BR112017009276B1 - PYRAZOLO[1,5-A]SUBSTITUTED PYRIMIDINES, PHARMACEUTICAL COMPOSITION AND THEIR USES - Google Patents

Abstract

PYRAZOLO[1,5-a]SUBSTITUTED PYRIMIDINES AND THEIR USE IN THE TREATMENT OF MEDICAL DISORDERS. The present invention relates to substituted pyrazolo[1,5-a]pyrimidine and related organic compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat medical disorders, e.g., Gaucher disease. , Parkinson's disease, Lewy body disease, dementia, or multiple system atrophy, in a patient. Exemplary substituted pyrazolo[1,5-a]pyrimidine compounds described herein include 5,7-dimethyl-N-phenylpyrazolo[1,5-a]pyrimidine-3-carboxamide compounds and variants thereof.

Description

CROSS REFERENCE TO RELATED ORDERS

[0001] This application claims the benefit of, and priority to, United States Provisional Patent Application serial number 62/076,062, filed on November 6, 2014, the contents of which are hereby incorporated by reference.

FIELD OF INVENTION

[0002] The invention provides substituted pyrazolo[1,5-a]pyrimidine and related organic compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions and treating medical disorders in a patient.

BACKGROUND

[0003] Gaucher disease is a genetic disorder associated with a deficiency of the lysosomal enzyme, glucocerebrosidase. Gaucher disease has been reported to have an incidence of approximately 1 in 20,000 live births in the general population, and it is a common lysosomal storage disorder. Current treatments for patients suffering from this disease include enzyme replacement therapy, which tends to be expensive, analgesics for relief of bone pain, and medical procedures such as blood and platelet transfusions, splenectomy, and replacement for patients who experience erosion. bone. However, new treatment options are needed that have improved efficacy in a wider range of patients and/or reduced adverse side effects.

[0004] Mutations in the gene encoding glucocerebrosidase are also a risk factor for Parkinson's disease and diffuse Lewy body disease. Parkinson's disease is a degenerative disorder of the central nervous system associated with the death of dopamine-containing cells in a region of the midbrain. Parkinson's disease afflicts millions of people, and the incidence of the disease increases with age. Treatment of Parkinson's disease often involves the use of levodopa and dopamine agonists. However, these drugs can produce significant side effects, such as hallucinations, insomnia, nausea and constipation. Furthermore, patients often develop tolerance to these drugs, so that the drugs become ineffective in treating the symptoms of the disease, although they sometimes also produce a movement disorder side effect called dyskinesia. Diffuse Lewy body disease is dementia that is sometimes confused with Alzheimer's disease.

[0005] Consequently, there is a need for new therapeutic agents for the treatment of Gaucher disease, Parkinson's disease, and related medical disorders. The present invention addresses this need and provides other related advantages.

SUMMARY

[0006] The invention provides substituted pyrazolo[1,5-a]pyrimidine and related organic compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions and treating medical disorders, for example, Gaucher disease, Parkinson's disease, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis, and myeloma multiple, in one patient. Various aspects and embodiments of the invention are described in greater detail below.

[0007] Accordingly, one aspect of the invention provides a family of substituted pyrazolo[1,5-a]pyrimidine and related organic compounds encompassed by formula I that can be used in the methods, compositions, and kits described herein, wherein formula I is represented by: or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the detailed description. Additional generic formulas and specific pyrazolo[1,5-a]pyrimidines are described in the detailed description and examples.

[0008] Another aspect of the invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a substituted pyrazolo[1,5-a]pyrimidine or related organic compound described herein, such as a compound of formula I.

[0009] Another aspect of the invention provides a method of treating a disorder, for example, Gaucher disease, Parkinson's disease, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, a disorder of anxiety, major depression, polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis, and multiple myeloma, in one patient. The method comprises administering to a patient in need thereof, a therapeutically effective amount of a substituted pyrazolo[1,5-a]pyrimidine or related organic compound described herein, such as a compound of formula I, to treat the disorder, e.g. , Gaucher disease, Parkinson's disease, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis, or multiple myeloma.

DETAILED DESCRIPTION

[0010] The invention provides substituted pyrazolo[1,5-a]pyrimidine and related organic compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions and treating medical disorders in a patient. The practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, cell biology, and biochemistry. Such techniques are explained in the literature, such as in "Comprehensive Organic Synthesis" (B.M. Trost & I. Fleming, eds., 1991-1992); "Current protocols in molecular biology" (F.M. Ausubel et al., eds., 1987, and periodic updates); and "Current protocols in immunology" (J.E. Coligan et al., eds., 1991), each of which is incorporated herein by reference in its entirety. Various aspects of the invention are mentioned below in sections; however, aspects of the invention described in a particular section should not be limited to any particular section.

I. Definitions

[0011] To facilitate an understanding of the present invention, several terms and phrases are defined below.

[0012] The terms "one, one, one, one (a)" and "one, one, one, one (an)" as used herein mean "one or more" and include the plural, unless the context is inappropriate.

[0013] The term "alkyl" as used herein refers to a saturated linear or branched hydrocarbon, such as a linear or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12alkyl, C1-C10alkyl, and C1-C6alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl , 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl , 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t -butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.

[0014] The term "alkylene" refers to a diradical of an alkyl group. An exemplary alkylene group is -CH2CH2-.

[0015] The term "haloalkyl" refers to an alkyl group that is substituted by at least one halogen. For example, -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like.

[0016] The term "heteroalkyl" as used herein refers to an "alkyl" group in which at least one carbon atom has been replaced by an O or S group. The heteroalkyl can be, for example, an -O-Ci- Cio alkyl, a -C1-C6alkylene-O-C1-C6 alkyl group, or a C1-C6 alkylene-OH group. In certain embodiments, the "heteroalkyl" may be 2 to 8 membered heteroalkyl, indicating that the heteroalkyl contains 2 to 8 atoms selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. In still other embodiments, the heteroalkyl may be a 2- to 6-membered, 4 to 8-membered, or 5 to 8-membered heteroalkyl group (which may contain, for example, 1 or 2 heteroatoms selected from the oxygen and nitrogen group). In certain embodiments, the heteroalkyl is an "alkyl" group in which 1 to 3 carbon atoms have been replaced by oxygen atoms. One type of heteroalkyl group is an "alkoxy" group.

[0017] The term "alkenyl" as used herein refers to an unsaturated linear or branched hydrocarbon having at least one carbon-carbon double bond, such as a linear or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C2-C12alkenyl, C2-C10alkenyl, and C2-C6alkenyl, respectively. Exemplary alkenyl groups include vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl and the like.

[0018] The term "alkynyl" as used herein refers to an unsaturated linear or branched hydrocarbon having at least one carbon-carbon triple bond, such as a linear or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C2-C12alkynyl, C2-C10alkynyl, and C2-C6alkynyl, respectively. Exemplary alkynyl groups include ethynyl, prop-1-yn-1-yl, and but-1-yn-1-yl.

[0019] The term "cycloalkyl" refers to a saturated monovalent cyclic, bicyclic, or cyclic bridged hydrocarbon group (e.g., adamantyl) of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, for example, as "C4-8 cycloalkyl," derived from a cycloalkane. Examples of cycloalkyl groups include, but are not limited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes. Unless otherwise specified, cycloalkyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido , carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonate, phosphinate, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl . Cycloalkyl groups can be fused to other cycloalkyl, aryl or heterocyclyl groups. In certain embodiments, the cycloalkyl group is unsubstituted, that is, it is unsubstituted.

[0020] The term "cycloalkylene" refers to a diradical of a cycloalkyl group. An example of a cycloalkylene group is

[0021] The term "cycloalkenyl" as used herein refers to a monovalent unsaturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons containing a carbon-carbon double bond, referred to herein, for example, as "C4-8 cycloalkenyl," derived from a cycloalkane. Example of cycloalkenyl groups include, but are not limited to, cyclohexenes, cyclopentenes and cyclobutenes. Unless otherwise specified, cycloalkenyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido , carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonate, phosphinate, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl . In certain embodiments, the cycloalkenyl group is unsubstituted, that is, it is unsubstituted.

[0022] The term "aryl" is recognized in the art and refers to a carbocyclic aromatic group. Representative aryl groups include phenyl, naphthyl, anthracenyl and the like. The term "aryl" includes polycyclic ring systems having two or more carbocyclic rings in which two or more carbons are common to two adjacent rings (the rings are "fused rings") in which at least one of the rings is aromatic and, e.g. , the other ring(s) may be cycloalkyl, cycloalkenyl, cycloalkynyl, and/or aryl. Unless otherwise specified, the aromatic ring may be substituted at one or more ring positions with, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro moieties. , sulfhydryl, imino, starch, carboxylic acid, -C(O)alkyl, -CO2alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl, -CF3, -CN, or similar. In certain embodiments, the aromatic ring is substituted at one or more ring positions with halogen, alkyl, hydroxyl or alkoxyl. In certain other embodiments, the aromatic ring is not substituted, that is, it is unsubstituted. In certain embodiments, the aryl group is a 6- to 10-membered ring structure.

[0023] The term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0024] The term "bicyclic carbocyclic that is partially unsaturated" refers to a bicyclic carbocyclic group containing at least one double bond between the ring atoms and at least one ring in the bicyclic carbocyclic group is non-aromatic. Representative examples of a bicyclic carbocyclyl that is partially unsaturated include, for example:

[0025] The terms ortho, meta and para are recognized in the art and refer to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

[0026] The terms "heterocyclyl group" and "heterocyclic" are recognized in the art and refer to saturated, partially unsaturated, or aromatic 3- to 10-membered ring structures, alternatively 3 to 7-membered rings, whose structures of ring include one to four heteroatoms, such as nitrogen, oxygen, and sulfur. The number of ring atoms in the heterocyclyl group can be specified using the Cx-Cx nomenclature where x is an integer specifying the number of ring atoms. For example, a C3-C7 heterocyclyl group refers to a saturated or partially unsaturated 3- to 7-membered ring structure containing one to four heteroatoms, such as nitrogen, oxygen, and sulfur. The designation "C3-C7" indicates that the heterocyclic ring contains a total of 3 to 7 ring atoms, inclusive of any hetero aroms occupying a ring atom position. An example of a C3 heterocyclyl is aziridinyl. Heterocycles can also be mono-, bi-, or other multi-cyclic ring systems including a spirocyclic ring system, where at least one ring contains a ring heteroatom. A heterocycle can be fused to one or more partially unsaturated or saturated aryl rings. Heterocyclyl groups include, for example, biotinyl, chromenyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, homopiperidinyl, imidazolidinyl, isoquinolyl, isothiazolidinyl, isooxazolidinyl, morpholinyl, oxolanyl, oxazolidinyl , phenoxanthenyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, thiazolidinyl, thiolanyl, thiomorpholinyl , thiopyranil, xanthenyl, lactones, lactams such as azetidinones and pyrrolidinones, sultans, sultones, and the like. Unless otherwise specified, the heterocyclic ring is optionally substituted at one or more positions with substituents such as alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate , carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, oxo, phosphate, phosphonate, phosphinate, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl. In certain embodiments, the heterocyclyl group is unsubstituted, that is, it is unsubstituted.

[0027] The term "bicyclic heterocyclyl" refers to a heterocyclyl group that contains two rings that are fused together. Representative examples of a bicyclic heterocyclyl include, for example:

[0028] In certain embodiments, the bicyclic heterocyclyl is a carbocyclic ring fused to a partially unsaturated heterocyclic ring, which together form a bicyclic ring structure having 8 to 10 ring atoms (e.g., where there are 1, 2, 3, or 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur).

[0029] The term "heterocycloalkyl" is recognized in the art and refers to a saturated heterocyclyl group, as defined above. In certain embodiments, the "heterocycloalkyl" is a 3- to 10-membered ring structure, alternatively a 3 to 7-membered ring, which ring structures include one to four heteroatoms, such as nitrogen, oxygen, and sulfur.

[0030] The term "heterocycloalkylene" refers to a diradical of a heterocycloalkyl group. An example of a heterocycloalkylene group is . Heterocycloalkylene may contain, for example, 3 to 6 ring atoms (i.e., a 3 to 6 membered heterocycloalkylene). In certain embodiments, heterocycloalkylene is a 3- to 6-membered heterocycloalkylene containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur.

[0031] The term "heteroaryl" is recognized in the art and refers to aromatic groups that include at least one ring heteroatom. In certain cases, a heteroaryl group contains 1, 2, 3, or 4 ring heteroatoms. Representative examples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, and the like. Unless otherwise specified, the heteroaryl ring may be substituted at one or more ring positions with, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro moieties. , sulfhydryl, imino, starch, carboxylic acid, -C(O)alkyl, -CO2alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl, -CF3 , -CN, or similar. The term "heteroaryl" also includes polycyclic ring systems having two or more rings in which two or more carbons are common to two adjacent rings (the rings are "fused rings") in which at least one of the rings is heteroaromatic, e.g. For example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, and/or aryl. In certain embodiments, the heteroaryl ring is substituted at one or more ring positions with halogen, alkyl, hydroxyl or alkoxy. In certain other embodiments, the heteroaryl ring is unsubstituted, that is, it is unsubstituted. In certain embodiments, the heteroaryl group is a 5- to 10-membered ring structure, alternatively a 5 to 6-membered ring structure, which ring structure includes 1, 2, 3, or 4 heteroatoms, such as nitrogen, oxygen and sulfur.

[0032] The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group.

[0033] The terms "amine" and "amino" are recognized in the art and refer to both unsubstituted and substituted amines, for example, a moiety represented by the general formula -N(R50)(R51), where R50 and R51 each independently represents hydrogen, alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl, aralkyl, or -(CH2)m-R61; or R50 and R51, used together with the N atom to which they are linked, complete a heterocycle having 4 to 8 atoms in the ring structure; R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In certain embodiments, R50 and R51 each independently represent hydrogen, alkyl, alkenyl, or -(CH2)m-R61.

[0034] The terms "alkoxy" or "alkoxy" are recognized in the art and refer to an alkyl group, as defined above, having an oxygen radical attached to it. Representative alkoxy groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An "ether" is two hydrocarbons covalently bonded by an oxygen. Consequently, the substituent on an alkyl that makes that alkyl an ether is or resembles an alkoxyl, as may be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -O- (CH2) m-R61, where m and R61 are as described above.

[0035] The term "carbamate" as used herein refers to a radical of the form -RgOC(O)N(Rh)-, -RgOC(O)N(Rh)Ri-, or -OC(O)NRhRi, wherein Rg, Rh and Ri are each independently alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl , hydroxyl, ketone, nitro, sulfide, sulfonyl, or sulfonamide. Examples of carbamates include arylcarbamates and heteroarylcarbamates, for example, wherein at least one of Rg, Rh and Ri is independently aryl or heteroaryl, such as phenyl and pyridinyl.

[0036] The term "carbonyl" as used here refers to the radical - C(O)-.

[0037] The term "carboxamido" as used here refers to the radical -C(O)NRR', where R and R' can be the same or different. R and R' can independently be alkyl, aryl, arylalkyl, cycloalkyl, formyl, haloalkyl, heteroaryl or heterocyclyl.

[0038] The term "carboxy" as used here refers to the radical -COOH or its corresponding salts, for example -COONa, etc.

[0039] The term "amide" or "starch" as used herein refers to a radical of the form -RaC(O)N(Rb)-, -RaC(O)N(Rb)Rc-, -C(O) NRbRc, or -C(O)NH2, where Ra, Rb and Rc are each independently alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ester, ether, formyl , halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, or nitro. The amide can be linked to another group through carbon, nitrogen, Rb, Rc or Ra. The amide may also be cyclic, for example, Rb and Rc, Ra and Rb, or Ra and Rc may be linked to form a 3 to 12 membered ring, such as a 3 to 10 membered ring or a 5 to 12 membered ring. 6 members.

[0040] The term "amidino" as used herein refers to a radical of the form -C(=NR)NR'R'' where R, R', and R'' are each independently alkyl, alkenyl, alkynyl , amide, aryl, arylalkyl, cyano, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, or nitro.

[0041] The term "alkanoyl" as used here refers to an -O-CO-alkyl radical.

[0042] The term "oxo" is recognized in the art and refers to a substituent "=O". For example, a cyclopentane substituted with an oxo group is cyclopentanone.

[0043] The term "sulfonamide" or "sulfonamido" as used herein refers to a radical having the structure -N(Rr)-S(O)2-Rs- or -S(O)2—N(Rr)Rs , where Rr, and Rs can be, for example, hydrogen, alkyl, aryl, cycloalkyl, and heterocyclyl. Examples of sulfonamides include alkylsulfonamides (e.g., where Rs is alkyl), arylsulfonamides (e.g., where Rs is aryl), cycloalkyl sulfonamides (e.g., where Rs is cycloalkyl), and heterocyclyl sulfonamides (e.g., where Rs is heterocyclyl). , etc.

