexyl)phenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000203.jpg45170 The title compound (11.89 mg, 14%) was prepared from 5-chloro-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (100 mg, 0.16 mmol) and 2-(4-(1-fluorocyclohexyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (122 mg, 0.24 mmol) following the procedure outlined for Example 48, Step 4. 1 H NMR(400MHz,DMSO-d6):δ 8.60-8.40(m,2H), 8.14-7.85(m,2H), 7.58-7.45(m,2H), 6.16(s,1H), 4.74-3.60(m,6H), 2.98-2 .83(m,1H), 2.53(s,3H), 2.03-1.82(m,4H), 1.75-1.63(m,5H), 1.43-1.32(s,1H);LCMS(ESI):m / z 519.3(M+H) + .

[0439] Example 53 Preparation of 5-([1,1'-biphenyl]-4-yl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000204.jpg40170

[0440] Step 1: 5-(4-chlorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000205.jpg33170 The title compound (3.10 g, 30%) was prepared from 2-bromo-5-(4-chlorophenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (10.0 g, 22.74 mmol) and 2-methyl-3-(tributylstannyl)pyrazine (10.46 g, 27.29 mmol) following the procedure outlined for Intermediate F. 1 H NMR(400MHz,DMSO-d6):δ 8.71-8.51(m,2H), 7.96-7.77(m,2H), 7.67(d,J=6.8Hz,2H), 6.22(s,1H), 4.48(dd,J=46.8,5.2Hz ,2H), 4.05-3.79(m,2H), 3.73-3.48(m,2H), 2.96-2.79(m,1H), 2.77-2.57(m,3H);LCMS(ESI):m / z 453.1(M+H) + .

[0441] Step 2: 5-([1,1'-biphenyl]-4-yl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000206.jpg45170 The title compound (98 mg, 89%) was prepared from 5-(4-chlorophenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-(3-methylpyrazin-2-yl)-4H-pyrazolo[1,5-a]pyrimidin-7-one (100 mg, 0.22 mmol) and 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (67 mg, 0.33 mmol) following the procedure outlined for Example 48, Step 4. 1 H NMR(400MHz,DMSO-d6):δ 12.5(br s,1H), 8.71-7.96(m,4H), 7.85(d,J=7.2Hz,2H), 7.78(d,J=7.2Hz,2H), 7.55-7.48(m,2H), 7.45-7.40(m,1H), 6.27(s ,1H), 4.66-4.49(m,2H), 4.02-3.97(m,2H), 3.87-3.58(m,2H), 2.96-2.89(m,1H), 2.61-2.58(m,3H);LCMS(ESI):m / z 495.2(M+H) + .

[0442] Example 54 Preparation of (R)-1-(5-(4-cyclohexylphenyl)-2-((S)-1-hydroxypropan-2-yl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonyl)pyrrolidine-3-carbonitrile and (R)-1-(5-(4-cyclohexylphenyl)-2-((R)-1-hydroxypropan-2-yl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonyl)pyrrolidine-3-carbonitrile The general reaction scheme was as follows: JPEG0007759877000207.jpg219170

[0443] Step 1: Ethyl 5-(4-cyclohexylphenyl)-7-oxo-2-(3-((triisopropylsilyl)oxy)prop-1-en-2-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate A solution of ethyl 2-bromo-5-(4-cyclohexylphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate (500 mg, 1.13 mmol), triisopropyl-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyloxy]silane (575 mg, 1.69 mmol), Xphos (54 mg, 0.11 mmol), NaCO (358 mg, 3.38 mmol), and Xphos Pd G (96 mg, 0.11 mmol) in DMSO (10 mL) and water (2 mL) in a microwave vial was stirred at 120 °C for 2 h. The reaction mixture was adjusted to pH 6 by the addition of 2 M aqueous HCl and diluted with EtOAc (50 mL). The organic layer was washed with brine (50 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column to give the title compound (220 mg, 34%) as a colorless oil. 1 H NMR(400MHz,DMSO-d6):δ 11.25(s,1H), 7.72(d,J=8.4Hz,2H), 7.46(d,J=8.4Hz,2H), 6.29(s,1H), 5.80(d,J=2.0,1H), 5.76(s,1H), 4.62(s,2H), 4.28 (q,J=7.2Hz,2H), 2.65-2.57(m,1H), 1.86-1.68(m,5H), 1.52-1.24(m,8H), 1.19-1.11(m,3H), 1.08-1.02(d,J=7.2Hz,18H).

[0444] Step 2: Ethyl 5-(4-cyclohexylphenyl)-7-oxo-2-(1-((triisopropylsilyl)oxy)propan-2-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate JPEG0007759877000209.jpg43170 A solution of ethyl 5-(4-cyclohexylphenyl)-7-oxo-2-(3-((triisopropylsilyl)oxy)prop-1-en-2-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate (480 mg, 0.83 mmol) and 10% Pd / C (9 mg, 0.08 mmol) in ethanol (10 mL) was stirred under a hydrogen atmosphere (1 atm) at room temperature for 1 hour. The reaction mixture was filtered and concentrated to give the title compound (0.40 g, 83%) as a colorless oil. LCMS (ESI): m / z 580.4 (M+H) + .

[0445] Step 3: 5-(4-cyclohexylphenyl)-7-oxo-2-(1-((triisopropylsilyl)oxy)propan-2-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid A mixture of ethyl 5-(4-cyclohexylphenyl)-7-oxo-2-(1-((triisopropylsilyl)oxy)propan-2-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate (650 mg, 1.12 mmol) and lithium hydroxide monohydrate (470 mg, 11.21 mmol) in water (10 mL) and EtOH (50 mL) was stirred at 80° C. for 16 hours. The reaction mixture was adjusted to pH 5 with 2 M aqueous HCl, diluted with EtOAc (50 mL), washed with brine (50 mL × 2), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column (5% MeOH in DCM) to give the title compound (450 mg, 73%) as a white solid. LCMS(ESI):m / z 552.2(M+H) + .

[0446] Step 4: (S)-5-(4-cyclohexylphenyl)-7-oxo-2-(1-((triisopropylsilyl)oxy)propan-2-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid and (R)-5-(4-cyclohexylphenyl)-7-oxo-2-(1-((triisopropylsilyl)oxy)propan-2-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid JPEG0007759877000211.jpg441705-(4-Cyclohexylphenyl)-7-oxo-2-(1-((triisopropylsilyl)oxy)propan-2-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (450 mg, 0.82 mmol) was dissolved in a 250 mm SFC (DAICEL CHIRALCEL OD-H) chromatograph. * Separation with 0.1% NH3H2O ​​(EtOH) gave Enantiomer A (1st peak, 200 mg, 44%) as a white solid and Enantiomer B (2nd peak, 200 mg, 44%) as a white solid.