[0044] The term "sulfonyl" as used here refers to a radical having the structure RuSO2-, where Ru can be alkyl, aryl, cycloalkyl, and heterocyclyl, for example, alkylsulfonyl. The term "alkylsulfonyl" as used herein refers to an alkyl group attached to a sulfonyl group.

[0045] The symbol indicates a connection point.

[0046] The compounds of the invention may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term "stereoisomers" when used herein consists of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols "R" or "S," depending on the configuration of substituents around the stereogenic carbon atom. The present invention encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated "(±)" in nomenclature, but the skilled artisan will recognize that a structure may implicitly denote a chiral center. It is understood that graphical representations of chiral structures, e.g., generic chemical structures, encompass all stereoisomeric forms of the specified compounds unless otherwise indicated.

[0047] Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric and stereogenic centers, or by preparing racemic mixtures following resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) binding a mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography and releasing the optically pure product from the auxiliary, (2) salt formation employing a optically active resolution, or (3) direct separation of the mixture of optical enantiomers in chiral chromatographic columns. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral phase gas chromatography, chiral phase high performance liquid chromatography, crystallizing the compound in a chiral solvent. Furthermore, enantiomers can be separated using supercritical fluid chromatographic (SFC) techniques described in the literature. Furthermore, stereoisomers can be obtained from stereomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0048] Geometric isomers may also exist in the compounds of the present invention. The symbol denotes a bond that can be a single, double or triple bond, as described here. The present invention covers various geometric isomers and mixtures thereof, resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a carbocyclic ring. Substituents around a carbon-carbon double bond are designated as being in the "Z" or "E" configuration where the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures representing double bonds encompass both "E" and "Z" isomers.

[0049] Substituents around a carbon-carbon double bond may alternatively be referred to as "cis" or "trans," where "cis" represents substituents on the same side of the double bond and "trans" represents substituents on opposite sides of the bond pair. The arrangement of substituents around a carbocyclic ring is designated as "cis" or "trans." The term "cis" represents substituents on the same side of the ring plane and the term "trans" represents substituents on opposite sides of the ring plane. Mixtures of compounds in which the substituents are arranged on both the same side and opposite sides of the ring plane are termed "cis/trans."

[0050] The invention also encompasses isotopically labeled compounds of the invention that are identical to those mentioned herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number generally found in nature. . Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively.

[0051] Certain described isotopically labeled compounds (e.g., those labeled with 3H and 14C) are useful in substrate and/or compound tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium (i.e., 2H) may give rise to certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by the following procedures analogous to those described, for example, in the examples mentioned herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0052] As used herein, the terms "subject" and "patient" refer to organisms to be treated by the methods of the present invention. Such organisms are preferably mammals (e.g., murine, ape, equine, bovine, porcine, canine, feline and the like), and most preferably human.

[0053] As used herein, the term "effective amount" refers to the amount of a compound (e.g., a compound of the present invention) sufficient for beneficial effect or desired results. An effective amount may be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or route of administration. As used herein, the term "treat" includes any effect, for example, lessening, reducing, modulating, improving or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or improvement of a symptom thereof.

[0054] As used herein, the term "pharmaceutical composition" refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0055] As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, such as phosphate-buffered saline, water, emulsions (e.g., such as an oil/water emulsion or water /oil), and various types of wetting agents. The compositions may also include stabilizers and preservatives. For examples of vehicles, stabilizers, and adjuvants, see Martin, Remington's Pharmaceutical Sciences, 15a. Ed., Mack Publ. Co., Easton, PA [1975].

[0056] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present invention that, upon administration to an individual, is capable of providing a compound of this invention or an active metabolite or residue thereof. As is known to those skilled in the art, "salts" of the compounds of the present invention can be derived from inorganic and organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, and the like. Other acids, such as oxalic, although not in themselves pharmaceutically acceptable, can be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

[0057] Examples of bases include, but are not limited to, alkali metal hydroxides (e.g., sodium), alkaline earth metal hydroxides (e.g., magnesium), ammonia, and compounds of formula NW4+, where W is C1-4 alkyl and the like.

[0058] Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane-propionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flu- coeptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodate, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present invention compounded with a suitable cation, such as Na+, NH4+, and NW4+ (wherein W is a C1-4 alkyl group), and the like.

[0059] For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0060] Abbreviations as used herein include O -(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); diisopropylethylamine (DIPEA); dimethylformamide (DMF); methylene chloride (DCM); tert-butoxycarbonyl (Boc); tetrahydrofuran (THF); trifluoroacetic acid (TFA); N-methylmorpholine (NMM); triethylamine (TEA); Boc anhydride ((Boc)2O); dimethyl sulfoxide (DMSO); diisopropylethylamine (DIEA); N,N-Dimethylpyridin-4-amine (DMAP); flash column chromatography (FCC); and supercritical fluid chromatography (SFC).

[0061] Throughout the description, where compositions and kits are described as having, including, or comprising specific components, where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, in addition, there are compositions and kits of the present invention that consist essentially of, or consist of, the mentioned components, that there are processes and methods according to the present invention that essentially consist of, or consist of, the mentioned processing steps.

[0062] Generally speaking, compositions specifying a percentage are by weight unless otherwise specified. Furthermore, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

II. Substituted pyrazolo[1,5-a]pyrimidine and related organic compounds

[0063] One aspect of the invention provides substituted pyrazolo[1,5-a]pyrimidine and related organic compounds. Substituted pyrazolo[1,5-a]pyrimidine and related organic compounds are contemplated to be useful in the methods, compositions, and kits described herein. In certain embodiments, the substituted pyrazolo[1,5-a]pyrimidine or related organic compound is a compound encompassed by formula I: or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 each independently represent for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, -(C1-4 alkylene)-(heteroalkyl of 2 6-membered), cyclopropyl, cyano, chlorine, fluorine, or -N(H)(R3); R3 represents independently for each occurrence hydrogen or C1-4 alkyl; R4 represents independently for each occurrence hydrogen, C1-4 alkyl, or -C(O)R3; X1 is one of the following: (a) a carbonyl-containing ligand selected from - C(O)N(H)-V and -C(O)N(H)(CI-6 alkylene)—v; where v is a connection to A1; or (b) an amine-containing ligand selected from -(C1-4 alkylene)-N(H)-ve -(C1-4 alkylene)-N(H)-(C1-4 alkylene)-v; A1 is a cyclic group selected from: • C3-10 cycloalkyl that is substituted by 1 or 2 occurrences of Y1 and 0, 1, 2 or 3 occurrences of Y2; • 1,2,3,4-tetrahydronaphthalenyl, 2,3-dihydro-1H-inden-1-yl, or 2,3-dihydro-1H-inden-2-yl, each of which is replaced by 0, 1, or 2 occurrences of Y1 and 0, 1, 2, or 3 occurrences of Y2; • phenyl substituted by (a) 0, 1, 2 or 3 occurrences of Y2 and (b) one of the following: (i) 4 to 8 membered heteroalkyl; (ii) 2 to 6 membered heteroalkyl substituted by a 5 to 10 membered heteroaryl; (iii) -C=C-(CI-6 alkylene)-OR4 or -(C2-4 alkynylene)- (5- to 6-membered heterocyclyl); (iv) -O-((3- to 6-membered heterocyclyl) -O-(6- to 10-membered aryl), -O-(C2-6 alkynyl), or azido; or (v) C2-4 alkynyl; and • a bicyclic heterocyclyl containing at least one ring nitrogen atom, wherein the bicyclic heterocyclyl is substituted by 0, 1, or 2 occurrences of Y1 and 0, 1, 2, or 3 occurrences of Y2 • 1 represents, independently for each; occurrence, one of the following: • 2 to 8 membered heteroalkyl optionally substituted by a 6 to 10 membered aryl or a 3 to 10 membered heterocyclyl • 3 to 10 membered heterocyclyls, 6 to 10 membered aryl, -O-; ((3- to 6-membered heterocyclyl) -O-(6- to 10-membered aryl), or -O-(C2-6 alkynyl); or • C2-6 alkynyl, -CsC-(Ci-β alkylene)-OR4 , -CsC-(Ci-β alkylene)-N(R3)2, -(C2-4 alkynylene)-(5- to 6-membered heteroaryl), or C2-β alkenyl • 2 represents, independently for each occurrence; -( Ci-β alkylene)-(5- to β-membered heterocyclyl), -(Ci-β alkylene)-CO2R3, or C3-β cycloalkyl substituted by Ci-β haloalkyl; n is i, 2, or 3; and provided that the following: • when Ai is phenyl substituted by heteroalkyl, at least one of Ri or R2 is other than hydrogen; • when Ai is phenyl substituted by C2-4 alkynyl, then at least one of Ri and R2 is Ci-4 alkoxyl, -(Ci-4 alkylene)-(2- to β-membered heteroalkyl), cyclopropyl, cyano, chlorine, fluorine , or -N(H)(R3); and • there is at least one Yi or Y2 when Ai is a bicyclic heterocyclyl containing at least one ring nitrogen atom and X1 is -C(O)N(H)-v-

[0064] Definitions of variables in formula I above cover multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups mentioned above, ii) the definition is a collection of two or more of the chemical groups selected from those mentioned above, and iii) the compound is defined by a combination of variables where the variables are defined by (i) or (ii), for example, such as where Ri is Ci-4 alkyl or cyclopropyl, Xi is -C(O)N(H) - V, and A1 is phenyl substituted by 4 to 8 membered heteroalkyl.

[0065] Consequently, in certain embodiments, R1 represents independently for each occurrence C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, cyclopropyl, cyano, chlorine or fluorine. In certain embodiments, R1 is methyl. In certain embodiments, the R1 groups are located at positions 5 and 7 of the pyrazolo[1,5-a]pyrimidinyl.

[0066] In certain embodiments, n is 2. In certain other embodiments, n is 1.

[0067] In certain embodiments, R2 is hydrogen. In certain embodiments, R2 is methyl or halogen. In certain embodiments, R2 is methyl or halomethyl. In certain embodiments, R2 is methyl or cyclopropyl.

[0068] In certain embodiments, R3 and R4 each independently represent hydrogen, methyl or ethyl for each occurrence. In certain embodiments, R3 is hydrogen. In certain embodiments, R4 is hydrogen.

[0069] In certain embodiments, X1 is -C(O)N(H)-V.

[0070] In certain embodiments, any occurrence of Y2 is independently C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl or hydroxyl. In certain embodiments, any occurrence of Y2 is independently C1-3 alkyl.

[0071] In certain embodiments, A1 is phenyl substituted by (a) 0, 1, 2 or 3 occurrences of Y2 and (b) one of the following: (i) 4 to 8 membered heteroalkyl; (ii) 2 to 6 membered heteroalkyl substituted by a 5 to 10 membered heteroaryl; (iii) -C=C-(CI-6 alkylene)-OR4 or -(C2-4 alkynylene)- (5- to 6-membered heterocyclyl); or (iv) -O-((3-6 membered heterocyclyl) -O-(6-10 membered aryl), -O-(C2-6 alkynyl) or azido.

[0072] In certain embodiments, A1 is phenyl substituted by (a) 0, 1, 2 or 3 occurrences of Y2 and (b) one of the following: (i) 4 to 8 membered heteroalkyl; (ii) 2- to 6-membered heteroalkyl substituted by a 5- to 10-membered heteroaryl; (iii) -C=C-(C1-6 alkylene)-OR4 or -(C2-4 alkynylene)- (5- to 6-membered heteroaryl); or (iv) -O-((3-6 membered heterocyclyl) -O-(6-10 membered aryl), -O-(C2-6 alkynyl) or azido.

[0073] In certain embodiments, A1 is phenyl substituted by (a) 0 or 1 occurrence of Y2 and (b) a 4 to 8 membered heteroalkyl. In certain embodiments, A1 is phenyl substituted by -O-(C1-7 alkyl). In certain embodiments, A1 is phenyl substituted by -O- (C4-7 alkyl). In certain embodiments, A1 is phenyl substituted by -O-butyl, -O-pentyl or -O-hexyl. In certain embodiments, A1 is substituted phenyl is -OCH2CH2OCH2CH2.

[0074] In certain embodiments, A1 is phenyl substituted by (a) 0 or 1 occurrence of Y2 and (b) a 2 to 6 membered heteroalkyl optionally substituted by a 5 to 10 membered heteroaryl. In certain embodiments, A1 is phenyl substituted by (a) 0 or 1 occurrence of Y2 and (b) the 2- to 6-membered heteroalkyl substituted by a 5- to 6-membered heteroaryl (which may be, for example, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl or thiazolinyl, each of which is optionally substituted by one or two substituents independently selected from the group consisting of C16 alkyl, C3-6 cycloalkyl , halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, -N(R4)2, amide, and -CO2H). In certain embodiments, A1 is phenyl substituted by (a) 0 or 1 occurrence of Y2 and (b) a 2 to 4 membered heteroalkyl substituted by pyridinyl.

[0075] In certain embodiments, A1 is phenyl substituted by (a) 0 or 1 occurrence of Y2 and (b) -C^C-(Ci-6 alkylene)-OR4. In certain embodiments, A1 is phenyl substituted by (a) 0 or 1 occurrence of Y2 and (b) -CHC-CH2-O-CH3. In certain embodiments, A1 is phenyl substituted by -CHC-CH2-O-CH3.

[0076] In certain embodiments, A1 is C3-7 cycloalkyl replaced once by Y1 and 0 to 1 occurrence of Y2. In certain embodiments, A1 is C5-10 cycloalkyl which is substituted by 1 or 2 occurrences of Y1 and 0, 1, 2 or 3 occurrences of Y2.

[0077] In certain embodiments, A1 is a bicyclic heterocyclyl containing at least one ring nitrogen atom, in which the bicyclic heterocyclyl is replaced by 0, 1 or 2 occurrences of Y1 and 0, 1, 2 or 3 occurrences of Y2.

[0078] In certain embodiments, A1 is 1,2,3,4-tetrahydronaphthalenyl substituted by 0, 1, 2 or 3 occurrences of Y2.

[0079] In certain embodiments, Y1 is a 2 to 8 membered heteroalkyl optionally substituted by a 6 to 10 membered aryl or a 3 to 10 membered heterocyclyl. In certain embodiments, Y1 is a 2 to 8 membered heteroalkyl substituted by a 6 to 10 membered aryl or a 3 to 10 membered heterocyclyl. In certain embodiments, Y1 is a 2 to 8 membered heteroalkyl substituted by a 3 to 10 membered heterocyclyl. In certain embodiments, Y1 is a 2 to 8 membered heteroalkyl substituted by a 5 to 6 membered heteroaryl, such as pyrrolyl, furanyl or pyridinyl. In certain embodiments, Y1 is a 2 to 8 membered heteroalkyl.

[0080] In certain embodiments, Y1 is a 2- to 8-membered heteroalkyl. In certain embodiments, Y1 is -O-(C1-7 alkyl). In certain embodiments, Y1 is -O-butyl, -O-pentyl or -O-hexyl. In certain embodiments, Y1 is -(C1-3 alkylene)-O-(5-6 membered heteroaryl). In certain embodiments, Y1 is -CH2-O-(5-6 membered heteroaryl). In certain embodiments, Y1 is -CH2-O- (5- to 6-membered heteroaryl), wherein the 5- to 6-membered heteroaryl is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, -N(R4)2, amide, and -CO2H.

[0081] In certain embodiments, Y1 is a 3 to 10 membered heterocyclyl, 6 to 10 membered aryl, -O-((3 to 6 membered heterocyclyl) -O-(6 to 10 membered aryl) or -O -(C2-6 alkynyl). In certain embodiments, Y1 is a 3- to 10-membered heterocyclyl selected from the group consisting of a 5- to 6-membered heteroaryl and a 5- to 6-membered heterocyclyl. 5-membered heteroaryl. , C1-6 alkoxy, cyano, -N(R4)2, amide, and -CO2H In certain embodiments, Y1 is 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C1-6 alkyl, C3. -6 cycloalkyl, halogen, C1-6 haloalkyl, hydroxyl, and C1-6 alkoxy.

[0082] In certain embodiments, Y1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl or thiazolyl. In certain embodiments, Y1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, -N(R4)2, amide, and -CO2H.

[0083] In certain embodiments, Y1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl or triazolinyl. In certain embodiments, Y1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl or triazolinyl, each of which is substituted by one or two substituents independently selected from the group that consists of C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, -N(R4)2, amide, and -CO2H.

[0084] In certain embodiments, Y1 is C2-6 alkynyl, -C=C- (C1-6 alkylene)-OR4, -CHC-(CI-6 alkylene)-N(R3)2, -(C2-4 alkynylene )- (5- to 6-membered heteroaryl), or C2-6 alkenyl. In certain embodiments, Y1 is C2-6 alkynyl. In certain embodiments, Y1 is - C^CH. In certain embodiments, Y1 is -CHC-(CI-6 alkylene)-OR4. In certain embodiments, Y1 is -CHC-(CI-6 alkylene)-O-(C1-2 alkyl). In certain embodiments, Y1 is -CHC-CH2-O-CH3.

[0085] The above description describes multiple modalities relating to compounds of formula I. The patent application specifically contemplates all combinations of modalities. For example, the invention contemplates a compound of formula I in which X1 is -C(O)N(H)- V, A1 is phenyl substituted by (a) 0, 1, 2 or 3 occurrences of Y2 and (b) heteroalkyl 4 to 8 members, and Y1 is C1-6 alkyl or halogen.

[0086] In certain embodiments, the compound is represented by formula I-1: or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 each independently represent for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, cyclopropyl, cyano, chlorine or fluorine; R3 represents independently for each occurrence hydrogen or C1-4 alkyl; R4 represents independently for each occurrence hydrogen, C1-4 alkyl or -C(O)R3; X1 is one of the following: (a) a carbonyl-containing ligand selected from -C(O)N(H)- V and -C(O)N(H)(CI-6 alkylene)—v; where v is a connection to A1; or (b) an amine-containing ligand selected from -(C1-4 alkylene)-N(H)-V and -(C1-4 alkylene)-N(H)-(C1-4 alkylene)-V; A1 is a cyclic group selected from: • phenyl substituted by (a) 0, 1, 2 or 3 occurrences of Y2 and (b) one of the following: (i) 4 to 8 membered heteroalkyl; (ii) 2- to 6-membered heteroalkyl substituted by a 5- to 10-membered heteroaryl; (iii) -C=C-(C1-6 alkylene)-OR4 or -(C2-4 alkynylene)-(5- to 6-membered heterocyclyl); or (iv) -O-((3- to 6-membered heterocyclyl) -O-(6- to 10-membered aryl), -O-(C2-6 alkynyl) or azido; • C3-7 cycloalkyl which is substituted by 1 or 2 occurrences of Y1 and 0, 1, 2 or 3 occurrences of Y2; and • bicyclic heterocyclyl containing at least one ring nitrogen atom, wherein the bicyclic heterocyclyl is replaced by 0, 1 or 2 occurrences of Y1 and 0, 1, 2 or 3 occurrences of Y2; Y1 represents, independently for each occurrence, one of the following: • 2 to 8 membered heteroalkyl optionally substituted by a 6 to 10 membered aryl or a 3 to 10 membered heterocyclyl; 3 to 10 members, 6 to 10 member aryl, -O-((3 to 6 member heterocyclyl) -O-(6 to 10 member aryl) or -O-(C2-6 alkynyl); or • C2- 6 alkynyl, -CHC-(CI-6 alkylene)-OR4, -C=C-(Ci—6 alkylene)-N(R3)2, -(C2-4 alkynylene)-(5- to 6-membered heteroaryl ), or C2-6 alkenyl; Y2 represents, independently for each occurrence, C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, C2-4 alkynyl, cyano, azido, -N(R3)2, -(C1-6 alkylene)-(5- to 6-membered heterocyclyl), -(C1-6 alkylene)-CO2R3 or C3-6 cycloalkyl substituted by C1-6 haloalkyl ; n is 1, 2 or 3; and provided that at least one of R1 or R2 is other than hydrogen when A1 is phenyl substituted by heteroalkyl.

[0087] Definitions of variables in formula I-1 above cover multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups mentioned above, ii) the definition is a collection of two or more of the chemical groups selected from those mentioned above, and iii) the compound is defined by a combination of variables where the variables are defined by (i) or (ii), for example, such as where R1 is C1-4 alkyl or cyclopropyl, X1 is -C(O)N(H) - V, and A1 is phenyl substituted by 4 to 8 membered heteroalkyl.

[0088] Consequently, in certain embodiments, R1 independently represents for each occurrence C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, cyclopropyl, cyano, chlorine or fluorine. In certain embodiments, R1 is methyl. In certain embodiments, the R1 groups are located at positions 5 and 7 of the pyrazolo[1,5-a]pyrimidinyl.

[0089] In certain embodiments, n is 2. In certain other embodiments, n is 1.

[0090] In certain embodiments, R2 is hydrogen. In certain embodiments, R2 is methyl or halogen. In certain embodiments, R2 is methyl or halomethyl. In certain embodiments, R2 is methyl or cyclopropyl.

[0091] In certain embodiments, R3 and R4 each independently represent hydrogen, methyl or ethyl for each occurrence. In certain embodiments, R3 is hydrogen. In certain embodiments, R4 is hydrogen.

[0092] In certain embodiments, X1 is -C(O)N(H)-^.

[0093] In certain embodiments, any occurrence of Y2 is independently C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl or hydroxyl. In certain embodiments, any occurrence of Y2 is independently C1-3 alkyl.

[0094] In certain embodiments, A1 is phenyl substituted by (a) 0, 1, 2 or 3 occurrences of Y2 and (b) one of the following: (i) 4 to 8 membered heteroalkyl; (ii) 2 to 6 membered heteroalkyl substituted by a 5 to 10 membered heteroaryl; (iii) -C=C-(C1-6 alkylene)-OR4 or -(C2-4 alkynylene)- (5- to 6-membered heterocyclyl); or (iv) -O-((3-6 membered heterocyclyl) -O-(6-10 membered aryl), -O-(C2-6 alkynyl) or azido.

[0095] In certain embodiments, A1 is phenyl substituted by (a) 0, 1, 2 or 3 occurrences of Y2 and (b) one of the following: (v) 4 to 8 membered heteroalkyl; (vi) 2 to 6 membered heteroalkyl substituted by a 5 to 10 membered heteroaryl; (vii) -C1-6 alkylene)-OR4 or -(C2-4 alkynylene)- (5- to 6-membered heteroaryl); or (viii) -O-((3-6 membered heterocyclyl) -O-(6-10 membered aryl), -O-(C2-6 alkynyl) or azido.

[0096] In certain embodiments, A1 is phenyl substituted by (a) 0 or 1 occurrence of Y2 and (b) a 4 to 8 membered heteroalkyl. In certain embodiments, A1 is phenyl substituted by -O-(C1-7 alkyl). In certain embodiments, A1 is phenyl substituted by -O- (C4-7 alkyl). In certain embodiments, A1 is phenyl substituted by -O-butyl, -O-pentyl or -O-hexyl. In certain embodiments, A1 is substituted phenyl is -OCH2CH2OCH2CH2.

[0097] In certain embodiments, A1 is phenyl substituted by (a) 0 or 1 occurrence of Y2 and (b) a 2 to 6 membered heteroalkyl optionally substituted by a 5 to 10 membered heteroaryl. In certain embodiments, A1 is phenyl substituted by (a) 0 or 1 occurrence of Y2 and (b) the 2- to 6-membered heteroalkyl substituted by a 5- to 6-membered heteroaryl (which may be, for example, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl or thiazolinyl, each of which is optionally substituted by one or two substituents independently selected from the group consisting of C1-6 alkyl, C3- 6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, -N(R4)2, amide, and -CO2H). In certain embodiments, A1 is phenyl substituted by (a) 0 or 1 occurrence of Y2 and (b) a 2 to 4 membered heteroalkyl substituted by pyridinyl.

[0098] In certain embodiments, A1 is phenyl substituted by (a) 0 or 1 occurrence of Y2 and (b) -CHC-(CI-6 alkylene)-OR4. In certain embodiments, A1 is phenyl substituted by (a) 0 or 1 occurrence of Y2 and (b) -CHC-CH2-O-CH3. In certain embodiments, A1 is phenyl substituted by -CHC-CH2-O-CH3.

[0099] In certain embodiments, A1 is C3-7 cycloalkyl replaced once by Y1 and 0 to 1 occurrence of Y2.

[00100] In certain embodiments, A1 is a bicyclic heterocyclyl containing at least one ring nitrogen atom, in which the bicyclic heterocyclyl is replaced by 0, 1 or 2 occurrences of Y1 and 0, 1, 2 or 3 occurrences of Y2.

[00101] In certain embodiments, Y1 is a 2 to 8 membered heteroalkyl optionally substituted by a 6 to 10 membered aryl or a 3 to 10 membered heterocyclyl. In certain embodiments, Y1 is a 2 to 8 membered heteroalkyl substituted by a 6 to 10 membered aryl or a 3 to 10 membered heterocyclyl. In certain embodiments, Y1 is a 2 to 8 membered heteroalkyl substituted by a 3 to 10 membered heterocyclyl. In certain embodiments, Y1 is a 2 to 8 membered heteroalkyl substituted by a 5 to 6 membered heteroaryl, such as pyrrolyl, furanyl or pyridinyl. In certain embodiments, Y1 is a 2 to 8 membered heteroalkyl.

[00102] In certain embodiments, Y1 is -O-(C1-7 alkyl). In certain embodiments, Y1 is -O-butyl, -O-pentyl or -O-hexyl. In certain embodiments, Y1 is -(C1-3 alkylene)-O-(5-6 membered heteroaryl). In certain embodiments, Y1 is -CH2-O-(5-6 membered heteroaryl). In certain embodiments, Y1 is -CH2-O- (5- to 6-membered heteroaryl), wherein the 5- to 6-membered heteroaryl is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, -N(R4)2, amide, and -CO2H.

[00103] In certain embodiments, Y1 is a 3 to 10 membered heterocyclyl, 6 to 10 membered aryl, -O-((3 to 6 membered heterocyclyl) -O-(6 to 10 membered aryl) or -O -(C2-6 alkynyl). In certain embodiments, Y1 is a 3-10 membered heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocyclyl. 5-membered heteroaryl. In certain embodiments, Y1 is 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C1-6 alkyl, C3-7 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, -N(R4)2, amide, and -CO2H In certain embodiments, Y1 is 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C1. -6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, hydroxyl, and C1-6 alkoxy.

[00104] In certain embodiments, Y1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl or thiazolyl. In certain embodiments, Y1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, -N(R4)2, amide, and -CO2H.

[00105] In certain embodiments, Y1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl or triazolinyl. In certain embodiments, Y1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl or triazolinyl, each of which is substituted by one or two substituents independently selected from the group that consists of C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, -N(R4)2, amide, and -CO2H.

[00106] In certain embodiments, Y1 is C2-6 alkynyl, -C=C- (C1-6 alkylene)-OR4, -CHC-(CI-6 alkylene)-N(R3)2, -(C2-4 alkynylene )- (5- to 6-membered heteroaryl), or C2-6 alkenyl. In certain embodiments, Y1 is C2-6 alkynyl. In certain embodiments, Y1 is - C^CH. In certain embodiments, Y1 is -CHC-(CI-6 alkylene)-OR4. In certain embodiments, Y1 is -CHC-(CI-6 alkylene)-O-(C1-2 alkyl). In certain embodiments, Y1 is -CHC-CH2-O-CH3.

[00107] The above description describes multiple modalities relating to compounds of formula I-1. The patent application specifically contemplates all combinations of modalities. For example, the invention contemplates a compound of formula I-1 in which X1 is - C(O)N(H)-^, A1 is phenyl substituted by (a) 0, 1, 2 or 3 occurrences of Y2 and (b ) 4- to 8-membered heteroalkyl, and Y1 is C1-6 alkyl or halogen.

[00108] In certain embodiments, the compound is a compound of formula IA: or a pharmaceutically acceptable salt thereof, wherein: R1 is independently methyl, cyclopropyl, isopropyl or -(C1-4 alkylene)-(2 to 6 membered heteroalkyl); R2 is hydrogen; R3 and R4 each independently represent hydrogen or C1-4 alkyl; A1 is one of the following: • C3-10 cycloalkyl that is substituted by 1 or 2 occurrences of Y1 and 0, 1, 2 or 3 occurrences of Y2; and • 1,2,3,4-tetrahydronaphthalenyl substituted by 0, 1, 2 or 3 occurrences of Y2; • 1 represents, independently for each occurrence, 2 to 8 membered heteroalkyl; • 2 represents, independently for each occurrence, C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, azido, -N(R3)2 , -(C1-6 alkylene)- (5- to 6-membered heterocyclyl), -(C1-6 alkylene)-CO2R3 or C3-6 cycloalkyl substituted by C1-6 haloalkyl.

[00109] Definitions of variables in formula I-A above cover multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups mentioned above, ii) the definition is a collection of two or more of the chemical groups selected from those mentioned above, and iii) the compound is defined by a combination of variables where the variables are defined by (i) or (ii).

[00110] Consequently, in certain embodiments, any occurrence of Y2 is independently C1-3 alkyl, halogen or C1-3 haloalkyl.

[00111] In certain embodiments, A1 is C3-10 cycloalkyl that is replaced by 1 or 2 occurrences of Y1 and 0, 1, 2 or 3 occurrences of Y2. In certain embodiments, A1 is 1,2,3,4-tetrahydronaphthalenyl substituted by 0, 1, 2 or 3 occurrences of Y2.

[00112] In certain embodiments, R1 is methyl. In certain embodiments, R1 is also selected from halogen and halomethyl, such that R1 can be methyl, halogen or halomethyl.

[00113] In certain embodiments, R2 is also selected from halogen, such that R2 can be hydrogen or halogen.

[00114] The above description describes multiple modalities relating to compounds of formula I-A. The patent application specifically contemplates all combinations of modalities. For example, the invention contemplates a compound of formula I-A in which R1 is methyl, and A1 is phenyl substituted by (a) 0, 1, 2 or 3 occurrences of Y2 and (b) C4-8 alkoxy.

[00115] In certain embodiments, the compound is a compound of formula I-A1: or a pharmaceutically acceptable salt thereof, wherein: R1 is independently methyl, cyclopropyl or isopropyl; R2 is hydrogen; R3 and R4 each independently represent hydrogen or C1-4 alkyl; A1 is phenyl substituted by (a) 0, 1, 2 or 3 occurrences of Y2 and (b) one of the following: (i) C4-8 alkoxy; (ii) 2- to 4-membered heteroalkyl, substituted by a 5- to 10-membered heteroaryl; or (iii) -CHC-(C1-6alkylene)-OR4; and Y2 represents, independently for each occurrence, C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, azido, -N(R3)2 , -(C1-6 alkylene)- (5- to 6-membered heterocyclyl), -(C1-6 alkylene)-CO2R3 or C3-6 cycloalkyl substituted by C1-6 haloalkyl.

[00116] Definitions of variables in formula I-A above cover multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups mentioned above, ii) the definition is a collection of two or more of the chemical groups selected from those mentioned above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), for example, such as where R1 is methyl, and A1 is phenyl substituted by C4-8 alkoxy.

[00117] Consequently, in certain embodiments, any occurrence of Y2 is independently C1-3 alkyl, halogen or C1-3 haloalkyl.

[00118] In certain embodiments, A1 is phenyl substituted by (a) 0 or 1 occurrence of Y2 and (b) C4-8 alkoxy. In certain embodiments, A1 is phenyl substituted by -O-(C4-7 alkyl). In certain embodiments, A1 is phenyl substituted by -O-(C4-7 alkyl) in the para position of the phenyl group. In certain embodiments, A1 is phenyl substituted by -O-butyl, -O-pentyl or -O-hexyl. In certain embodiments, A1 is phenyl substituted by -O-butyl, -O-pentyl or -O-hexyl in the para position of the phenyl group. In certain embodiments, A1 is substituted phenyl, it is -OCH2CH2OCH2CH2.

[00119] In certain embodiments, A1 is phenyl substituted by (a) 0 or 1 occurrence of Y2 and (b) a 2 to 4 membered heteroalkyl substituted by a 5 to 6 membered heteroaryl (which may be, for example, pyridinyl , pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl or thiazolinyl, each of which is optionally substituted by one or two substituents independently selected from the group consisting of C1-6 alkyl, C3 -6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, -N(R4)2, and amide). In certain embodiments, A1 is phenyl substituted by (a) 0 or 1 occurrence of Y2 and (b) a 2 to 4 membered heteroalkyl substituted by pyridinyl.

[00120] In certain embodiments, A1 is phenyl substituted by (a) 0 or 1 occurrence of Y2 and (b) -CHC-(CI-6 alkylene)-OR4, where R4 is C1-4 alkyl. In certain embodiments, A1 is phenyl substituted by (a) 0 or 1 occurrence of Y2 and (b) -C=C-CH2-O-CH3. In certain embodiments, A1 is phenyl substituted by -CHC-CH2-O-CH3.

[00121] In certain embodiments, R1 is methyl. In certain embodiments, R1 is also selected from halogen and halomethyl, such that R1 can be methyl, halogen or halomethyl.

[00122] In certain embodiments, R2 is also selected from halogen, such that R2 can be hydrogen or halogen.

[00123] The above description describes multiple modalities relating to compounds of formula I-A1. The patent application specifically contemplates all combinations of modalities. For example, the invention contemplates a compound of formula I-A1 in which R1 is methyl, and A1 is phenyl substituted by (a) 0, 1, 2 or 3 occurrences of Y2 and (b) C4-8 alkoxy.