[0447] Step 5: (R)-1-(5-(4-cyclohexylphenyl)-7-oxo-2-(1-((triisopropylsilyl)oxy)propan-2-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonyl)pyrrolidine-3-carbonitrile To a solution of Enantiomer A (200 mg, 0.36 mmol) and HATU (207 mg, 0.54 mmol) in DMF (5 mL) was added DIPEA (468 mg, 3.62 mmol) and stirred for 20 minutes. (3R)-Pyrrolidine-3-carbonitrile hydrochloride (72 mg, 0.54 mmol) was added and the reaction solution was stirred for 2 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with brine (50 mL x 2). The organic layer was purified by preparative TLC (50% ethyl acetate in petroleum ether) to give the title compound (100 mg, 44%) as a white solid. LCMS (ESI): m / z 630.4 (M+H) + .

[0448] Step 6: (R)-1-(5-(4-cyclohexylphenyl)-2-(1-hydroxypropan-2-yl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonyl)pyrrolidine-3-carbonitrile To a stirred solution of (R)-1-(5-(4-cyclohexylphenyl)-7-oxo-2-(1-((triisopropylsilyl)oxy)propan-2-yl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonyl)pyrrolidine-3-carbonitrile (80 mg, 0.13 mmol; obtained from Enantiomer A) in THF (5 mL) was added TBAF (1 M in THF, 0.25 mL, 0.25 mmol). The mixture was stirred at room temperature for 15 hours. The reaction mixture was then diluted with EtOAc (50 mL) and washed with brine (50 mL × 2). The combined organic layers were purified by TLC (10% MeOH in DCM) and HPLC (H2O and water modified with 0.04% NH3 in 10 mM NH4HCO3-MeCN, column) to give the title compound (6.9 mg, 11%) as a white solid.

[0449] Final product obtained using Enantiomer A in step 4: 1 H NMR(400MHz,CD3OD):δ 7.76(d,J=7.6Hz,2H), 7.37(d,J=7.6Hz,2H), 6.16(s,1H), 4.00-3.72(m,6H), 3.45-3.35(m,2H), 2.65-2 .55(m,1H), 2.44-2.23(m,2H), 1.93-1.74(m,5H), 1.55-1.43(m,4H), 1.40-1.30(m,4H);LCMS(ESI):m / z 474.2(M+H) + .

[0450] Steps 5 and 6 were repeated starting with enantiomer B from step 4 to give (R)-1-(5-(4-cyclohexylphenyl)-2-(1-hydroxypropan-2-yl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonyl)pyrrolidine-3-carbonitrile (9.67 mg, 13%).

[0451] Final product obtained using enantiomer B in step 4: 1 H NMR(400MHz,CD3OD):δ 7.84-7.75(m,2H), 7.38-7.33(m,2H), 6.18(s,1H), 4.00-3.90(m,2H), 3.85-3.75(m,4H), 3.46-3.36(m,2H), 2.65-2.55 (m,1H), 2.46-2.25(m,2H), 1.92-1.85(m,4H), 1.83-1.75(m,1H), 1.55-1.42(m,4H), 1.40-1.30(m,4H);LCMS(ESI):m / z 474.2(M+H) + .

[0452] Example 55 Preparation of (S)-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(1-hydroxypropan-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and (R)-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(1-hydroxypropan-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000212.jpg39170

[0453] Step 1: 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-hydroxyprop-1-en-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000213.jpg38170 The title compound (300 mg, 63%) was prepared from 2-bromo-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (500 mg, 1.03 mmol) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-ol (479 mg, 2.6 mmol) following the procedure outlined for Example 54, Step 1.1 H NMR (400 MHz, DMSO-d): δ 12.30(s,1H), 7.69(d,J=7.6Hz,2H), 7.43(d,J=7.6Hz,2H), 6.06(s,1H),5. 68-5.56(m,2H), 5.30-5.10(m,1H), 4.65(dd,J=47.2,5.2Hz,2H), 4.37(s,2H) ), 4.20-4.00(m,2H), 3.85-3.70(m,2H), 3.02-2.86(m,2H), 1.85-1.77(m,4 H), 1.75-1.68(m,1H), 1.47-1.36(m,4H), 1.30-1.22(m,1H);LCMS(ESI):m / z 465.2(M+H) + .

[0454] Step 2: 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(1-hydroxypropan-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000214.jpg38170 The title compound (100 mg, 33%) was prepared from 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-hydroxyprop-1-en-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (300 mg, 0.65 mmol) following the procedure outlined for Example 54, Step 2.

[0455] Step 3: (S)-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(1-hydroxypropan-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one & (R)-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(1-hydroxypropan-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000215.jpg381705-(4-Cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(1-hydroxypropan-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (100 mg, 0.21 mmol) was dissolved in 100 mL of HCl (250 mL) and 100 mL of HCl (250 mL). * Separation using a 30 mm, 10 μm, 0.1% NH₃H₂O / MeOH column gave enantiomer A ((S)-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(1-hydroxypropan-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; first peak by SFC, 18.5 mg, 18%) and enantiomer B ((R)-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(1-hydroxypropan-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; second peak by SFC, 16.7 mg, 17%), both as white solids.

[0456] Enantiomer A, 1 H NMR(400MHz,CD3OD):δ 7.85-7.75(m,2H), 7.43-7.35(m,2H), 6.19(s,1H), 4.68-4.56(m,2H) , 4.38-4.25(m,2H), 4.15-4.00(m,2H), 3.92-3.75(m,2H), 3.46-3.36 (m,1H), 3.10-3.00(m,1H), 2.65-2.59(m,1H), 1.92-1.86(m,4H), 1.81-1.76(m,1H), 1.55-1.44(m,4H), 1.40-1.31(m,4H);LCMS(ESI):m / z 467.2(M+H) + .

[0457] Enantiomer B, 1H NMR (400 MHz, DMSO-d): δ 8.00(d,J=7.6Hz,2H), 7.30(d,J=8.0Hz,2H), 6.23(s,1H), 5.50-5.35( m,1H), 4.67-4.55(m,2H), 4.40-4.05(m,3H), 3.80-3.75(m,1H), 3.60-3 .55(m,2H), 3.50-3.44(m,1H), 3.02-2.89(m,1H), 2.60-2.55(m,1H), 1 .85-1.68(m,5H), 1.48-1.33(m,4H), 1.30-1.20(m,4H);LCMS(ESI):m / z 467.2(M+H) + .