[00124] In certain embodiments, the compound is a compound of formula IB: or a pharmaceutically acceptable salt thereof, wherein: A1 is phenyl substituted by (a) 0 or 1 occurrence of Y2 and (b) C4-8 alkoxy or -C=C-(C1-6alkylene)-O-(C1- 3 alkyl); and Y2 represents, independently for each occurrence, C1-6 alkyl, C3-6 cycloalkyl, halogen or C1-6 haloalkyl.

[00125] Definitions of variables in formula I-B above cover multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups mentioned above, ii) the definition is a collection of two or more of the chemical groups selected from those mentioned above, and iii) the compound is defined by a combination of variables where the variables are defined by (i) or (ii).

[00126] Another aspect of the invention provides a compound of formula II: or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 each independently represent for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, cyclopropyl, cyano, chlorine or fluorine; R3 represents independently for each occurrence hydrogen or C1-4 alkyl; R4 represents independently for each occurrence hydrogen, C1-4 alkyl or -C(O)R3; X1 is one of the following: (a) a carbonyl-containing ligand selected from - C(O)N(H)-V and -C(O)N(H)(CI-6 alkylene)—v; where v is a connection to A1; or (b) an amine-containing ligand selected from -(C1-4 alkylene)-N(H)-ve -(C1-4 alkylene)-N(H)-(C1-4 alkylene)-v; A1 is phenyl substituted by (a) 0, 1, 2 or 3 occurrences of Y2 and (b) one of the following: • phenyl substituted by 0, 1, 2 or 3 occurrences of Y2; • 4-pyridinyl substituted by 0, 1, 2 or 3 occurrences of Y2; • -C=C-(Ci-6 alkylene)-(5- to 6-membered heterocyclyl); • a bicyclic carbocyclyl that is partially unsaturated and substituted by (a) a 3- to 10-membered heterocyclyl, and (b) 0, 1, 2 or 3 occurrences of Y2; • piperazinyl substituted by 0, 1 or 2 occurrences of Y2; or • both C1-6 alkoxy and C2-4 alkynyl; Y2 represents, independently for each occurrence, C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, azido, -N(R3)2, -(C1-6 alkylene)- (5- to 6-membered heterocyclyl), -(C1-6 alkylene)-CO2R3 or C3-6 cycloalkyl substituted by C1-6 haloalkyl; en is 1, 2 or 3.

[00127] Definitions of variables in formula II above cover multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups mentioned above, ii) the definition is a collection of two or more of the chemical groups selected from those mentioned above, and iii) the compound is defined by a combination of variables where the variables are defined by (i) or (ii), for example, such as where R1 is C1-4 alkyl or cyclopropyl, X1 is - C(O)N(H) -^, and A1 is phenyl substituted for phenyl.

[00128] Consequently, in certain embodiments, R1 independently represents for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, cyclopropyl, cyano, chlorine or fluorine. In certain embodiments, R1 is methyl. In certain embodiments, the R1 groups are located at positions 5 and 7 of the pyrazolo[1,5-a]pyrimidinyl.

[00129] In certain embodiments, n is 2. In certain other embodiments, n is 1.

[00130] In certain embodiments, R2 is hydrogen. In certain embodiments, R2 is methyl or halogen. In certain embodiments, R2 is methyl or halomethyl. In certain embodiments, R2 is methyl or cyclopropyl.

[00131] In certain embodiments, R3 and R4 each independently represent hydrogen, methyl or ethyl for each occurrence. In certain embodiments, R3 is hydrogen. In certain embodiments, R4 is hydrogen.

[00132] In certain embodiments, X1 is -C(O)N(H)-v.

[00133] In certain embodiments, any occurrence of Y2 is independently C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl or hydroxyl. In certain embodiments, any occurrence of Y2 is independently C1-3 alkyl.

[00134] The above description describes multiple modalities relating to compounds of formula II. The patent application specifically contemplates all combinations of modalities. For example, the invention contemplates a compound of formula II in which X1 is -C(O)N(H)- V and A1 is phenyl substituted by (a) 0, 1, 2 or 3 occurrences of Y2 and (b) phenyl .

[00135] Another aspect of the invention provides a compound of formula IIa: or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 each independently represent for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, -(C1-4 alkylene)-(heteroalkyl of 2 to 6 members), cyclopropyl, cyano, chlorine or fluorine; R3 represents independently for each occurrence hydrogen or C1-4 alkyl; R4 represents independently for each occurrence hydrogen, C1-4 alkyl or -C(O)R3; X1 is one of the following: (a) a carbonyl-containing ligand selected from - C(O)N(H)-V and -C(O)N(H)(CI-6 alkylene)—v; where v is a connection to A1; or (b) an amine-containing ligand selected from -(C1-4 alkylene)-N(H)-ve -(C1-4 alkylene)-N(H)-(C1-4 alkylene)-v; A1 is one of the following: • C3-10 cycloalkyl that is substituted by (a) 1, 2 or 3 halogens and (b) 0, 1, 2 or 3 occurrences of Y2; • phenyl substituted by (a) halogen or C1-6 alkoxy and (b) 0, 1, 2 or 3 occurrences of Y2; or • phenyl substituted by (a) 0, 1, 2 or 3 occurrences of Y2 and (b) one of the following: the phenyl substituted by 0, 1, 2 or 3 occurrences of Y2; the 4-pyridinyl substituted by 0, 1, 2 or 3 occurrences of Y2; o -C=C-(CI-6 alkylene)-(5- to 6-membered heterocyclyl); o a bicyclic carbocyclyl that is partially unsaturated and substituted by (a) a 3- to 10-membered heterocyclyl, and (b) 0, 1, 2 or 3 occurrences of Y2; the piperazinyl substituted by 0, 1 or 2 occurrences of Y2; or both C1-6 alkoxy and C2-4 alkynyl; Y2 represents, independently for each occurrence, C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, azido, -N(R3)2, -(C1-6 alkylene)- (5-6 membered heterocyclyl), -(C1-6 alkylene)-CO2R3 or C3-6 cycloalkyl substituted by C1-6 haloalkyl; en is 1, 2 or 3; provided that if X1 is optionally substituted halophenyl or -phenyl-methoxy, then X1 is -C(O)N(H)(C2-6 branched alkylene)-^.

[00136] Definitions of variables in formula IIa above cover multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups mentioned above, ii) the definition is a collection of two or more of the chemical groups selected from those mentioned above, and iii) the compound is defined by a combination of variables where the variables are defined by (i) or (ii), for example, such as where R1 is C1-4 alkyl or cyclopropyl, X1 is - C(O)N(H) -\|/, and A1 is phenyl substituted for phenyl.

[00137] Consequently, in certain embodiments, R1 independently represents for each occurrence C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, cyclopropyl, cyano, chlorine or fluorine. In certain embodiments, R1 is methyl.

[00138] In certain embodiments, n is 2.

[00139] In certain embodiments, R1 groups are located at positions 5 and 7 of the pyrazolo[1,5-a]pyrimidinyl.

[00140] In certain embodiments, X1 is -C(O)N(H)-^.

[00141] Another aspect of the invention provides a compound of formula III: or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 each independently represent for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, -(C1-4 alkylene)-(2-heteroalkyl) to 6 members), cyclopropyl, cyano, chlorine or fluorine; R3 represents independently for each occurrence hydrogen or C1-4 alkyl; R4 represents independently for each occurrence hydrogen, C1-4 alkyl or -C(O)R3; X1 is one of the following: (a) a carbonyl-containing ligand selected from - C(O)N(H)-V and -C(O)N(H)(CI-6 alkylene)—v; where v is a connection to A1; or (b) an amine-containing ligand selected from -(C1-4 alkylene)-N(H)-ve -(C1-4 alkylene)-N(H)-(C1-4 alkylene)-v; A1 is a cyclic group selected from: • phenyl substituted by (a) 0, 1, 2 or 3 occurrences of Y2 and (b) one of the following: (i) a 5-membered heteroryl substituted by 0, 1, 2 or 3 occurrences of Y2; (ii) -(C1-6 alkylene)-CO2R3; or (iii) C1-6 hydroxyalkyl; • 5- to 6-membered heteroaryl substituted by 1 or 2 occurrences of Y1 and 0, 1, 2 or 3 occurrences of Y2; • 1 represents, independently for each occurrence, one of the following: • 2 to 8 membered heteroalkyl optionally substituted by a 6 to 10 membered aryl or a 3 to 10 membered heterocyclyl; • 3- to 10-membered heterocyclyls, 6 to 10-membered aryl, C3-7 cycloalkyl, -O-((3- to 6-membered heterocyclyl) -O-(6- to 10-membered aryl) or -O-(C2- 6 alkynyl); or • C2-6 alkynyl, -CsC-(Ci-β alkylene)-OR4, -CsC-(Ci-β alkylene)-N(R3)2, -(C2-4 alkynylene)-( 5- to 6-membered heteroaryl), or C2-β alkenyl; • 2 represents, independently for each occurrence, Ci-β alkyl, C3-β cycloalkyl, halogen, Ci-β haloalkyl, Ci-β hydroxyalkyl, hydroxyl, Ci -β alkoxyl, cyano, azido, -N(R3)2, -(Ci-β alkylene)- (5- to β-membered heterocyclyl), -(Ci-β alkylene)-CO2R3 or C3-β cycloalkyl substituted by Ci-β haloalkyl; en is i, 2 or 3.

[00142] Definitions of variables in formula III above cover multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups mentioned above, ii) the definition is a collection of two or more of the chemical groups selected from those mentioned above, and iii) the compound is defined by a combination of variables where the variables are defined by (i) or (ii), for example, such as where Ri is Ci-4 alkyl or cyclopropyl, X1 is -C(O)N(H) -^, and A1 is phenyl substituted by a 5-membered heteroaryl.

[00143] Consequently, in certain embodiments, R1 independently represents for each occurrence C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, cyclopropyl, cyano, chlorine or fluorine. In certain embodiments, R1 is methyl. In certain embodiments, the R1 groups are located at positions 5 and 7 of the pyrazolo[1,5-a]pyrimidinyl.

[00144] In certain embodiments, n is 2. In certain other embodiments, n is 1.

[00145] In certain embodiments, R2 is hydrogen. In certain embodiments, R2 is methyl or halogen. In certain embodiments, R2 is methyl or halomethyl. In certain embodiments, R2 is methyl or cyclopropyl.

[00146] In certain embodiments, R3 and R4 each independently represent hydrogen, methyl or ethyl for each occurrence. In certain embodiments, R3 is hydrogen. In certain embodiments, R4 is hydrogen.

[00147] In certain embodiments, X1 is -C(O)N(H)-^.

[00148] In certain embodiments, any occurrence of Y2 is independently C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl or hydroxyl. In certain embodiments, any occurrence of Y2 is independently C1-3 alkyl.

[00149] In certain embodiments, A1 is phenyl substituted by (a) 0, 1, 2 or 3 occurrences of Y2 and (b) 5-membered heteroaryl substituted by 0, 1, 2 or 3 occurrences of Y2. In certain embodiments, A1 is phenyl substituted by (a) C1-6 alkyl or halogen and (b) 5-membered heteroaryl selected from the group consisting of furanyl, thiophenyl or oxazolyl.

[00150] In certain embodiments, A1 is phenyl substituted by C1-6 hydroxyalkyl.

[00151] In certain embodiments, A1 is a 5- to 6-membered heteroaryl substituted by 1 or 2 occurrences of Y1 and a 5-membered heteroaryl selected from the group consisting of furanyl, thiophenyl or oxazolyl. In certain embodiments, A1 is pyridinyl substituted by 1 or 2 occurrences of Y1 and 5-membered heteroaryl selected from the group consisting of furanyl, thiophenyl or oxazolyl.

[00152] In certain embodiments, Y1 is a 2 to 8 membered heteroalkyl optionally substituted by a 6 to 10 membered aryl or a 3 to 10 membered heterocyclyl. In certain embodiments, Y1 is a 2 to 8 membered heteroalkyl substituted by a 6 to 10 membered aryl or a 3 to 10 membered heterocyclyl. In certain embodiments, Y1 is a 2 to 8 membered heteroalkyl substituted by a 3 to 10 membered heterocyclyl. In certain embodiments, Y1 is a 2 to 8 membered heteroalkyl substituted by a 5 to 6 membered heteroaryl, such as pyrrolyl, furanyl or pyridinyl. In certain embodiments, Y1 is a 2 to 8 membered heteroalkyl.

[00153] In certain embodiments, Y1 is -O-(C1-7 alkyl). In certain embodiments, Y1 is -O-butyl, -O-pentyl or -O-hexyl. In certain embodiments, Y1 is -(C1-3 alkylene)-O-(5-6 membered heteroaryl). In certain embodiments, Y1 is -CH2-O- (5- to 6-membered heteroaryl). In certain embodiments, Y1 is -CH2-O-(5- to 6-membered heteroaryl), wherein the 5- to 6-membered heteroaryl is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, or pyridinyl, each of which it is substituted by one or two substituents independently selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, -N( R4)2, and amide.

[00154] In certain embodiments, Y1 is a 3 to 10 membered heterocyclyl, 6 to 10 membered aryl, C3-7 cycloalkyl, -O- ((3 to 6 membered heterocyclyl) -O-(6 to 10 membered aryl members) or -O- (C2-6 alkynyl). In certain embodiments, Y1 is 5-membered heteroaryl. , C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, -N(R4)2, and amide In certain embodiments, Y1 is 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C1-. 6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, hydroxyl, and C1-6 alkoxy.

[00155] In certain embodiments, Y1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl or thiazolyl. In certain embodiments, Y1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, -N(R4)2, and amide.

[00156] In certain embodiments, Y1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl or thiazolinyl. In certain embodiments, Y1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl or thiazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, -N(R4)2, and amide.

[00157] In certain embodiments, Y1 is C2-6 alkynyl, -C=C- (C1-6 alkylene)-OR4, -CHC-(CI-6 alkylene)-N(R3)2, -(C2-4 alkynylene )- (5- to 6-membered heteroaryl), or C2-6 alkenyl. In certain embodiments, Y1 is C2-6 alkynyl. In certain embodiments, Y1 is -C=CH. In certain embodiments, Y1 is -CHC-(CI-6 alkylene)-OR4. In certain embodiments, Y1 is -CHC-(C1-6 alkylene)-O- (C1-2 alkyl). In certain embodiments, Y1 is -CHC-CH2-O-CH3.

[00158] The above description describes multiple modalities relating to compounds of formula III. The patent application specifically contemplates all combinations of modalities. For example, the invention contemplates a compound of formula III in which R1 is methyl, X1 is -C(O)N(H)-v, A1 is phenyl substituted by (a) 0, 1, 2 or 3 occurrences of Y2 and (b) a 5-membered heteroaryl.

[00159] In certain embodiments, the compound is a compound of formula III-A: or a pharmaceutically acceptable salt thereof, wherein: R1 is independently methyl, cyclopropyl or isopropyl; R2 is hydrogen; and A1 is phenyl substituted by (a) C1-6 alkyl or halogen and (b) 5-membered heteroaryl selected from the group consisting of furanyl, thiophenyl or oxazolyl C4-8 alkoxy, each of which is optionally substituted by 1 or substituents independently selected from the group consisting of alkyl, halogen, and haloalkyl.

[00160] Definitions of variables in formula III-A above cover multiple chemical groups. The application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups mentioned above, ii) the definition is a collection of two or more of the chemical groups selected from those mentioned above, and iii) the compound is defined by a combination of variables where the variables are defined by (i) or (ii).

[00161] In certain other embodiments, the compound is one of the compounds listed in table 1 or 2 below or a pharmaceutically acceptable salt thereof. TABLE 1. Where in Table 1, y is a link to A1. TABLE 2.

[00162] Methods for preparing compounds described here are illustrated in the following synthetic schemes. These diagrams are given for the purpose of illustrating the invention, and should not be considered in any way as limiting the scope or spirit of the invention. Starting materials shown in the diagrams can be obtained from commercial sources or can be prepared based on procedures described in the literature.