[0458] Example 56 Preparation of 3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)-5-(4-((S)-2,2,2-trifluoro-1-phenylethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and 3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)-5-(4-((R)-2,2,2-trifluoro-1-phenylethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000216.jpg37170

[0459] Step 1: (S)-Ethyl 2-(3-methylpyrazin-2-yl)-7-oxo-5-(4-(2,2,2-trifluoro-1-phenylethoxy)phenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate and (R)-Ethyl 2-(3-methylpyrazin-2-yl)-7-oxo-5-(4-(2,2,2-trifluoro-1-phenylethoxy)phenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate JPEG0007759877000217.jpg37170

[0460] Ethyl 2-(3-methylpyrazin-2-yl)-7-oxo-5-(4-(2,2,2-trifluoro-1-phenylethoxy)phenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate (500 mg, 0.91 mmol) was purified by preparative SFC (conditions: DAICEL CHIRALPAK AS-H (250 mm * Separation with 30 mm, 5 μm, 0.1% NH3H2O ​​(EtOH) gave Enantiomer A (200 mg, 40%, first peak in SFC) and Enantiomer B (200 mg, 40%, second peak in SFC), both as white solids.

[0461] Step 2: 2-(3-methylpyrazin-2-yl)-7-oxo-5-(4-(2,2,2-trifluoro-1-phenylethoxy)phenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid A mixture of Enantiomer A (200 mg, 0.36 mmol) and lithium hydroxide monohydrate (76 mg, 1.82 mmol) in water (10 mL) and ethanol (10 mL) was stirred at 75° C. for 16 hours. The reaction solution was concentrated, adjusted to pH 6 with 1 M aqueous HCl, extracted with EtOAc (50 mL×3), filtered, and concentrated in vacuo to give the title compound (160 mg, 84%) as a brown solid. LCMS (ESI): m / z 522.1 (M+H). + .

[0462] Step 3: 3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)-5-(4-(2,2,2-trifluoro-1-phenylethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one from Enantiomer A To a solution of 2-(3-methylpyrazin-2-yl)-7-oxo-5-(4-(2,2,2-trifluoro-1-phenylethoxy)phenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (60 mg, 0.12 mmol; obtained from enantiomer A) and DIPEA (148 mg, 1.15 mmol) in DMF (5 mL) was added HATU (66 mg, 0.17 mmol), and the reaction mixture was stirred at 25 °C for 30 min. (2S,3S)-3-(fluoromethyl)-2-methyl-azetidine 2,2,2-trifluoroacetate (50 mg, 0.23 mmol) was added, and the solution was stirred for 2 h. The reaction mixture was poured into water (50 mL), extracted with EtOAc (50 mL × 2), washed with brine (50 mL), and concentrated to dryness. The residue was purified by preparative TLC (5% MeOH in DCM) to afford the title compound (15.4 mg, 21%) as a white solid.

[0463] Final product obtained using Enantiomer A from step 1: 1 H NMR(400MHz,DMSO-d6):δ 8.47(s,2H), 7.99(d,J=8.4Hz,2H), 7.64(d,J=6.8Hz,2H), 7.49-7.42(m,3H), 7.10(d,J=8.4Hz,2H), 6.40(q,J= 6.4Hz,1H), 6.04(s,1H), 4.82-3.86(m,5H), 3.11-2.81(m,1H), 2.41(s,3H), 1.23-1.14(m,3H);LCMS(ESI):m / z 607.1(M+H) + .

[0464] Preparation of 3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)-5-(4-(2,2,2-trifluoro-1-phenylethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one from Enantiomer B

[0465] The title compound (14.1 mg, 19%) was provided as a white solid prepared from Enantiomer B (200 mg, 0.36 mmol) following the procedure outlined for steps 2 and 3 above.

[0466] Final product obtained using enantiomer B from step 1: 1 H NMR(400MHz,DMSO-d6):δ 8.47(br s,2H), 7.99(d,J=8.4Hz,2H), 7.64-7.62(d,J=7.2Hz,2H), 7.49-7.42(m,3H), 7.10(d,J=8.4Hz,2H), 6.40(q,J= 6.4Hz,1H), 6.04(s,1H), 4.82-3.88(m,5H), 2.95-2.81(m,1H), 2.42(s,3H), 1.23-1.14(m,3H);LCMS(ESI):m / z 607.1(M+H) + .

[0467] Example 57 Preparation of (S)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)-5-(4-(2,2,2-trifluoro-1-phenylethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and (R)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)-5-(4-(2,2,2-trifluoro-1-phenylethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one To a mixture of (S)-2-(3-methylpyrazin-2-yl)-7-oxo-5-(4-(2,2,2-trifluoro-1-phenylethoxy)phenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (30 mg, 0.06 mmol) and HATU (33 mg, 0.09 mmol) in DMF (1 mL) was added DIPEA (0.05 mL, 0.29 mmol), and the mixture was stirred at 20 °C for 30 minutes. 3-(Fluoromethyl)azetidine hydrochloride (11 mg, 0.09 mmol) was added, and the reaction was stirred at 20 °C for 2 hours. The resulting solution was diluted with water (60 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (8% methanol in dichloromethane) to afford the title compound (18.2 mg, 53%) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 8.49(br s,2H), 8.03(d,J=8.4Hz,2H), 7.63(d,J=7.2Hz,2H), 7.51-7.41(m,3H), 7.13(d,J=8.4Hz,2H), 6.40(q,J=6.4Hz,1 H), 6.06(s,1H), 4.64(dd,J=47.2,6.0Hz,2H), 4.44-3.60(m,4H), 2.97-2.84(m,1H), 2.45(s,3H);LCMS(ESI):m / z 593.1(M+H) + .

[0468] Preparation of (R)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)-5-(4-(2,2,2-trifluoro-1-phenylethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000219.jpg36170 The title compound (14.1 mg, 19%) was provided as a white solid, prepared from (R)-2-(3-methylpyrazin-2-yl)-7-oxo-5-(4-(2,2,2-trifluoro-1-phenylethoxy)phenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (30 mg, 0.06 mmol) and 3-(fluoromethyl)azetidine hydrochloride (11 mg, 0.09 mmol) according to the procedure outlined above. 1 H NMR(400MHz,DMSO-d6):δ 8.49(br s,2H), 8.01(d,J=8.0Hz,2H), 7.63(d,J=7.2Hz,2H), 7.51-7.42(m,3H), 7.12(d,J=8.0Hz,2H), 6.41(q,J=6.4Hz,1 H), 6.05(s,1H), 4.65(dd,J=47.2,6.0Hz,2H), 4.45-3.43(m,4H), 2.95-2.85(m,1H), 2.42(s,3H);LCMS(ESI):m / z 593.1(M+H) + .

[0469] Example 58 Preparation of 5-(4-cyclopentylphenyl)-3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000220.jpg37170

[0470] Step 1: 2-(4-cyclopentylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A mixture of bis(pinacolato)diboron (451 mg, 1.78 mmol), Pd(dppf)Cl2 (130 mg, 0.18 mmol), KOAc (523 mg, 5.33 mmol), and 1-bromo-4-cyclopentyl-benzene (0.4 g, 1.78 mmol) in 1,4-dioxane (5 mL) was stirred at 100 °C for 16 h under a nitrogen atmosphere. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (0-5% EtOAc in petroleum ether) to afford the title compound (300 mg, 62%) as a yellow solid. 1 H NMR(400MHz,CDCl3):δ 7.76(d,J=8.0Hz,2H), 7.28(d,J=8.0Hz,2H), 3.08-2.96(m,1H), 2.16-2.02(m,2H), 1.89-1.77(m,2H), 1.76-1.56(m,4H), 1.36(s,12H).

[0471] Step 2: Ethyl 5-(4-cyclopentylphenyl)-2-(3-methylpyrazin-2-yl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate A mixture of ethyl 5-chloro-2-(3-methylpyrazin-2-yl)-7-oxo-4H-pyrazolo[1,5-a]pyrimidine-3-carboxylate (150 mg, 0.45 mmol), Xphos Pd G2 (35 mg, 0.04 mmol), Xphos (21 mg, 0.04 mmol), Cs2CO3 (439 mg, 1.35 mmol), and 2-(4-cyclopentylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (245 mg, 0.90 mmol) in DMSO (5 mL) and HO (1 mL) was stirred at 120 °C under a nitrogen atmosphere for 16 h. The reaction mixture was diluted with water (10 mL), adjusted to pH 5 with 2 M aqueous HCl, and extracted with EtOAc (10 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (5% methanol in dichloromethane) to give the title compound (110 mg, 55%) as a white solid. 1 H NMR(400MHz,CD3OD):δ 8.63(d,J=2.4Hz,1H), 8.56(d,J=2.4Hz,1H), 7.81(d,J=8.0Hz,2H), 7.49(d,J=8.0Hz,2H), 6.37(s,1H), 4.17(q,J=7.2Hz,2H), 3.20-3.0 5(m,1H), 2.51(s,3H), 2.19-2.06(m,2H), 1.92-1.83(m,2H), 1.81-1.73(m,2H), 1.72-1.60(m,2H), 1.08(t,J=7.2Hz,3H);LCMS(ESI):m / z 444.2(M+H) + .

[0472] Step 3: 5-(4-cyclopentylphenyl)-2-(3-methylpyrazin-2-yl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid A mixture of lithium hydroxide monohydrate (104 mg, 2.48 mmol) and ethyl 5-(4-cyclopentylphenyl)-2-(3-methylpyrazin-2-yl)-7-oxo-4H-pyrazolo[1,5-a]pyrimidine-3-carboxylate (110 mg, 0.25 mmol) in water (5 mL) and EtOH (5 mL) was stirred at 80 °C for 16 hours. The reaction solution was concentrated, adjusted to pH 6 with 1 M aqueous HCl, and then extracted with EtOAc (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (100 mg, 97%) as a white solid. LCMS (ESI): m / z 416.2 (M+H) + .

[0473] Step 4: 5-(4-cyclopentylphenyl)-3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one A solution of 5-(4-cyclopentylphenyl)-2-(3-methylpyrazin-2-yl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (100 mg, 0.24 mmol), DIPEA (0.2 mL, 1.2 mmol), and HATU (194 mg, 0.51 mmol) in DMF (8 mL) was stirred at room temperature for 15 min. Then, (2S,3S)-3-(fluoromethyl)-2-methylazetidine 2,2,2-trifluoroacetate (131 mg, 0.6 mmol, 5% R-isomer) was added, and the mixture was stirred at room temperature for 2 h. The mixture was diluted with water (25 mL), adjusted to pH 6 with 2 M aqueous HCl, and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (MeCN 52%-82% / 0.2% FA in water, Xtimate C18 150 * 40mm * 10 μm, followed by preparative SFC (DAICEL CHIRALPAK AD-H (250 mm* Purification by elution with 30 mm, 5 um), 0.1% NH3H2O ​​IPA, 30%-30%) afforded the title compound (30 mg, 25%) as a white solid. 1 H NMR(400MHz,CD3OD):δ 8.60(d,J=2.4Hz,1H), 8.59(d,J=2.4Hz,1H), 7.76(d,J=8.0Hz,2H), 7.49(d ,J=8.0Hz,2H), 6.25(s,1H), 4.77-3.81(m,5H), 3.67-3.37(m,1H), 3.20-3.0 6(m,1H), 3.00-2.88(m,1H), 2.82(s,3H), 2.19-2.08(m,2H), 1.93-1.83(m,2 H), 1.82-1.72(m,2H), 1.72-1.60(m,2H), 1.50-1.36(m,3H).LCMS(ESI):m / z 501.2(M+H) + .

[0474] Example 59 Preparation of 3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)-5-((E)-non-1-en-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000225.jpg38170

[0475] Step 1: (E)-4,4,5,5-tetramethyl-2-(non-1-en-1-yl)-1,3,2-dioxaborolane In a glovebox under a nitrogen atmosphere, a mixture of HZrCp2Cl (1.08 g, 4.22 mmol), non-1-yne (2.50 mL, 15.47 mmol), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.10 mL, 14.06 mmol) was stirred at 60° C. for 16 hours. The residue was purified by silica gel column chromatography (0-5% EtOAc in petroleum ether) to give the title compound (900 mg, 90% purity) as a colorless oil. 1H NMR(400MHz,CDCl3):δ 6.64-6.60(m,1H), 5.43(d,J=18.0Hz,1H), 2.19-2.11(m,2H), 1.66-1.59(m,2H), 1.29-1.27(m,8H), 1.26(s,12H), 0.85-0.83(m,3H).

[0476] Step 2: (E)-Ethyl 2-(3-methylpyrazin-2-yl)-5-(non-1-en-1-yl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate To a mixture of ethyl 5-chloro-2-(3-methylpyrazin-2-yl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate (200 mg, 0.60 mmol), (E)-4,4,5,5-tetramethyl-2-(non-1-en-1-yl)-1,3,2-dioxaborolane (378 mg, 1.50 mmol) in DMSO (6 mL) and water (1.2 mL) was added Xphos-Pd-G2 (47.0 mg, 0.06 mmol), Xphos (28.0 mg, 0.06 mmol), and Na2CO3 (197 mg, 1.80 mmol), and the mixture was stirred at 110 °C for 16 h under a nitrogen atmosphere. The resulting solution was diluted with water (60 mL), extracted with ethyl acetate (50×2 mL), and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (8% MeOH in DCM) to give the title compound (100 mg, 39%) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 11.64(s,1H), 8.60(d,J=2.4Hz,1H), 8.53(d,J=2.4Hz,1H), 6.95-6.77(m,1H), 6.63(d,J=16.0Hz,1H), 6.20(s,1H), 4.02(q,J=7.2H) z,2H), 2.35(s,3H), 2.26-2.19(m,2H), 1.49-1.39(m,2H), 1.33-1.22(m,8H), 0.91(t,J=7.2Hz,3H), 0.84(t,J=6.8Hz,3H);LCMS:m / z 424.1(M+H)+ .