[00163] The synthetic route illustrated in Scheme 1 represents an exemplary procedure for the preparation of substituted pyrazolo[1,5-a]pyrimidine compounds. In the first step, ethyl 5-amino-1H-pyrazol-4-carboxylate (Ri=H) A is condensed with pentan-2,4-dione (Rii=Riv=Me; Riii=H) in acetic acid at 80oC to give rise to 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid B. Hydrolysis of ethyl ester B under basic conditions gives 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3- acid carboxylic C. SCHEME 1

[00164] The synthetic route illustrated in Scheme 2 represents an exemplary procedure for the preparation of substituted pyrazolo[1,5-a]pyrimidine compounds. In the first step, coupling of C carboxylic acid with a variety of substituted aromatic or heteroaromatic amines can be performed using standard peptide coupling procedures such as HATU and/or HOBT in DMF in the presence of DIPEA. Alternatively, carboxylic ester B can be treated with AlMe3 to give the Weinreb amide intermediate, which upon reaction with an amine gives substituted amide D. In some cases, the reaction is carried out in a stepwise manner, where a heteroaromatic or substituted aromatic amine by iodine or bromine is coupled with the Weinreb amide to form the iodine- or bromine-substituted amide E. The bromine or iodine moiety can be used to couple a variety of functional groups using standard coupling procedures, such as acetylenes using Sonogashira coupling , boronic acids using Suzuki coupling, and amines using Buchwald coupling to produce substituted amide D. SCHEME 2

[00165] The reaction procedures in Scheme 2 are contemplated to be amenable to the preparation of a wide variety of substituted pyrazolo[1,5-a]pyrimidine carboxamide compounds having different substituents at the A1 and Y1 positions. Furthermore, if a functional group that is part of A1 and/or Y1 is not amenable to a reaction condition described in Scheme 2, it is contemplated that the functional group may first be protected using chemistry and protecting group strategies. standard, and then the protecting group is removed after completing the desired synthetic transformation. See, for example, Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991, for another description of chemistry and protection strategies. In certain other embodiments, a functional group on the A1 and Y1 substituent can be converted to another functional group using standard functional group manipulation procedures known in the art. See, for example, "Comprehensive Organic Synthesis" (B.M. Trost & I. Fleming, eds., 19911992).

III. THERAPEUTIC REQUESTS

[00166] The invention provides methods of treating medical disorders such as Gaucher disease, Parkinson's disease, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, major depression , polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis, and multiple myeloma, using the substituted pyrazolo[1,5-a]pyrimidine, related compounds, and pharmaceutical compositions described herein. Treatment methods include the use of substituted pyrazolo[1,5-a]pyrimidine or related organic compounds described herein as independent therapeutic agents and/or as part of a combination therapy with another therapeutic agent. While not wishing to be bound by a particular theory, it is understood that substituted pyrazolo[1,5-a]pyrimidine and related organic compounds described herein can activate glucocerebrosidase (Gcase).

Methods of Treating Medical Disorders

[00167] One aspect of the invention provides a method of treating a disorder selected from the group consisting of Gaucher disease, Parkinson's disease, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis, and multiple myeloma. The method comprises administering to a patient in need thereof, a therapeutically effective amount of a substituted pyrazolo[1,5-a]pyrimidine or related organic compound described herein to treat the disorder. The compound may be a compound of formula I, which, as described above in Section II, is represented by: or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 each independently represent for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, -(C1-4 alkylene)-(heteroalkyl of 2 6-membered), cyclopropyl, cyano, chlorine, fluorine or -N(H)(R3); R3 represents independently for each occurrence hydrogen or C1-4 alkyl; R4 represents independently for each occurrence hydrogen, C1-4 alkyl or -C(O)R3; X1 is one of the following: (a) a carbonyl-containing ligand selected from -C(O)N(H)- V and -C(O)N(H)(CI-6 alkylene)—v; where v is a connection to A1; or (b) an amine-containing ligand selected from -(C1-4 alkylene)-N(H)-V and -(C1-4 alkylene)-N(H)-(C1-4 alkylene)-V; A1 is a cyclic group selected from: • C3-10 cycloalkyl that is substituted by one or two occurrences of Y1 and 0, 1, 2 or 3 occurrences of Y2; • 1,2,3,4-tetrahydronaphthalenyl, 2,3-dihydro-1H-inden-1-yl or 2,3-dihydro-1H-inden-2-yl, each of which is replaced by 0, 1 or 2 occurrences of Y1 and 0, 1, 2 or 3 occurrences of Y2; • phenyl substituted by (a) 0, 1, 2 or 3 occurrences of Y2 and (b) one of the following: (i) 4 to 8 membered heteroalkyl; (ii) 2 to 6 membered heteroalkyl substituted by a 5 to 10 membered heteroaryl; (iii) -C=C-(C1-6 alkylene)-OR4 or -(C2-4 alkynylene)- (5- to 6-membered heterocyclyl); (iv) -O-((3- to 6-membered heterocyclyl) -O-(6- to 10-membered aryl), -O-(C2-6 alkynyl) or azido; or (v) C2-4 alkynyl; and • a bicyclic heterocyclyl containing at least one ring nitrogen atom, wherein the bicyclic heterocyclyl is substituted by 0, 1 or 2 occurrences of Y1 and 0, 1, 2 or 3 occurrences of Y2; one of the following: • 2 to 8 membered heteroalkyl optionally substituted by a 6 to 10 membered aryl or a 3 to 10 membered heterocyclyl; • 3 to 10 membered heterocyclyls, 6 to 10 membered aryl, -O-; ((3-6 membered heterocyclyl) -O-(6-10 membered aryl) or -O-(C2-6 alkynyl); or • C2-6 alkynyl, -CsC-(Ci-6 alkylene)-OR4, -CsC-(Ci-β alkylene)-N(R3)2, -(C2-4 alkynylene)-(5- to 6-membered heteroaryl), or C2-6 alkenyl; C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxyl, C2-4 alkynyl, cyano, azido, -N(R3)2, -(C1 -6 alkylene)-(5-6 membered heterocyclyl), -(C1-6 alkylene)-CO2R3 or C3-6 cycloalkyl substituted by C1-6 haloalkyl; n is 1, 2 or 3; and provided that the following: • when A1 is phenyl substituted by heteroalkyl, at least one of R1 or R2 is other than hydrogen; • when A1 is phenyl substituted by C2-4 alkynyl, then at least one of R1 and R2 is C1-4 alkoxy, -(C1-4 alkylene)- (2 to 6 membered heteroalkyl), cyclopropyl, cyano, chlorine, fluorine or -N(H)(R3); and • there is at least one Y1 or Y2 when A1 is a bicyclic heterocyclyl containing at least one ring nitrogen atom and X1 is -C(O)N(H)-y.

[00168] In certain embodiments, the compound is a compound of formula II. In certain embodiments, the compound is a compound of formula III.

[00169] In certain embodiments, the disorder is Gaucher disease, Parkinson's disease, Lewy body disease, dementia, or multiple system atrophy. In certain embodiments, the disorder is Gaucher disease, Parkinson's disease, Lewy body disease, dementia, or multiple system atrophy. In certain other embodiments, the disorder is Gaucher disease. In certain embodiments, the disorder is Parkinson's disease. In certain embodiments, the disorder is Lewy body disease. In certain embodiments, the disorder is dementia. In certain embodiments, the disorder is dementia selected from the group consisting of Alzheimer's disease, frontotemporal dementia, and a Lewy body variant of Alzheimer's disease. In certain embodiments, the disorder is multiple system atrophy.

[00170] In certain embodiments, the disorder is an anxiety disorder, such as panic disorder, social anxiety disorder, or generalized anxiety disorder.

[00171] Efficacy of the compounds in the treatment of Gaucher disease, Parkinson's disease, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, major depression, polycystic kidney disease, diabetes type 2, open-angle glaucoma, multiple sclerosis, and multiple myeloma can be evaluated by testing the compounds in assays known in the art to evaluate efficacy against these diseases and/or, for example, for activation of glucocerebrosidase (Gcase), as described in the examples below.

[00172] In certain embodiments, the patient is a human.

[00173] In certain embodiments, the compound is one of the generic or specific compounds in Section II, such as a compound of formula I, a compound encompassed by one of the other embodiments describing definitions for certain variables of formula I, a compound of formula I-A or a compound encompassed by one of the other embodiments describing definitions for certain variables of formula I-A. In certain other embodiments, the compound is a compound of formula II or III or a compound encompassed by one of the other embodiments describing definitions for certain variables of formula II or III.

[00174] The above description describes multiple modalities relating to methods of treating various disorders using certain substituted pyrazolo[1,5-a]pyrimidine or related organic compounds. The patent application specifically contemplates all combinations of modalities. For example, the invention contemplates methods for treating Gaucher disease, Parkinson's disease, Lewy body disease, dementia or multiple system atrophy by administering a therapeutically effective amount of a compound of formula IA in which A1 is phenyl replaced by a C4-8 alkoxy.

Medical Use and Medicine Preparation

[00175] Another aspect of the invention relates to compounds and compositions described here for use in treating a disorder described here. Another aspect of the invention relates to the use of a compound or composition described herein in the preparation of a medicament for the treatment of a disorder described herein.

Combination Therapy

[00176] The invention encompasses combination therapy, which includes administration of a substituted pyrazolo[1,5-a]pyrimidine or related compound described herein (such as a compound of formula I, I-A, II or III) and a second agent such as part of a specific treatment regimen designed to provide the beneficial effect of the coercion of these therapeutic agents. The beneficial effect of the combination may include pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.

[00177] Examples of second agents for use in the treatment of Gaucher disease include, for example, taliglucerase alfa, velaglucerase alfa, eliglustat and miglustat. Examples of second agents for use in the treatment of Parkinson's disease include, for example, levodopa, pramipexole, ropinirole, rotigotine and apomorphine.

IV. PHARMACEUTICAL COMPOSITIONS

[00178] The invention provides pharmaceutical compositions comprising a substituted pyrazolo[1,5-a]pyrimidine or related organic compound described herein, such as a compound of formula I, I-A, II or III. In certain embodiments, pharmaceutical compositions preferably comprise a therapeutically effective amount of one or more of the substituted pyrazolo[1,5-a]pyrimidine or related organic compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and /or diluents. As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, potions (aqueous or non-aqueous solutions or suspensions). aqueous), tablets (e.g., those intended for buccal, sublingual, and/or systemic absorption), bolus, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension or extended-release formulation; (3) topical application, for example, as a cream, ointment, or controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream, or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.

[00179] The phrase "therapeutically effective amount" as used herein means that amount of a compound, material or composition comprising a compound of the present invention that is effective to produce some desired therapeutic effects in at least one subpopulation of cells in an animal in a reasonable benefit/risk relationship applicable to any medical treatment.

[00180] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and/or dosage forms that fall within the scope of safe medical diagnosis, suitable for use in contact with the tissues of human beings. and animals without excessive toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[00181] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the compositions.

[00182] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[00183] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration.

[00184] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, from one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent active ingredient, preferably from about 5 percent to about 70 percent, more preferably from about from 10 percent to about 30 percent.

[00185] In certain embodiments, the formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle-forming agents, for example, bile acids, and polymeric carriers, for example, polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, an above-mentioned formulation makes a compound of the present invention orally bioavailable.

[00186] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the vehicle and, optionally, one or more auxiliary ingredients. In general, formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[00187] Formulations of the invention suitable for oral administration may be in the form of capsules, stamps, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powders, granules or as a solution or suspension in a aqueous or non-aqueous liquid or as a liquid oil-in-water or water-in-oil emulsion or as an elixir or syrup or as lozenges (using an inert base such as gelatin and glycerin or sucrose and acacia) and/or as mouthwashes and the like , each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.

[00188] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, tablets, powders, granules, lozenges and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and nonionic surfactants; (8) absorbents, such as kaolin clay and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents, such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard shell gelatin capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[00189] A tablet can be made by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared using binder (e.g., gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfactant or dispersant. Molded tablets can be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[00190] Tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as tablets, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings as well. known in the art of pharmaceutical formulation. They may also be formulated to provide slow or controlled release of the active ingredient herein, using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They can be formulated for rapid release, for example, freeze-dried. They can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporation of sterilizing agents in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately. before use. These compositions may also optionally contain opacifying agents and may be of such a composition that they release the active ingredient(s) only or preferentially, in a certain part of the gastrointestinal tract, optionally, in a delayed manner. Examples of inlay compositions that can be used include waxes and polymeric substances. The active ingredient may also be in microencapsulated form, if appropriate, with one or more of the excipients described above.

[00191] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, acetate. ethyl alcohol, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol , polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof.

[00192] In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavorings, colorings, perfumes and preservatives.

[00193] Suspensions, in addition to active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, esters of sorbitan and polyoxyethylene sorbitol, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and gum - singing, and mixtures thereof.

[00194] Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration can be presented as a suppository, which can be prepared by mixing one or more compounds of the invention with one or more suitable excipients or non-irritating vehicles comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature but liquid at body temperature and will therefore melt in the rectum or vaginal cavity and release the active compound.

[00195] Formulations of the present invention that are suitable for vaginal administration also include pessary, tampon, cream, gel, paste, foam or spray formulations containing such vehicles as are known in the art to be appropriate.

[00196] Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, plasters and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers or propellants, which may be required.

[00197] Ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures thereof.

[00198] Powders and sprays may contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[00199] Transdermal patches have the additional advantage of providing controlled release of a compound of the present invention into the body. Such dosage forms can be made by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The rate of such flow can be controlled either by providing a rate-controlling membrane or by dispersing the compound in a gel or polymer matrix.

[00200] Ophthalmic formulations, ophthalmic ointments, powders, solutions and the like are also contemplated as falling within the scope of this invention.

[00201] Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders that can be reconstituted into solutions or sterile injectable dispersions just before use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[00202] Examples of suitable aqueous and non-aqueous vehicles that can be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Appropriate fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[00203] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms on the subject compounds can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like in the compositions. Furthermore, prolonged absorption of the injectable pharmaceutical form can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[00204] In some cases, in order to prolong the effect of a drug, it is desirable to delay the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends on its rate of dissolution which, in turn, may depend on the crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered form of drug is accomplished by dissolving or suspending the drug in an oily vehicle.

[00205] Injectable depot forms are made by forming microencapsulation matrices of the subject compounds in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

[00206] When the compounds of the present invention are administered as pharmaceuticals to humans and animals, they can be administered alone or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) active ingredient in combination with a pharmaceutically acceptable carrier.

[00207] The preparations of the present invention can be administered orally, parenterally, topically or rectally. They are in fact administered in forms suitable for each route of administration. For example, they are administered in the form of tablets or capsules, by injection, inhalation, ophthalmic lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectally by suppositories. Oral administrations are preferred.

[00208] The phrases "parenteral administration" and "parenterally administered" as used herein mean modes of administration other than enteral and topical administration, generally by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal infusion and injection , intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal.

[00209] The phrases "systemic administration", "systemically administered", "peripheral administration" and "peripherally administered" as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and is thereby subjected to metabolism and other similar processes, for example, subcutaneous administration.

[00210] These compounds can be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as, for example, by a spray, rectally, intravaginally, parenterally, intracisternally, and topically, as by powders, ointments or drops, including buccally and sublingually.

[00211] Regardless of the selected route of administration, the compounds of the present invention, which can be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by known conventional methods by those skilled in the art.

[00212] The actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention can be varied in order to obtain an amount of the active ingredient that is effective to obtain the desired therapeutic response for a particular patient, composition, and mode of administration, without be toxic to the patient.

[00213] The dosage level selected will depend on a variety of factors, including the activity of the particular compound of the present invention employed or the ester, salt or mide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, age, sex, weight, condition, health general and previous medical history of the patient being treated, and similar factors well known in the medical arts.

[00214] A physician or veterinarian skilled in the art can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, the physician or veterinarian may begin doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to obtain the desired therapeutic effect and gradually increase the dosage until the desired effect is obtained.

[00215] In general, a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest effective dose to produce a therapeutic effect. Such effective dose will generally depend on the factors described above. Preferably, the compounds are described at about 0.01 mg/kg to about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0. 5 mg/kg to about 50 mg/kg. When the compounds described herein are co-administered with another agent (e.g., as sensitizing agents), the effective amount may be less than when the agent is used alone.

[00216] If desired, the effective daily dose of the active compound can be administered as two, three, four, five, six or more subdoses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. The preferred dosage is one administration per day.

V. Kits for Use in Medical Applications

[00217] Another aspect of the invention provides a kit for treating a disorder. The kit comprises: i) instructions for treating a medical disorder, such as Gaucher disease, Parkinson's disease, Lewy body disease, dementia or multiple system atrophy; and ii) a substituted pyrazolo[1,5-a]pyrimidine or related organic compound described herein, such as a compound of formula I, I-A, II or III. The kit may comprise one or more unit dosage forms containing an amount of a substituted pyrazolo[1,5-a]pyrimidine or related organic compound described herein, such as a compound of formula I, which is effective for treating said medical disorder. , for example, Gaucher disease, Parkinson's disease, Lewy body disease, dementia or multiple system atrophy.

[00218] The above description describes multiple aspects and embodiments of the invention, including substituted pyrazolo[1,5-a]pyrimidine and related organic compounds, compositions comprising a substituted pyrazolo[1,5-a]pyrimidine or related organic compounds, methods of using substituted pyrazolo[1,5-a]pyrimidine or related organic compounds, and kits. The patent application specifically contemplates all combinations and permutations of aspects and embodiments. For example, the invention contemplates treating Gaucher disease, Parkinson's disease, Lewy body disease, dementia or multiple system atrophy in a human patient by administering a therapeutically effective amount of a compound of formula I-A. Furthermore, for example, the invention contemplates a kit for treating Gaucher disease, Parkinson's disease, Lewy body disease, dementia or multiple system atrophy, the kit comprising instructions for treating Gaucher disease, Parkinson's disease, Lewy body, dementia or multiple system atrophy and ii) a substituted pyrazolo[1,5-a]pyrimidine or related organic compound described herein, such as a compound of formula I-A.

EXAMPLES

[00219] The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for the purposes of illustrating certain aspects and embodiments of the present invention, and are not intended to limit the invention. Example 1 - Preparation of ethyl 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylate (1)

[00220] A mixture of ethyl 3-amino-1H-pyrazol-4-carboxylate (2.0 g, 12.9 mmols) and pentane-2,4-dione (1.46 mL, 14.0 mmols) in acetic acid (10 mL) was refluxed for 16 hours. The reaction mixture was cooled to room temperature and neutralized with saturated NaHCO3, then extracted with ethyl acetate (3 x 100 mL). The organic layer was dried over sodium sulfate and the solvent removed in vacuo to provide the title compound 1 (2.2 g, 78%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.11 (s, 1 H), 4.27 (q, J=7.07 Hz, 2 H), 2, 71 (s, 3 H), 2.57 (s, 3 H), 1.30 (t, J=7.07 Hz, 3 H). ES-MS m/z 220.10 (M+H)+. Example 2 - Preparation of 5,7-dimethylpyrazolo[1,5-a] pyrimidine-3-carboxylic acid (2)

[00221] To a solution of compound 1 (2.2 g, 10.0 mmols) in MeOH (15 mL) was added NaOH (5.67 mL, 7.2 M solution) and the reaction mixture heated to 80 °C for 5 hours. Then, the reaction mixture was cooled and neutralized by 2 M HCl. The solid precipitated from the solution and was filtered and washed with water, ether, and dried under vacuum to give the title compound 2 as a white solid ( 1.3 g, 68%). 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1 H), 6.84 (s, 1 H), 2.65 (s, 3 H), 2.53 (s, 3 H) . ES-MS m/z 192.00 (M+H)+. Example 3 - Preparation of 4-(isoxazol-3-iL)aniline (3)

[00222] To a solution of 3-(4-nitrophenyl)isoxazole (500 mg, 2.63 mmols) in MeOH (30 mL) was added 10% Pd/C (70 mg, 10% weight) under nitrogen atmosphere at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 14 hours. Then, the reaction mixture was filtered, and the filtrate was concentrated under vacuum to give the title compound 3 as a brown sticky oil (550 mg, 93%). 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 1.35 Hz, 1H), 7.54 (d, J = 8.53 Hz, 2H), 6.92 (d, J = 1.35 Hz, 1H), 6.63 (d, J = 8.53 Hz, 2H), 5.53 (s, 2H). Example 4 - Preparation of 4-(oxazol-4-iL)aniline (4)

[00223] To a solution of 4-(4-nitrophenyl)oxazole (500 mg, 2.60 mmols) in MeOH:THF (3:3 mL) was added 10% Pd/C (50 mg, 10% weight) under nitrogen atmosphere at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. Then, the reaction mixture was filtered over a celite pad, and the filtrate was concentrated under vacuum to give the crude compound. The crude compound was purified by FCC (eluent, 30% ethyl acetate in hexane) to give the title compound 4 as a light brown thick liquid (260 mg, 62%). 1H NMR (400 MHz, DMSO-d6) δ 8.27-8.34 (m, 2H), 7.40-7.46 (m, 2H), 6.56-6.62 (m, 2H), 5.23 (s, 2H). ES-MS m/z 160.95 (M+H)+. Example 5 - Preparation of N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide (5)

[00224] A solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (1.5 g, 7.84 mmols) in DMF (7.5 mL) was charged with HATU (4 .4 g, 11.7 mmols), DIPEA (4.2 mL, 23.5 mmols) and 4-iodoaniline (2.06 g, 9.4 mmols) at room temperature and stirred for 16 hours. The reaction mixture was quenched with water (1 mL), the precipitated solid was filtered and dried to obtain the crude compound. The crude compound was purified by 100 to 200 mesh size silica gel column chromatography (eluent, 3 to 5% methanol) to give the title compound 5 as a white solid in DCM (1.7 g, 56%). 1H NMR (400 MHz, CDCl3) δ 10.14 (br s, 1H), 8.67 (s, 1H), 7.65 (d, J=8.38 Hz, 2H), 7.54 (d, J=8.38 Hz, 2H), 6.77 (s, 1H), 2.82 (s, 3H), 2.71 (s, 3H). Example 6 - Preparation of 5,7-dimethyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine -3-carboxamide (6)

[00225] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide 5 (1 g, 2.5 mmols) in DMF (25 mL) was charged with bispinacholate diboron (1.3 g, 5.1 mmols), potassium acetate (736 mg, 7.5 mmols) and Pd(dppf)Cl2 DCM adduct (204 mg, 0.25 mmol) under argon at room temperature . The reaction mixture was heated at 100°C for two hours. The reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (3 X 30 mL) and concentrated in vacuo to obtain the crude compound. The crude compound was purified by trituration in 10% ethanol:n-hexane to give title compound 6 as a brown solid (800 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 10.20 (br s, 1H), 8.69 (s, 1H), 7.84 (d, J=8.13 Hz, 2H), 7.76 (d, J=8.13 Hz, 2H), 6.76 (s, 1H), 2.82 (s, 3H), 2.73 (s, 3H), 1.26 (s, 12H). Example 7 - General procedure A (Amidation reaction)

[00226] A mixture of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (150 mg, 0.78 mmol), DIPEA (0.408 mL, 2.35 mmols) and HATU (300 mg , 0.78 mmol) was dissolved in DMF (4 mL) and stirred at room temperature (RT) for one hour. Then, the corresponding amine (0.78 mmol) was added to a reaction mixture and stirred at RT for 16 hours. The reaction mixture was diluted with water and filtered. The residue was washed again with water (3 x 20 mL) and recrystallized from ether to obtain a white solid compound. Example 8 - General procedure B (Amidation reaction)

[00227] To a stirred solution of amine (1.1 eq) in toluene (8 mL) was added AlMe3 (2 M solution, 4 eq) at 0°C and the mixture stirred at room temperature for 30 minutes. To this reaction mixture ethyl 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylate 1 (1 eq) was added and the reaction mixture stirred at 110°C for 18 hours or until the starting material be consumed. The reaction was quenched with HCl (1 M, 0.5 mL) and extracted with ethyl acetate (3 X 10 mL) to obtain the crude compound. The crude compound was purified by FCC (eluent, MeOH in 2% DCM) and again trituration with ether to give the desired compound as a solid. Example 9 - Preparation of 5,7-dimethyl-N-(5-ethynylpyridin-2-iL)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00228] Using general procedure B, the title compound was obtained as a white solid (20%). 1H NMR (400 MHz, CDCl3) δ 10.69 (br s, 1 H), 8.70 (s, 1 H), 8.47 (d, J=1.82 Hz, 1 H), 8.41 (d, J=8.63 Hz, 1 H), 7.81 (dd, J=8.63, 1.82 Hz, 1 H), 6.78 (s, 1 H), 3.16 (s , 1 H), 2.82 (s, 3 H), 2.76 (s, 3 H). ES-MS m/z 292.15 (M+H)+. HPLC purity 99.8%. Example 10 - Preparation of 5,7-dimethyl-N-(6-ethynylpyridin-3-iL)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00229] Using general procedure B, the title compound was obtained as a white solid (50%). 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1 H), 8.89 (d, J=2.13 Hz, 1 H), 8.67 (s, 1 H), 8, 27 (dd, J=8.31, 2.77 Hz, 1 H), 7.59 (d, J=8.40 Hz, 1 H), 7.22 (s, 1 H), 4.26 ( s, 1 H), 2.77 (s, 3 H), 2.72 (s, 3 H). ES-MS m/z 292.15 (M+H)+. HPLC: 98.3%. Example 11 - Preparation of N-([1,1'-biphenyl]-4-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00230] Using general procedure A, the title compound was obtained as a white solid (29 mg, 11%). 1H NMR (400 MHz, CDCl3) δ 10.20 (s, 1 H), 8.70 (s, 1 H), 7.83 (d, J=8.76 Hz, 2 H), 7.61 ( d, J=8.34 Hz, 4 H), 7.44 (t, J=7.71 Hz, 2 H), 7.30 - 7.35 (m, 1 H), 6.71 - 6, 81 (m, 1 H), 2.81 (s, 3 H), 2.72 (s, 3 H). ES-MS m/z 343.25 (M+H)+. HPLC purity 98.4%. Example 12 - Preparation of N-(4-(3-methoxyprop-1-yn-1-iL)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00231] Using general procedure A, the title compound was obtained as a white solid (39 mg, 15%). 1H NMR (400 MHz, CDCl3) δ 10.22 (br s, 1 H), 8.68 (s, 1 H), 7.72 (d, J=8.61 Hz, 2 H), 7.46 (d, J=8.61 Hz, 2 H), 6.71 - 6.82 (m, 1 H), 4.34 (s, 2 H), 3.47 (s, 3 H), 2, 82 (s, 3 H), 2.71 (s, 3 H). ES-MS m/z 335.15 (M+H)+. HPLC purity 95.1%. Example 13 - Preparation of 5,7-dimethyl-N-(4-phenoxyphenyl)pyrazolo [1,5-a]pyrimidine-3-carboxamide

[00232] Using general procedure A, the title compound was obtained as an off-white solid (90 mg, 32%). 1H NMR (400 MHz, CDCl3) δ 10.10 (br s, 1 H), 8.69 (s, 1 H), 7.72 (d, J=8.76 Hz, 2 H), 7.30 - 7.38 (m, 2 H), 6.96 - 7.13 (m, 5 H), 6.76 (s, 1 H), 2.82 (s, 3 H), 2.70 (s , 3H). ES-MS m/z 359.20 (M+H)+. HPLC purity 98.3%. Example 14 - Preparation of 5,7-dimethyl-N-(4-(1H-Imidazol-1-iL)phenyl) pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00233] Using general procedure A, the title compound was obtained as an off-white solid (151 mg, 58%). 1H NMR (400 MHz, CDCl3) δ 10.27 (s, 1 H), 8.70 (s, 1 H), 7.80 (d, J=8.40 Hz, 2 H), 7.87 ( s, 1 H), 7.39 (d, J=8.40 Hz, 2 H), 7.27 (d, J=4.26 Hz, 2 H), 6.79 (s, 1 H), 2.85 (s, 3 H), 2.74 (s, 3 H). ES-MS m/z 333.15 (M+H)+. HPLC purity 99.9%. Example 15 - Preparation of 5,7-dimethyl-N-(4-(thiazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00234] Using general procedure A, the title compound was obtained as an off-white solid (90 mg, 33%). 1H NMR (400 MHz, CDCl3) δ 10.29 (br s, 1 H), 8.70 (s, 1 H), 7.97 (d, J=8.61 Hz, 2 H), 7.81 - 7.89 (m, 3 H), 7.29 (d, J=2.87 Hz, 1 H), 6.78 (s, 1 H), 2.84 (s, 3 H), 2, 74 (s, 3H). ES-MS m/z 350.15 (M+H)+. HPLC purity 98.3%. Example 16 - Preparation of 5,7-dimethyl-N-(4-ethynyl-2-methoxyphenyl) pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00235] Using general procedure B, the title compound was obtained as a white solid (9%). 1H NMR (400 MHz, CDCl3) δ 10.73 (br s, 1 H), 8.69 (s, 1 H), 8.64 (d, J=8.00 Hz, 1 H), 7.19 (d, J=8.63 Hz, 1 H), 7.04 (s, 1 H), 6.77 (s, 1 H), 4.00 (s, 3 H), 3.05 (s, 1 H), 2.82 (s, 3 H), 2.73 (s, 3 H). ES-MS m/z 321.10 (M+H)+. HPLC purity 98.9%. Example 17 - Preparation of 5,7-dimethyl-N-(4-(isoxazol-3-yl)phenyl) pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00236] Using general procedure B, the title compound was obtained as a white solid (27%). 1H NMR (400 MHz, CDCl3) δ 10.31 (br s, 1 H), 8.71 (s, 1 H), 8.45 (s, 1 H), 7.75 - 7.99 (m, 4 H), 6.79 (s, 1 H), 6.67 (s, 1 H), 2.83 (s, 3 H), 2.74 (s, 3 H). ES-MS m/z 334.10 (M+H)+. HPLC purity 96.1%. Example 18 - Preparation of 5,7-dimethyl-N -(4-(oxazol-4-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00237] Using general procedure B, the title compound was obtained as a white solid (18%). 1H NMR (400 MHz, CDCl3) δ 10.22 (br s, 1 H), 8.71 (s, 1 H), 7.94 (s, 2 H), 7.81 - 7.86 (m, 2 H), 7.75 - 7.79 (m, 2 H), 6.78 (s, 1 H), 2.83 (s, 3 H), 2.74 (s, 3 H). ES-MS m/z 334.15 (M+H)+. HPLC purity 99.6%. Example 19 - Preparation of 5,7-dimethyl-N -(4-(oxazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00238] Using general procedure B, the title compound was obtained as a white solid (10%). 1H NMR (400 MHz, CDCl3) δ 10.32 (br s, 1 H) 8.71 (s, 1 H), 8.06 (d, J=8.62 Hz, 2 H), 7.88 ( d, J=8.62 Hz, 2 H), 7.70 (s, 1 H), 7.22 (s, 1 H), 6.79 (s, 1 H), 2.83 (s, 3 H), 2.74 (s, 3 H). ES-MS m/z 334.15 (M+H)+. HPLC purity 97.9%. Example 20 - Preparation of N -(4-ethynylcyclohexyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00239] A solution of 4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (1 g, 4.11 mmols) and N,O-dimethyl hydroxyl amine hydrochloride (602 mg, 6 .17 mmols) in DMF (10 mL) was charged with EDCI (955 mg, 6.16 mmols) and HOBt (277 mg, 2.05 mmols) and stirred at room temperature for 12 hours. The reaction mixture was quenched with water (30 mL), extracted with ethyl acetate (3 X 30 mL) and the combined organic layer was dried over sodium sulfate and concentrated to obtain crude compound. The crude compound was purified by FCC (eluent, 20 to 25% ethyl acetate in hexane) to give tert-butyl (4-(methoxy(methyl)carbamoyl)cyclohexyl)carbamate as a colorless liquid (133 mg, 68%). 1H NMR (400 MHz, CDCl3) δ 4.81 (br s, 1H), 3.75-3.85 (m, 1H), 3.70 (s, 3H), 3.19 (s, 3H), 2.69-2.81 (m, 1H), 1.85 (d, J=10.80 Hz, 2H), 1.59-1.74 (m, 6H), 1.45 (s, 9H) . ES-MS m/z 287.15 (M+H)+.

[00240] A solution of tert-butyl (4-(methoxy(methyl)carbamoyl) cyclohexyl)carbamate (1.2 g, 4.19 mmols) in THF (30 mL) was charged at -70°C with lithium aluminum hydride (LAH) (1.75g, 4.60 mmols) in portions. The reaction mixture was warmed to room temperature and stirred for 5 hours. The reaction mixture was quenched with 10% NaOH solution and extracted with ethyl acetate (3 X 25 mL). The combined organic layer was dried over sodium sulfate and concentrated to give the crude compound which was purified by FCC (eluent, 15 to 20% ethyl acetate in hexane) to give sodium (4-formylcyclohexyl)carbamate. tert-butyl (647 mg, 68%) as a yellow sticky oil which was used directly in the next step.

[00241] A solution of dimethyl (2-oxopropyl)phosphonate (219 mg, 1.32 mmol) in acetonitrile (20 mL) was charged with 4-methylbenzenesulfonyl azide (260 mg, 1.32 mmol) and K2CO3 (485 mg, 3.52 mmols) and stirred at room temperature for 12 hours. To the resulting solution was added tert-butyl (4-formylcyclohexyl)carbamate (200 mg, 0.88 mmol) and stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo, diluted with water (20 mL), extracted with ethyl acetate (3 X 15 mL), dried over Na2SO4 and concentrated in vacuo. The crude compound was purified by FCC (eluent, 15 to 20% ethyl acetate in hexane) to give tert-butyl (4-ethynylcyclohexyl)carbamate as a colorless oil (133 mg, 68%).

[00242] A solution of tert-butyl (4-ethynylcyclohexyl)carbamate (250 mg, 1.12 mmol) in DCM (10 mL) was charged with TFA (0.25 mL) and stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and purified by trituration with n-pentane to give 4-ethynylcyclohexan-1-amine as a yellow oil (120 mg, 87%).