[0477] Step 3: (E)-2-(3-methylpyrazin-2-yl)-5-(non-1-en-1-yl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid A mixture of (E)-ethyl 2-(3-methylpyrazin-2-yl)-5-(non-1-en-1-yl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate (100 mg, 0.24 mmol), lithium hydroxide monohydrate (99 mg, 2.36 mmol) in water (3 mL) and ethanol (3 mL) was stirred at 80° C. for 16 hours. The reaction solution was concentrated in vacuo, and the pH was adjusted to 4 by adding 4 M aqueous HCl. The resulting solution was extracted with ethyl acetate (40 mL × 2), and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (90 mg, 96%) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 12.93(s,1H), 11.53(s,1H), 8.62(d,J=2.4Hz,1H), 8.57(d,J=2.4Hz,1H), 6.92-6.81(m,1H), 6.74(d,J=16.0Hz,1H) , 6.25(s,1H), 2.41(s,3H), 2.29-2.21(m,2H), 1.53-1.43(m,2H), 1.37-1.22(m,8H), 0.87(t,J=7.2Hz,3H);LCMS:m / z 396.0(M+H) + .

[0478] Step 4: 3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)-5-((E)-non-1-en-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one To a mixture of (E)-2-(3-methylpyrazin-2-yl)-5-(non-1-en-1-yl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (90 mg, 0.23 mmol) and HATU (130 mg, 0.34 mmol) in DMF (2 mL) was added DIPEA (147 mg, 1.14 mmol). The mixture was stirred at 20 °C for 30 minutes. Then, (2S,3S)-3-(fluoromethyl)-2-methylazetidine 2,2,2-trifluoroacetate salt (74 mg, 0.34 mmol) was added. The mixture was stirred at 20 °C for 2 hours. The resulting solution was diluted with water (60 mL) and extracted with ethyl acetate (40 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and then purified by preparative TLC (8% MeOH in DCM) to afford the title compound (80 mg, 72%) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 12.10(s,1H), 8.60-8.58(m,2H), 6.97-6.75(m,1H), 6.46(d,J=13.6Hz,1H), 6.06(s,1H), 4.74-4.21(m,3H), 3.89-3.38(m,2H), 2.9 0-2.78(m,1H), 2.70-2.58(m,3H), 2.28-2.20(m,2H), 1.52-1.42(m,2H), 1.38-1.14(m,11H), 0.86(t,J=6.8Hz,3H);LCMS(ESI):m / z 481.2(M+H) + .

[0479] Example 60 Preparation of 3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)-5-nonylpyrazolo[1,5-a]pyrimidin-7(4H)-one To a mixture of 3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)-5-((E)-non-1-en-1-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (40 mg, 0.08 mmol) in methanol (2 mL) was added 10% Pd on carbon (9 mg, 0.01 mmol) at 15° C. under a hydrogen atmosphere (15 psi). The mixture was stirred for 1 hour and filtered through Celite®. The filtrate was concentrated in vacuo and purified by preparative TLC (8% MeOH in DCM) to afford the title compound (27.2 mg, 67%) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 12.21(s,1H), 8.62(d,J=2.4Hz,1H), 8.60(d,J=2.4Hz,1H), 5.78(s,1H), 4.67-4.20(m,3H), 3.88-3.38(m,2H), 2.88-2. 77(m,1H), 2.67(s,3H), 2.66-2.61(m,2H), 1.73-1.55(m,2H), 1.39-1.14(m,15H), 0.85(t,J=6.8Hz,3H);LCMS(ESI):m / z 483.2(M+H) + .

[0480] Example 61 Preparation of 3-[(2S,3S)-3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-2-(3-methylpyrazin-2-yl)-5-[4-(1,2,2,3,3,4,4,5,5,6,6-undecadeuteriocyclohexyl)phenyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one JPEG0007759877000231.jpg44170

[0481] Step 1: 1-(4-chlorophenyl)-1,2,2,3,3,4,4,5,5,6,6-undecadeuterio-cyclohexane In a glove box, a vial was charged with 1-bromo-4-chlorobenzene (200 mg, 1.04 mmol), (Ir[dF(CF)ppy](dtbpy))PF (12 mg, 0.01 mmol), dry molecular sieves (100 mg), and NaCO (221 mg, 2.09 mmol). 11 A solution of 4,4'-di-tert-butyl-2,2'-dipyridyl (3 mg, 0.01 mmol) of nickel chloride dimethoxyethane adduct (0.19 mL, 1.57 mmol) in anhydrous 1,2-dimethoxyethane (2 mL) was added, followed by tris(trimethylsilyl)silane (390 mg, 1.57 mmol). Meanwhile, a second vial was charged with nickel chloride dimethoxyethane adduct (3 mg, 0.01 mmol) and 4,4'-di-tert-butyl-2,2'-dipyridyl (3 mg, 0.01 mmol). 1,2-Dimethoxyethane (2 mL) was then added. This resulted in the formation of a green, activated Ni catalyst solution. The solution was withdrawn via syringe and transferred to the first vial. The reaction mixture was sealed and removed from the glovebox. The reaction mixture was then stirred at room temperature and irradiated with a 34 W blue LED and cooling fan for 16 h. The reaction was then concentrated in vacuo and purified by preparative TLC (petroleum ether) to afford the title compound (50 mg, 23%) as a colorless oil. 1 H NMR(400MHz, CDCl3) 7.26(d,J=8.4Hz,2H), 7.14(d,J=8.4Hz,2H).

[0482] Step 2: 4,4,5,5-tetramethyl-2-[4-(1,2,2,3,3,4,4,5,5,6,6-undecadeuteriocyclohexyl)phenyl]-1,3,2-dioxaborolane JPEG0007759877000233.jpg41170 Potassium acetate (86 mg, 0.87 mmol) in 1,4-dioxane (5 mL) was treated with Xphos Pd G 3 (25 mg, 0.03 mmol), Xphos (14 mg, 0.03 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (111 mg, 0.44 mmol), and 1-(4-chlorophenyl)-1,2,2,3,3,4,4,5,5,6,6-undecadeuterio-cyclohexane (60 mg, 0.29 mmol) were added. The reaction mixture was then placed under a nitrogen atmosphere and stirred at 100 °C for 16 h. The reaction mixture was concentrated in vacuo and purified by preparative TLC (5% ethyl acetate in petroleum ether) to afford the title compound (40 mg, 46%) as a white solid. 1 H NMR (400MHz, CDCl3): δ 7.48(d,J=8.0Hz,2H), 6.96(d,J=8.0Hz,2H), 1.07(s,12H).