[00243] A solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (120 mg, 0.62 mmol), HOBt (125 mg, 0.93 mmol), EDCI (144 mg , 0.93 mmol) in DMF (5 mL) was stirred at room temperature for 30 minutes and charged with 4-ethynylcyclohexan-1-amine (92 mg, 0.75 mmol) and stirred for another 16 hours at room temperature. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3 X 10 mL), dried over Na2SO4 and concentrated in vacuo. The crude compound was purified by FCC (eluent, 2 to 4% methanol in DCM) to give the title compound as a white solid (120 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.04 (d, J=5.73 Hz, 1H), 6.70 (br s, 1H), 4.06-4, 16 (m, 1H), 2.78 (s, 3H), 2.67 (s, 1H), 2.63 (s, 3H), 2.29-2.41 (m, 1H), 2.16 (d, J=10.58 Hz, 2H), 2.12-1.84 (m, 2H), 1.34-1.43 (m, 2H), 1.22-1.31 (m, 2H ). ESMS m/z 297.25 (M+H)+. HPLC purity 99.9%. Example 21 - Preparation of N-(4-(isothiazol-4-yl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00244] A solution of 5,7-dimethyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-iL)phenyl)pyrazolo[1,5-a] pyrimidine-3-carboxamide 6 (286 mg, 0.73 mmol) in DMF (5 mL) was loaded with 4-bromoisothiazole (100 mg, 0.60 mmol), potassium acetate (179 mg, 1.8 mmol) and Pd(dppf)Cl2 DCM adduct (49 mg, 0.06 mmol) under argon at room temperature. The reaction mixture was heated at 100°C for 16 hours. The reaction mixture was quenched with water (5 mL), extracted with ethyl acetate (3 X 10 mL) and concentrated in vacuo to obtain crude compound. The crude compound was purified by FCC (eluent, 3 to 5% methanol in DCM) to give the title compound as an off-white solid (50 mg, 23%). 1H NMR (400 MHz, CDCl3) δ 10.24 (s, 1H), 8.79 (s, 1H), 8.71 (s, 1H), 8.68 (s, 1H), 7.84 (d , J=8.57 Hz, 2H), 7.61 (d, J=8.57 Hz, 2H), 6.78 (s, 1H), 2.83 (s, 3H), 2.74 (s , 3H). ES-MS m/z 350.20 (M+H)+. HPLC purity 99.1%. Example 22 - Preparation of N-(4-(isoxazol-4-yl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00245] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5- a]pyrimidine-3-carboxamide 5 (350 mg, 0.89 mmol), isoxazol-4-iLboronic acid (164 mg, 1.33 mmol), KF (155 mg, 2.67 mmols) in DMF was degassed with argon for 30 minutes. To the resulting solution, Pd(dppf)Cl2 (73 mg, 0.08 mmol) was added and the solution was degassed for another 10 minutes in a sealed tube and heated at 50°C for 8 hours. The reaction mixture was cooled to room temperature, diluted with water and stirred for 15 minutes. The solid that precipitated was filtered and dried to obtain crude compound which was purified by FCC (eluent, 2 to 4% methanol in DCM) to give the title compound as a light gray solid (45 mg, 15%). 1H NMR (400 MHz, CDCl3) δ 10.23 (br s, 1H), 8.68 (d, J=16.76 Hz, 2H), 8.56 (s, 1H), 7.83 (d, J=8.38 Hz, 2H), 7.48 (d, J=7.94 Hz, 2H), 6.78 (s, 1H), 2.83 (s, 3H), 2.73 (s, 3H). ES-MS m/z 334.20 (M+H)+. HPLC purity 98.3%. Example 23 - Preparation of N-(3-cyclopropylisoxazol-5-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00246] A solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (200 mg, 1.04 mmol) in DCM (5 mL) at 0°C was charged with oxalyl chloride (2.6 mL, 30.1 mmols). The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was concentrated in vacuum to give 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carbonyl chloride as a brown solid (210 mg, 95%) which was used directly in the next step.

[00247] A solution of 3-cyclopropylisoxazol-5-amine (136 mg, 1.09 mmol) and DIPEA (0.87 mL, 4.90 mmols) in THF (3 mL) at 0°C under an argon atmosphere A solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carbonyl chloride 2 (210 mg, 0.95 mmol) in THF (2 mL) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours. Then, the reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (3 X 10 mL). The combined organic layer was dried over sodium sulfate and concentrated in vacuo to obtain crude product which was purified by preparatory HPLC (Column: YMC triart; Dimensions: (20 X 250mm X 5μ size); Method: mobile phase A - 5mM of ammonium formate in Water + 0.1% ammonia, mobile phase B - Acetonitrile + 0.1% ammonia; Gradient program: 10% B to 50% B) to give the title compound as an off-white solid (10 mg, 3%). 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.71 (s, 1H), 7.24 (s, 1H), 6.11 (s, 1H), 2.77 (s, 3H), 2.68 (s, 3H), 2.03 - 1.94 (m, 1H), 1.05 - 0.98 (m, 2H), 0.84 - 0.76 (m , 2H). ES-MS m/z 298.30 (M+H)+. HPLC purity 94.3%. Example 24 - Preparation of 5,7-dimethyl-N-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-iL)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00248] A solution of 5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-amine (241 mg, 1.25 mmol) and DIPEA (0.91 mL, 5.20 mmols) in THF (3 mL) at 0°C under argon atmosphere was added to a solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (210 mg, 0.95 mmol) in THF (2 mL). The reaction mixture was warmed to room temperature and stirred for 16 hours. Then, the reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (3 X 10 mL). The combined organic layer was dried over sodium sulfate and concentrated in vacuo to obtain crude product which was purified by FCC (eluent, 15 to 20% ethyl acetate in hexane) to give the title compound as an off-white solid (180 mg, 47%). 1H NMR (400 MHz, CDCl3) δ 10.63 (br s, 1H), 8.67 (s, 1H), 7.23 (s, 1H), 6.80 (s, 1H), 2.83 ( s, 3H), 2.72 (s, 3H), 1.51 (d, J=3.6 Hz, 2H), 1.47 (d, J=3.6 Hz, 2H). ES-MS m/z 365.95 (M+H)+. HPLC purity 99.2%. Example 25 - Preparation of N-(4-(1H-pyrrol-2-iL)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00249] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide 5 (100 mg, 0.25 mmol) in DMF (2 mL) was charged with (1-(tert-butoxycarbonyl)-1H-pyrrole-2-iL)boronic acid (64 mg, 0.31 mmol), K2CO3 (105 mg, 0.76 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol) and the mixture was degassed with argon for 30 minutes and heated at 100°C for 30 hours. Then, the reaction mixture was filtered through a celite pad and washed with ethyl acetate (10 mL). The filtrate was washed with ice water (10mL) and brine (10mL) and concentrated in vacuo to obtain crude compound which was purified by FCC (eluent, 5 to 10% methanol in DCM) to give the title compound as a white solid (50 mg, 59%). 1H NMR (400 MHz, DMSO-d6) δ 11.22 (br s, 1H), 10.16 (s, 1H), 8.63 (s, 1H), 7.72 (d, J=8.3 Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 7.20 (s, 1H), 6.84 - 6.80 (m, 1H), 6.47 - 6.44 (m, 1H), 6.10 (d, J=2.2 Hz, 1H), 2.77 (s, 3H), 2.72 (s, 3H). ES-MS m/z 332.20 (M+H)+. HPLC purity 98.1%. Example 26 - Preparation of 5,7-dimethyl-N-(6-(oxazol-4-iL)pyridin-3-iL)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00250] A solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 1 (53 mg, 0.27 mmol) in DMF (1 mL) at 0°C was charged with HATU (153 mg, 0.40 mmol), DIPEA (0.14 mL, 0.81 mmol) and 6-(oxazol-4-iL)pyridin-3-amine (45 mg, 0.27 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3 X 10 mL) and the combined organic layer was dried over sodium sulfate and concentrated in vacuo to obtain crude compound. The crude compound was purified by FCC (eluent, 1 to 3% methanol in DCM) to give the title compound as a white solid (18 mg, 19%). 1H NMR (400 MHz, CDCl3) δ 10.36 (br s, 1H), 8.82 (s, 1H), 8.71 (s, 1H), 8.46 (d, J=7.94 Hz, 1H), 8.33 (br s, 1H), 7.92-7.99 (m, 2H), 6.81 (s, 1H), 2.85 (s, 3H), 2.74 (s, 3H). ES-MS m/z 335.35 (M+H)+. HPLC purity 98.5%. Example 27 - Preparation of 5,7-dimethyl-N-(6-(thiophen-2-iL)pyridin-3-iL)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00251] A solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 1 (500 mg, 2.63 mmols), HATU (1.5 g, 3.94 mmols), DIPEA ( 1.2 mL, 7.89 mmols) in DMF (2 mL) was stirred at room temperature for 30 minutes and charged with 6-bromopyridin-3-amine (542 mg, 3.15 mmols) and stirred for another 16 hours at room temperature. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 X 10 mL), dried over Na2SO4 and concentrated in vacuo. The crude compound was purified by FCC (eluent, 1 to 3% methanol in DCM) to give N-(6-bromopyridin-3-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3 -carboxamide as a yellow solid (510 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 10.24 (br s, 1H), 8.65 (s, 1H), 8.54 (d, J=2.8 Hz, 1H), 8.24 (dd, J=6Hz, 11.6Hz, 1H), 7.51 (d, J=8.8Hz, 1H), 6.79 (s, 1H), 2.82 (s, 3H), 2.71 (s , 3H). ES-MS m/z 346.00(M+H)+.

[00252] A solution of N-(6-bromopyridin-3-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide (150 mg, 0.43 mmol) in DMF (5 mL) was loaded with 4,4,5,5-tetramethyl-2-(thiophen-2-iL)-1,3,2-dioxaborolane (136 mg, 0.65 mmol), K2CO3 (178 mg, 1.29 mmol) , Pd(PPh3)4 (49 mg, 0.042 mmol) and the reaction mixture was degassed with argon for 30 minutes and heated at 100°C for 30 hours. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (10 mL). The filtrate was washed with ice water (10mL) and brine (10mL) and concentrated in vacuo to obtain crude compound which was purified by trituration in methanol to give the title compound as an off-white solid (30mg, 20%) . 1H NMR (400 MHz, CDCl3) δ 10.28 (br s, 1H), 8.65 (s, 1H), 8.62 (s, 1H), 8.42 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.49 (d, J=2.2 Hz, 1H), 7.29 (d, J=4.9 Hz, 1H) , 7.04 (t, J=4.3 Hz, 1H), 6.72 (s, 1H), 2.76 (s, 3H), 2.65 (s, 3H). ES-MS m/z 350.30 (M+H)+. HPLC purity 99.5%. Example 28 - Preparation of N-([2,4'-Bipyridin]-5-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00253] A solution of N-(6-bromopyridin-3-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide (95 mg, 0.27 mmol) in DMF (5 mL) was charged with pyridin-4-ylboronic acid (40 mg, 0.32 mmol), K2CO3 (111 mg, 0.80 mmol), Pd(PPh3)4 (31 mg, 0.02 mmol) and the solution was degassed with argon for 30 minutes and heated to 100°C for 16 hours. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (10 mL). The filtrate was washed with ice water (10mL) and brine (10mL) and concentrated in vacuo to obtain crude compound which was purified by trituration in methanol to give the title compound as an off-white solid (30mg, 32%) . 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 8.79 (d, J=2.69 Hz, 1H), 8.61-8.68 (m, 3H), 8.56 (dd, J=2.47, 8.75 Hz, 1H), 7.94 (d, J=6.28 Hz, 2H), 7.82 (d, J=8.53 Hz, 1H), 6 .76 (s, 1H), 2.78 (s, 3H), 2.69 (s, 3H). ES-MS m/z 345.35 (M+H)+. HPLC purity 96.9%. Example 29 - Preparation of N-(6-(furan-2-iL)pyridin-3-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00254] A solution of N-(6-bromopyridin-3-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide (150 mg, 0.43 mmol) in DMF (5 mL) was charged with furan-2-iLboronic acid (77 mg, 0.65 mmol), K2CO3 (178 mg, 1.29 mmol), Pd(PPh3)4 (49 mg, 0.042 mmol) and the mixture was degassed with argon for 30 minutes and heated at 100°C for 30 hours. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (10 mL). The filtrate was washed with ice water (10 mL) and brine (10 mL) and concentrated in vacuo to obtain crude compound which was purified by trituration in methanol to give the title compound as a brown solid (40 mg, 28% ). 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 8.79 (d, J=2.7 Hz, 1H), 8.77 (s, 1H), 8.56 (dd, J =2.5, 8.8 Hz, 1H), 7.65 (d, J= 8.8 Hz, 1H), 7.56 (s, 1H), 7.04 (s, 1H), 6.82 (d, J=8.5 Hz, 1H), 6.52 (d, J=6.3 Hz, 1H), 2.78 (s, 3H), 2.69 (s, 3H). ESMS m/z 345.35 (M+H)+. HPLC purity 96.9%. Example 30 - Preparation of 5,7-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-iL)pyridin-3-iL)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00255] A solution of N-(6-bromopyridin-3-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide (95 mg, 0.27 mmol) in DMF (5 mL) was charged with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-iL)-1H-pyrazole (66 mg, 0.32 mmol), K2CO3 (111 mg , 0.80 mmol), Pd(PPh3)4 (31 mg, 0.02 mmol) and the reaction mixture was degassed with argon for 30 minutes and heated at 100°C for 30 hours. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (10 mL). The filtrate was washed with ice water (10 mL) and brine (10 mL) and concentrated in vacuo to obtain crude compound which was purified by trituration in methanol to give the title compound as an off-white solid (35 mg, 36 %). 1H NMR (400 MHz, CDCl3) δ 10.23 (s, 1H), 8.64 - 8.59 (m, 2H), 8.41 (d, J=8.2 Hz, 1H), 7.99 (br. s, 1H), 7.88 (s, 1H), 7.45 (d, J=8.7 Hz, 1H), 6.77 (s, 1H), 3.92 (s, 3H) , 2.76 (s, 3H), 2.66 (s, 3H). ES-MS m/z 348.40(M+H)+. HPLC purity 97.9%. Example 31 - Preparation of 5,7-dimethyl-N-(4-(thiazol-4-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00256] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5- a]pyrimidine-3-carboxamide 5 (250 mg, 0.64 mmol) and thiazol-4-ylboronic acid 2 ( 124 mg, 0.96 mmol) in dioxane (10 mL) in a sealed tube was charged with a solution of CH3CO2K (126 mg, 1.28 mmol) in water (0.5 mL) and the mixture was degassed with argon for 30 minutes. The resulting solution was charged with Pd(dppf)Cl2 DCM adduct (52 mg, 0.06 mmol) and heated to 90°C with stirring for 16 hours. Then, the reaction mixture was filtered through a celite pad and washed with an excess of DCM. The combined filtrate was concentrated in vacuo to obtain crude compound which was purified by FCC (eluent, 1 to 2% methanol in DCM) to give the title compound as a light brown solid (45 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.29 (d, J=7.9 Hz, 2H), 6.64 (d, J=8.2 Hz, 2H), 6.58 (s, 1H), 4.54 (s, 2H), 4.31 (s, 2H), 3.44 (s, 3H), 2.73 (s, 3H), 2.58 (s , 3H). ES-MS m/z 321.15 (M+H)+. HPLC purity 98.9%. Example 32 - Preparation of N-(1H-benzo[d]imidazol-2-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00257] A solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (100 mg, 0.52 mmol) in DMF (2 mL) at 0°C was charged with HATU (296 mg, 0.78 mmol), DIPEA (0.13 mL, 0.78 mmol) and 1H-benzo[d]imidazol-2-amine (83 mg, 0.62 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hours. Then, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3 X 10 mL), and the combined organic layer was dried over sodium sulfate and concentrated in vacuo to obtain crude compound. The crude compound was purified by FCC (eluent, 1 to 3% methanol in DCM) to give the title compound as a white solid (20 mg, 13%). 1H NMR (400 MHz, CDCl3) δ 11.18 (br s, 1H), 11.09 (br s, 1H), 8.71 (s, 1H), 7.66 (d, J=7.50 Hz , 1H), 7.43 (d, J=7.50 Hz, 1H), 7.15-7.24 (m, 2H), 6.83 (s, 1H), 2.84 (s, 3H) , 2.77 (s, 3H). ES-MS m/z 307.15 (M+H)+. HPLC purity 95.0%. Example 33 - Preparation of 5,7-dimethyl-N-(4-(3-(piperidin-1-iL)prop-1-yn-1-iL)phenyl)pyrazolo[1,5-a]pyrimidine-3- carboxamide

[00258] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5- a]pyrimidine-3-carboxamide 5 (200 mg, 0.51 mmol), prop-2-yn-1- ol (0.04 mL, 0.61 mmol), CuI (10 mg, 0.05 mmol) and Pd(PPh3)4 (58 mg, 0.005 mmol) in piperidine (3 mL) was heated in a sealed tube at 45 °C for 16 hours. Then, the reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (3 to 3% methanol in DCM) to give N-(4-(3-hydroxyprop-1-yn-1-iL)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide as an off-white solid (60 mg, 37%). 1H NMR (400 MHz, CDCl3) δ 10.24 (br s, 1H), 8.01 (s, 1H), 7.67 (dd, J=7.61, 11.58 Hz, 2H), 7, 55 (s, 1H), 7.48 (d, J=5.73 Hz, 2H), 3.49 (s, 3H), 3.31 (s, 3H), 2.85-2.71 (m , 2H), 2.61 (s, 1H). ES-MS m/z 321.10 (M+H)+.