[0483] Step 3: Ethyl 2-(3-methylpyrazin-2-yl)-7-oxo-5-[4-(1,2,2,3,3,4,4,5,5,6,6-undecadeuteriocyclohexyl)phenyl]-4H-pyrazolo[1,5-a]pyrimidine-3-carboxylate A mixture of Xphos Pd G3 (24 mg, 0.03 mmol), ethyl 5-chloro-2-(3-methylpyrazin-2-yl)-7-oxo-4H-pyrazolo[1,5-a]pyrimidine-3-carboxylate (100 mg, 0.30 mmol), 4,4,5,5-tetramethyl-2-[4-(1,2,2,3,3,4,4,5,5,6,6-undecadeuteriocyclohexyl)phenyl]-1,3,2-dioxaborolane (134 mg, 0.45 mmol), sodium carbonate (95 mg, 0.9 mmol), and Xphos (14 mg, 0.03 mmol) in DMSO (4 mL) and water (0.7 mL) was stirred at 110° C. under a nitrogen atmosphere for 16 hours. The mixture was diluted with HO (20 mL), adjusted to pH 6 with 1 M aqueous HCl, and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (5% MeOH in DCM) to give the title compound (40 mg, 29%) as a white solid. LCMS (ESI): m / z 469.3 (M+H) + .

[0484] Step 4: 2-(3-methylpyrazin-2-yl)-7-oxo-5-[4-(1,2,2,3,3,4,4,5,5,6,6-undecadeuteriocyclohexyl)phenyl]-4H-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid JPEG0007759877000235.jpg44170

[0485] To a mixture of ethyl 2-(3-methylpyrazin-2-yl)-7-oxo-5-[4-(1,2,2,3,3,4,4,5,5,6,6-undecadeuteriocyclohexyl)phenyl]-4H-pyrazolo[1,5-a]pyrimidine-3-carboxylate (40 mg, 0.09 mmol) in ethanol (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (36 mg, 0.85 mmol), and the mixture was stirred at 80 °C for 16 hours. The reaction mixture was adjusted to pH 6 with 2 M aqueous HCl and extracted with dichloromethane (50 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (37 mg, 98%) as a yellow solid. LCMS (ESI): m / z 441.3 (M+H). + .

[0486] Step 5: 3-[(2S,3S)-3-(fluoromethyl)-2-methyl-azetidine-1-carbonyl]-2-(3-methylpyrazin-2-yl)-5-[4-(1,2,2,3,3,4,4,5,5,6,6-undecadeuteriocyclohexyl)phenyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one To a solution of 2-(3-methylpyrazin-2-yl)-7-oxo-5-[4-(1,2,2,3,3,4,4,5,5,6,6-undecadeuteriocyclohexyl)phenyl]-4H-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (38 mg, 0.09 mmol) and DIPEA (0.07 mL, 0.43 mmol) in DMF (2 mL) was added HATU (49 mg, 0.13 mmol), and the reaction was stirred for 20 min. Then, (2S,3S)-3-(fluoromethyl)-2-methylazetidine-2,2,2-trifluoroacetate (37 mg, 0.17 mmol) was added, and the reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with 10% aqueous citric acid (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (10% MeOH in DCM) to give the title compound (28 mg, 62%) as a white solid.1 H NMR(400MHz,DMSO-d6):δ 8.48(br s,2H), 7.99(d,J=7.6Hz,2H), 7.30(d,J=7.6Hz,2H), 6.11(s,1H), 4.90-3.8 5(m,5H), 3.01-2.80(m,1H), 2.43(s,3H), 1.36-1.15(m,3H);LCMS(ESI):m / z 526.4(M+H) + .

[0487] Example 62 Preparation of 3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)-5-(4-neopentylphenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000237.jpg37170

[0488] Step 1: 1-Bromo-4-neopentylbenzene A mixture of neopentylbenzene (6.0 g, 40.47 mmol) and bromine (4.5 mL, 86.62 mmol) in 2,2,2-trifluoroacetic acid (60 mL) was stirred at 20 °C for 16 h. The reaction was quenched with aqueous NaHSO (50 mL) and extracted with EtOAc (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether to give the title compound (7 g, 76%) as a colorless oil. 1 H NMR (400MHz, CDCl3): δ 7.38(d,J=8.4Hz,2H), 6.98(d,J=8.4Hz,2H), 2.43(s,2H), 0.88(s,9H).

[0489] Step 2: 4,4,5,5-tetramethyl-2-(4-neopentylphenyl)-1,3,2-dioxaborolane A mixture of Pd(dppf)Cl (1.95 g, 2.63 mmol), 1-bromo-4-neopentylbenzene (2.0 g, 8.81 mmol), KOAc (2.59 g, 26.42 mmol), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.35 g, 13.21 mmol) in 1,4-dioxane was stirred at 100 °C for 16 h under a nitrogen atmosphere. The solution was then quenched with water (50 mL), extracted with EtOAc (50 mL × 2), and washed with water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-2% EtOAc in petroleum ether) to afford the title compound (2.2 g, 91%) as a yellow solid. 1 H NMR (400MHz, CDCl3): δ 7.72(d,J=7.6Hz,2H), 7.15(d,J=7.6Hz,2H), 2.51(s,2H), 1.35(s,12H), 0.90(s,9H).

[0490] Step 3: Ethyl 2-(3-methylpyrazin-2-yl)-5-(4-neopentylphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate A mixture of Xphos Pd G2 (47 mg, 0.06 mmol), ethyl 5-chloro-2-(3-methylpyrazin-2-yl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate (200 mg, 0.60 mmol), 4,4,5,5-tetramethyl-2-(4-neopentylphenyl)-1,3,2-dioxaborolane (328 mg, 1.2 mmol), Na2CO3 (190 mg, 1.8 mmol), and Xphos (29 mg, 0.06 mmol) in DMSO (8 mL) and water (1.5 mL) was stirred at 110 °C under a nitrogen atmosphere for 16 h. The solution was diluted with water (50 mL), extracted with EtOAc (30 mL × 2), and washed with water (50 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-5% MeOH in DCM) to give the title compound (120 mg, 45%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 11.67(s,1H), 8.64(d,J=2.0Hz,1H), 8.60(d,J=2.0Hz,1H), 7.78(d,J=8.0Hz,2H), 7.36(d,J=8.0Hz,2H), 6.3 5(s,1H), 4.11(q,J=7.2Hz,2H), 2.59(s,2H), 2.42(s,3H), 1.07(t,J=7.2Hz,3H), 0.92(s,9H);LCMS(ESI):m / z 446.2(M+H) + .

[0491] Step 4: 2-(3-methylpyrazin-2-yl)-5-(4-neopentylphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid A mixture of lithium hydroxide monohydrate (113 mg, 2.69 mmol) and ethyl 2-(3-methylpyrazin-2-yl)-5-(4-neopentylphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylate (120 mg, 0.27 mmol) in water (4 mL) and ethanol (4 mL) was stirred at 80° C. for 16 hours. The reaction mixture was adjusted to pH 4 with 1 M aqueous HCl. The resulting solution was extracted with EtOAc (30 mL × 2) and washed with water (20 mL). The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (100 mg, 89%) as a white solid. LCMS (ESI): m / z 418.2 (M+H) + .

[0492] Step 5: 3-((2S,3S)-3-(fluoromethyl)-2-methylazetidine-1-carbonyl)-2-(3-methylpyrazin-2-yl)-5-(4-neopentylphenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one To a solution of 2-(3-methylpyrazin-2-yl)-5-(4-neopentylphenyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (100 mg, 0.24 mmol) and HATU (136 mg, 0.36 mmol) in DMF (3 mL) was added DIPEA (0.1 mL, 0.64 mmol) and stirred for 20 minutes. (2S,3S)-3-(fluoromethyl)-2-methylazetidine 2,2,2-trifluoroacetate (78 mg, 0.36 mmol) was added, and the reaction mixture was stirred for an additional 2 hours. The solution was quenched with water (50 mL), extracted with EtOAc (30 mL × 2), and washed with water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (water (0.2% FA)-MeCN, 56-86%, Xtimate C18 150 * 40mm *10 μm, followed by preparative SFC (Phenomenex-Amylose-1 (250 μm * 30 mm, 5 um), 0.1% NH3H2O / EtOH, 30%-30%) to give the title compound (42.5 mg, 35%) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ 12.49(s,1H), 8.64(d,J=2.4Hz,1H), 8.62(d,J=2.4Hz,1H), 7.74(d,J=8.0Hz,2H), 7.36(d,J=8. 0Hz,2H), 6.19(s,1H), 4.67-3.80(m,5H), 3.00-2.80(m,1H), 2.71(s,3H), 2.58(s,2H), 1.22(br s,3H), 0.91(s,9H);LCMS(ESI):m / z 503.2(M+H) + .

[0493] Example 63 Preparation of (S)-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(morpholin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and (R)-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(morpholin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000243.jpg39170

[0494] Step 1: Tert-butyl 2-(5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-2-yl)morpholine-4-carboxylate In a glove box, a vial was charged with a solution of (Ir[dF(CF)ppy](dtbpy))PF (11 mg, 0.01 mmol), 2-bromo-5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-4H-pyrazolo[1,5-a]pyrimidin-7-one (500 mg, 1.03 mmol), 4-tert-butoxycarbonylmorpholine-2-carboxylic acid (711 mg, 3.08 mmol), CsCO (1 g, 3.08 mmol), and anhydrous DMF (10 mL). Meanwhile, a second vial was charged with nickel chloride dimethoxyethane adduct (22 mg, 0.10 mmol), followed by the addition of 4,4'-di-tert-butyl-2,2'-dipyridyl (41 mg, 0.15 mmol) in DMF (2 mL). This resulted in the formation of a green, activated Ni catalyst solution. The nickel solution was removed via syringe and transferred to the first vial. The reaction vial was sealed and removed from the glovebox. The reaction mixture was then stirred at 25 °C and irradiated with a 34 W blue LED and cooling fan for 36 h. The reaction was then filtered, diluted with water (50 mL), extracted with EtOAc (50 mL × 3), and concentrated in vacuo. The crude organic residue was purified by silica gel chromatography (5% MeOH in dichloromethane) to afford the crude title compound (200 mg, approximately 20% purity). The crude product was used directly in the next step without further purification. LCMS(ESI):m / z 538.2(M+H) + .

[0495] Step 2: 5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(morpholin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000245.jpg39170 To the resulting tert-butyl 2-[5-(4-cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-7-oxo-4H-pyrazolo[1,5-a]pyrimidin-2-yl]morpholine-4-carboxylate (600 mg) in MeOH (30 mL) was added 4 M hydrochloric acid in MeOH (30 mL, 120 mmol). The reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was basified to pH 8 with 1 M aqueous NaOH solution and extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column (0-30% MeOH in DCM) to give the crude product (500 mg). The crude product was purified by preparative HPLC (Xtimate C18 150 * 25mm * Further purification with 5 um, water (0.225% FA)-ACN, 25% -55%) afforded the title compound (30 mg, 2% over two steps) as a yellow solid.

[0496] Step 3: (S)-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(morpholin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one and (R)-5-(4-cyclohexylphenyl)-3-(3-(fluoromethyl)azetidine-1-carbonyl)-2-(morpholin-2-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one JPEG0007759877000246.jpg381705-(4-Cyclohexylphenyl)-3-[3-(fluoromethyl)azetidine-1-carbonyl]-2-morpholin-2-yl-4H-pyrazolo[1,5-a]pyrimidin-7-one (30 mg, 0.06 mmol) was added to a 250 mm SFC (Daicel Chiral Pack 1G). * Separation with 50 μm, 10 μm, 0.1% NH3HO EtOH, 50%) gave Enantiomer A (8.7 mg, 29%, first peak in SFC) and Enantiomer B (10.9 mg, 36%, second peak in SFC), both as white solids.

[0497] エナンチオマーA: 1 H NMR(400MHz,DMSO-d6):δ 7.97(d,J=6.8Hz,2H), 7.28(d,J=6.8Hz,2H), 6.14(s,1H), 5.39-5.37( m,1H), 4.76-4.44(m,6H), 4.20-4.03(m,2H), 3.82-3.76(m,2H), 3.54-3 .43(m,2H)、3.13-3.09(m,1H)、2.96-2.94(m,1H)、1.84-1.79(m,4H)、1 .73-1.69(m,1H), 1.52-1.32(m,4H), 1.27-1.24(m,1H);LCMS(ESI):m / z 494.3(M+H) + .

[0498] エナンチオマーB: 1 H NMR(400MHz,DMSO-d6):δ 7.97(d,J=6.8Hz,2H), 7.28(d,J=6.8Hz,2H), 6.12(s,1H), 5.40-5.37(m,1H), 4.75- 4.38(m,6H), 4.20-4.02(m,2H), 3.80-3.75(m,2H), 3.50-3.43(m,2H), 3.14-3.09(m 1H), 2.95-2.94(m,1H), 1.84-1.79(m,4H), 1.73-1.69(m,1H), 1.48-1.32(m,4H), 1.31-1.27(m,1H); LCMS(ESI): m / z 494.3(M+H) + .

[0499] A brief note JPEG0007759877000247.jpg136170

[0500] Example 64 Purified His-tagged TEAD protein (YAP Binding Domain, amino acids 217-447) is preincubated with a europium-labeled anti-His antibody tracer (Perkin Elmer Cat# AD0110). Small molecule inhibitors are then incubated with the TEAD-Eu protein complex for 30 minutes to allow binding to the TEAD protein. Biotinylated YAP peptide (AA 50-100) for the TEAD-YAP assay or biotinylated TAZ peptide (AA 13-57) for the TEAD-TAZ assay, preincubated with streptavidin-x1665 acceptor (cis-Bio Cat# 610SAXAC), is added to the compound-TEAD mixture. The TEAD-YAP-inhibitor mixture is then incubated for 60 minutes at room temperature. All reactions are performed in polystyrene plates. After 60 minutes, the plate is read on a plate reader using TR-FRET mode at wavelengths of 665 nm / 615 nm. If YAP or TAZ binds to TEAD as expected, a TR-FRET signal is obtained from the vicinity of YAP or TAZ and TEAD after binding. Inhibitors such as peptide 17 (Selleckchem Cat# S8164) interfere with YAP-TEAD or TAZ-TEAD binding, resulting in a decrease in the TR-FRET signal due to disruption of the YAP or TAZ:TEAD interaction. Compound potency as a YAP:TEAD or TAZ:TEAD protein-protein interaction (PPi) inhibitor is determined using IC values ​​generated using nonlinear four-parameter curve fitting. 50 or EC 50 The degree to which representative examples of the disclosed compounds are able to inhibit the interaction between TEAD1, TEAD2, TEAD3, or TEAD4 and YAP truncated from amino acids 50-100 or TAZ truncated from amino acids 13-57, as measured by homogeneous time-resolved fluorescence (HTRF), is determined by an EC value. 50 The data generated are shown in Table 3 below.

[0501] Biological data Table 3 JPEG0007759877000248.jpg252170JPEG0007759877000249.jpg250170JPEG0007759877000250.jpg250170JPEG0007759877000251.jpg95170

[0502] Table 4 JPEG0007759877000252.jpg253170JPEG0007759877000253.jpg250170JPEG0007759877000254.jpg251170JPEG0007759877000255.jpg88170

[0503] Table 5 JPEG0007759877000256.jpg253170JPEG0007759877000257.jpg250170JPEG0007759877000258.jpg251170JPEG0007759877000259.jpg62170

[0504] Table 6 JPEG0007759877000260.jpg253170JPEG0007759877000261.jpg250170JPEG0007759877000262.jpg251170JPEG0007759877000263.jpg62170

[0505] It is to be understood that the present invention is not limited to the particular embodiments and aspects of the disclosure described above, and therefore variations of the particular embodiments and aspects can be made and are within the scope of the claims. All documents cited or relied upon herein are expressly incorporated by reference.

Claims

1. Formula (IB): [In the above formula: R １ is C(O)N(R ａ ) (R ｂ ), C ６－２０ Aryl, 5-20 membered heteroaryl, 5-20 membered heterocyclyl, and C １－６ alkyl, wherein R １ C ６－２０ Aryl, 5-20 membered heteroaryl and 5-20 membered heterocyclyl are independently selected from halo, OH, cyano, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C ３－８ Cycloalkyl, and C ６－１０ aryl, and R １ C １－６ Alkyl is OH, cyano, C １－６ Alkoxy, C ３－８ Cycloalkyl, and C ６－１０ substituted with one or more substituents selected from the group consisting of aryl; R ａ and R ｂ are each independently H or C １－６ alkyl, where C １－６ Alkyl is halo, OH, cyano, C １－６ Alkyl, C １－６ Haloalkyl, and C １－６ Optionally substituted with one or more substituents selected from the group consisting of alkoxy; Or, R ａ and R ｂ together with the atom to which they are attached form a 3-10 membered heterocyclyl, where the 3-10 membered heterocyclyl is selected from halo, OH, cyano, C １－６ Alkyl, C １－６ Haloalkyl, and C １－６ optionally substituted with one or more substituents selected from the group consisting of alkoxy; L is absent, or ＊ -O-CH ２ - ＊＊ , ＊ -CH ２ -O- ＊＊ or —O—, where ＊＊ is R ２ represents the point of attachment to the moiety, ＊ represents the point of attachment to the rest of the molecule; R ２ is C ２－１２ Alkyl, C ２－１２ Alkenyl, or C ６－１０ aryl, where R ２ C ２－１２ Alkyl, C ２－１２ Alkenyl, and C ６－１０ Aryl is independently halo, OH, cyano, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C ６－１０ Aryl, and C ３－１０ cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of C １－６ Alkyl, C １－６ Alkoxy, and C ３－１０ Cycloalkyl independently includes one or more halo, C １－６ Haloalkyl, C ６－１０ Aryl, or C ３－１０ may be further substituted with cycloalkyl; R ５ is H, halo, OH, cyano, and C １－６ alkyl, wherein C １－６ Alkyl is halo, OH, cyano, C １－６ Alkyl, C １－６ Haloalkyl, and C １－６ and optionally further substituted with one or more substituents selected from the group consisting of alkoxy. or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof.

2. The compound of formula (IB) is 2. The compound of claim 1, wherein:

3. A compound selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof.

4. The compound of formula (IB) is 2. The compound of claim 1, wherein:

5. The compound of claim 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof, selected from the group consisting of:

6. R １ 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof, wherein: is a 6-membered heteroaryl.

7. R ２ is C ６ aryl, where C ６ Aryl is halo, OH, cyano, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C ６－１０ Aryl, C ３－１０ cycloalkyl, wherein C ３－１０ Cycloalkyl may be one or more halo or C ３－１０ 10. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof, optionally further substituted with cycloalkyl.

8. L does not exist and R ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof, wherein is 4-cyclohexylphenyl.

9. A compound selected from the group consisting of: or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof.

10. 10. A pharmaceutical composition comprising a compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analog thereof, and a therapeutically inert carrier.

11. 11. A medicament for the therapeutic and / or prophylactic treatment of cancer, comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue thereof, or a pharmaceutical composition according to claim 10.

12. 10. Use of a compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue thereof, for the preparation of a medicament for the therapeutic treatment of cancer.

13. The pharmaceutical composition of claim 11, wherein the cancer is a solid tumor.

14. The pharmaceutical composition according to claim 11, wherein the cancer is selected from the group consisting of lung cancer, liver cancer, ovarian cancer, breast cancer, and squamous cell carcinoma.

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