[00259] A solution of N-(4-(3-hydroxyprop-1-in-1-iL)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide (120 mg, 0. 37 mmol) in DMF (5 mL) was charged with piperidine (0.04 mL, 0.44 mmol), PPh3 (146 mg, 0.55 mmol) and DIAD (112 mg, 0.55 mmol) and the mixture was heated at 40°C for 16 hours. The reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (3 X 15 mL), dried over Na2SO4 and concentrated in vacuo. The crude compound was purified by FCC (eluent, 0 to 3% methanol in DCM) to give an off-white solid (22 mg, 15%). 1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 8.61 (s, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.37 (d, J =8.4 Hz, 2H), 6.70 (s, 1H), 3.48 (s, 2H), 2.75 (s, 3H), 2.65 (s, 3H), 2.61 - 2 .51 (m, 4H), 1.69 - 1.59 (m, 6H). ES-MS m/z 388.35 (M+H)+ . HPLC purity 95.4%. Example 34 - Preparation of N-(4-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00260] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide 5 (100 mg, 0.25 mmol), 3-bromoprop-1-ine ( 91 mg, 0.76 mmol), CuI (5 mg, 0.02 mmol) and PdCl2(PPh3)2 (10 mg, 0.01 mmol) in N,N dimethyl amine solution in 2 M THF (5 mL ) was heated in a sealed tube at 60°C for 16 hours. Then, the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 X 10 mL). The combined organic layer was dried over Na2SO4 and concentrated in vacuo to obtain crude compound which was purified by FCC (eluent, 0 to 3% methanol in DCM) to give the title compound as a light brown solid (56 mg, 63 %). 1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.65 (s, 1H), 7.76 (d, J=7.5 Hz, 2H), 7.45 (d , J=7.9 Hz, 2H), 7.21 (s, 1H), 3.46 (s, 2H), 2.77 (s, 3H), 2.71 (s, 3H), 2.26 (s, 6H). ES-MS m/z 389.35 (M+CH3CN)+ adduct. HPLC purity 98.8%. Example 35 - Preparation of 5,7-dimethyl-N-(4-(3-morpholinoprop-1-yn-1-iL)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00261] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide 5 (300 mg, 0.76 mmol), 3-bromoprop-1-ine ( 0.21 mL, 2.29 mmol), CuI (29 mg, 0.15 mmol) and PdCl2(PPh3)2 (54 mg, 0.07 mmol) in morpholine solution in 2 M THF (10 mL) was heated in a sealed tube at 60°C for 4 hours. Then, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 X 15 mL). The combined organic layer was dried over sodium sulfate and concentrated in vacuo to obtain crude compound which was purified by FCC (eluent, 0 to 3% methanol in DCM) to give the title compound as an off-white solid (60 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 10.21 (s, 1H), 8.69 (s, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.44 (d, J =7.9 Hz, 2H), 6.77 (s, 1H), 3.85 - 3.68 (m, 4H), 3.52 (s, 2H), 2.83 (s, 3H), 2 .72 (s, 3H), 2.69 - 2.53 (m, 4H). ES-MS m/z 390.35 (M+H)+. HPLC purity 99.9%. Example 36 - Preparation of N-(4-(1H-imidazol-2-iL)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00262] A solution of 5,7-dimethyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-iL)phenyl)pyrazolo[1,5-a] Pyrimidine-3-carboxamide 6 (440 mg, 1.12 mmol) in DMF (5 mL) was loaded with 2-bromo-1H-imidazole (150 mg, 1.02 mmol), potassium carbonate (422 mg, 3. 06 mmols) and the mixture was degassed with argon for 15 minutes. To a resulting solution Pd(PPh3)4 (117 mg, 0.10 mmol) was added and the reaction mixture was degassed for another 10 minutes and heated at 100°C for 15 hours. Then, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3 X 10 mL), and the combined organic layer was dried over sodium sulfate and concentrated in vacuo to obtain crude compound. The crude compound was purified by FCC (eluent, 1 to 3% methanol in DCM) to give the title compound as a white solid (40 mg, 12%). 1H NMR (400 MHz, DMSO-d6) δ 12.48 (br s, 1H), 10.27 (s, 1H), 8.65 (s, 1H), 7.93 (d, J=8.87 Hz, 2H), 7.82 (d, J=8.87 Hz, 2H), 7.07-7.24 (m, 3H), 2.78 (s, 3H), 2.73 (s, 3H ). ES-MS m/z 333.35 (M+H)+. HPLC purity 98.3%. Example 37 - Preparation of 5,7-dimethyl-N-(4-(piperidin-1-iL)phenyl) pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00263] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide 5 (200 mg, 0.51 mmol) in toluene (8 mL) was charged with piperidine (0.06 mL, 0.61 mmol), bis(dibenzylideneacetone)palladium(0) (2 mg, 0.002 mmol) and the mixture degassed with argon for 30 minutes. DavePhos (2 mg, 0.005 mmol) and KOtBu (114 mg, 1.02 mmol) were added and the mixture was heated at 90°C for 16 hours. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (3 X 10 mL). The combined filtrate was washed with water, dried over sodium sulfate and concentrated in vacuo to obtain crude compound which was purified by FCC (eluent, 1 to 2% methanol in DCM) to give the title compound as a white solid ( 160 mg, 47%). 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.59 (s, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.18 (s , 1H), 6.94 (d, J=8.8 Hz, 2H), 3.11 - 3.06 (m, 4H), 2.76 (s, 3H), 2.69 (s, 3H) , 1.63 (d, J=4.9 Hz, 4H), 1.53 (d, J=5.3 Hz, 2H). ES-MS m/z 350.25 (M+H)+. HPLC purity 96.7%. Example 38 - Preparation of 5,7-dimethyl-N-(4-(piperazin-1-iL)phenyl) pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00264] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide 5 (500 mg, 1.27 mmol) in toluene (5 mL) was charged with tert-butyl piperazine-1-carboxylate (283 mg, 1.53 mmol), Pd(dba)2 (3.5 mg, 0.006 mmol) and degassed with argon for 30 minutes. To a resulting solution was added t-BuOK (286 mg, 2.55 mmol) and DavePhos (5 mg, 0.01 mmol) and the mixture heated at 90°C for 16 hours. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (10 mL) and water (10 mL). The filtrate was extracted with ethyl acetate (3 X 10 mL) and the combined organic layer was dried over sodium sulfate and concentrated in vacuo to provide a crude compound which was then purified by FCC (eluent, 1 to 3% methanol in DCM) and triturated with methanol to give tert-butyl 4-(4-(5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamido)phenyl)piperazine-1-carboxylate as an off-white solid ( 380 mg, 36%). ES-MS m/z 451.40 (M+H)+.

[00265] A solution of tert-butyl 4-(4-(5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamido)phenyl)piperazine-1-carboxylate (280 mg, 0.62 mmol) in DCM (8 mL) was charged with TFA (1.5 mL) and stirred at room temperature for 12 hours. Next, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3 to 3% methanol in DCM) and triturated with methanol to give the title compound as an off-white solid (58 mg, 16%). 1H NMR (400 MHz, DMSO-d6) δ 9.97 (br s, 1H), 8.59 (s, 1H), 7.59 (d, J=7.20 Hz, 2H), 7.18 ( s, 1H), 6.96 (d, J=6.96 Hz, 2H), 3.10-2.97 (m, 4H), 2.76 (s, 3H), 2.69 (s, 3H ), 1.33-1.23 (m, 4H), 0.87 (br. s, 1H). ES-MS m/z 351.25 (M+H)+. HPLC purity 97.7%. Example 39 - Preparation of N-(4-(1H-pyrazol-3-iL)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00266] A solution of 5,7-dimethyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-iL)phenyl)pyrazolo[1,5-a] pyrimidine-3-carboxamide 6 (320 mg, 0.80 mmol) in propanol/water (4:1 mL) was charged with 5-bromo-1H-pyrazole (100 mg, 0.60 mmol), Ce2CO3 (585 mg, 1.80 mmol) and the mixture was degassed with argon for 15 minutes. To a resulting solution was added PdCl2(dppf) (49 mg, 0.60 mmol), and the resulting solution degassed for another 10 minutes and then heated at 100°C for 16 hours. Next, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3 , 1 to 3% methanol in DCM) and triturated with methanol to give the title compound as a brown solid (25 mg, 11%). 1H NMR (400 MHz, DMSO-d6) δ 12.81 (br s, 1H), 10.24 (br s, 1H), 8.65 (s, 1H), 7.43-7.89 (m, 6H), 7.21 (s, 1H), 2.78 (s, 3H), 2.73 (s, 3H). ES-MS m/z 333.25 (M+H)+. HPLC purity 92.4%. Example 40 - Preparation of 5,7-dimethyl-N -(4- (pentyloxy)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00267] A solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (300 mg, 1.56 mmol) in DMF (10 mL) at 0°C was charged with HATU (894 mg, 2.35 mmol), DIPEA (0.82 mL, 4.70 mmol) and 4-amino phenol (205 mg, 1.88 mmol). Then, the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with water (2 mL), extracted with ethyl acetate (3 X 10 mL), dried over Na2SO4 and concentrated in vacuo to provide a crude product which was then purified by FCC (eluent, methanol in 5% DCM) to give N-(4-hydroxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide as an off-white solid (284 mg, 64%). 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.26 (s, 1H), 8.58 (s, 1H), 7.51 (d, J=7.9 Hz , 2H), 7.16 (s, 1H), 6.77 (d, J=7.9 Hz, 2H), 2.76 (s, 3H), 2.68 (s, 3H). ES-MS m/z 283.15 (M+H)+.

[00268] A solution of N-(4-hydroxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide (140 mg, 0.49 mmol) in DMF was charged with K2CO3 (102 mg, 0.74 mmol) and bromopentane (0.1 mL, 0.74 mmol) at room temperature. The reaction mixture was heated at 100°C for 16 hours. Then, the reaction mixture was diluted with water (2 mL) and extracted with ethyl acetate (3 X 10 mL). The combined organic layer was dried over Na2SO4 and concentrated in vacuo to give a crude product which was then purified by preparatory HPLC (Column: YMC triart; Dimensions: (Size 20 X 250mm X 5μ); Method: Mobile Phase A - 5mM Ammonium formate in Water + 0.1% ammonia, Mobile Phase B - Acetonitrile + 0.1% ammonia; Gradient program: 10% B to 50% B) to give the title compound as a white solid (50 mg, 29%). 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.61 (s, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.18 (s , 1H), 6.94 (d, J=8.8 Hz, 2H), 3.95 (t, J=6.4 Hz, 2H), 2.77 (s, 3H), 2.69 (s , 3H), 1.77 - 1.66 (m, 2H), 1.46 - 1.31 (m, 4H), 0.90 (t, J=7.1 Hz, 3H). ES-MS m/z 353.30 (M+H)+. HPLC purity 99.8%. Example 41 - Preparation of 5,7-dimethyl-N-(4-(prop-2-yn-1-yloxy)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00269] A solution of N-(4-hydroxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide (50 mg, 0.17 mmol) in DMF (2 mL) was charged with carbonate of potassium (36 mg, 0.26 mmol) and 80% propargyl bromide (0.04 mL, 0.26 mmol) at room temperature and the reaction mixture was heated at 100 ° C for 12 hours. Then, the reaction mixture was diluted with water (2 mL), extracted with ethyl acetate (3 YMC triart; Dimensions: (size 20 X 250mm gradient: 10% B to 50% B) to give the title compound as a white solid (34 mg, 61%). 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.61 (s, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.18 (s , 1H), 7.01 (d, J=8.8 Hz, 2H), 4.79 (s, 2H), 3.56 (s, 1H), 2.77 (s, 3H), 2.70 (s, 3H). ES-MS m/z 321.20 (M+H)+. HPLC purity 99.7%. Example 42 - Preparation of 4-(4-(5,7-dimethylpyrazolo[1,5- a]pyrimidine-3-carboxamido)phenyl)butanoic acid

[00270] A solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (200 mg, 1.04 mmol) in DMF (5 mL) was charged with EDC.HCl (240 mg, 1.25 mmol), HOBT (170 mg, 1.25 mmol), triethyl amine (0.43 mL, 3.14 mmol) and stirred at room temperature for 30 minutes. To a resulting solution was added methyl 4-(4-aminophenyl)butanoate (240 mg, 1.25 mmol) and the mixture was stirred at room temperature for 16 hours. Then, the reaction mixture was quenched with ice water (50 mL) and stirred for another 30 minutes. The solid was collected by filtration and washed with water followed by n-hexane and dried to give the corresponding ester as a light brown solid (240 mg) which was used in the next step without further purification. ES-MS m/z 367.40 (M+H)+.

[00271] An ester solution in MeOH:THF (8 mL; 1:1) was charged with a solution of LiOH (46 mg, 1.09 mmol) in water (4 mL) and stirred at room temperature for 3 hours. Then, the reaction mixture was concentrated in vacuum to dryness and the residue was diluted with water and acidified (pH = 1) with 2N HCl. The resulting solution was stirred at room temperature for 30 minutes. The solid was filtered, washed with water followed by n-hexane and dried to give the title compound as a white solid (160 mg, 43% for 2 steps). 1H NMR (400 MHz, DMSO-d6) δ 12.06 (br s, 1H), 10.11 (s, 1H), 8.61 (s, 2H), 7.65 (d, J=8.0 Hz, 2H), 7.22 - 7.17 (m, 2H), 2.76 (s, 3H), 2.70 (s, 3H), 2.58 (t, J=7.6 Hz, 2H ), 2.22 (t, J=7.1 Hz, 2H), 1.85 - 1.74 (m, 2H). ES-MS m/z 353.40 (M+H)+. HPLC purity 99.3%. Example 43 - Preparation of N-(4-(1-hydroxyethyl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00272] A solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (100 mg, 0.52 mmol) in DMF (5 mL) was charged with EDCI (122 mg, 0. 78 mmol), HOBT (36 mg, 0.26 mmol) and triethyl amine (0.1 mL, 0.78 mmol) and stirred for 15 minutes at room temperature. To a resulting solution was added 1-(4-aminophenyl)ethan-1-ol (86 mg, 0.63 mmol) and the mixture stirred an additional 16 hours. Next, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3 purified by preparative TLC to give the title compound as an off-white solid (49 mg, 30%). 1H NMR (400 MHz, DMSO-d6) δ 10.12 (br s, 1H), 8.61 (s, 1H), 7.67 (d, J=7.50 Hz, 2H), 7.34 ( d, J=7.94 Hz, 2H), 7.18 (s, 1H), 5.11 (br. s, 1H), 4.69-4.72 (m, 1H), 2.76 (s , 3H), 2.70 (s, 3H), 1.33 (d, J=6.17 Hz, 3H). ES-MS m/z 310.3 (M+H)+. HPLC purity 99.2%. Example 44 - Preparation of 3-(4-(5,7-dimethylpyrazolo[1,5- a]pyrimidine-3-carboxamido)phenyl)propanoic acid

[00273] A solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (250 mg, 1.31 mmol) in DMF (5 mL) was charged with EDC.HCl (304 mg, 1.96 mmol), HOBT (299 mg, 1.96 mmol), NEt3 (0.54 mL, 3.93 mmol) and stirred at room temperature for 30 minutes. To a resulting solution was added methyl 3-(4-aminophenyl)propanoate (259 mg, 1.44 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with ice water (50 mL) and stirred for another 30 minutes. The precipitated solid was collected by filtration, washed with water followed by n-hexane and dried to give 3-(4-(5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamido)phenyl)propanoate. methyl as a light brown solid (350 mg, 76%), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 8.70 (s, 1H), 7.68 (d, J=8.33 Hz, 2H), 7.21 (d, J =8.33 Hz, 2H), 6.77 (s, 1H), 3.69 (s, 3H), 2.96 (t, J=7.67 Hz, 2H), 2.83 (s, 3H ), 2.71 (s, 3H), 2.62-2.68 (m, 2H). ES-MS m/z 353.25 (M+H)+.

[00274] A solution of methyl 3-(4-(5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamido)phenyl)propanoate in THF:H2O (10:10 mL) was charged with a solution of LiOH (51 mg, 2.13 mmols) and stirred at room temperature for 3 hours. Then, the reaction mixture was concentrated in vacuo, diluted with water and stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration, washed with water followed by n-hexane and dried to give the title compound as a white solid (170 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ 12.11 (br s, 1H), 10.11 (s, 1H), 8.62 (s, 1H), 7.64 (d, J=8.33 Hz, 2H), 7.23 (d, J=8.33 Hz, 2H), 7.19 (s, 1H), 2.78-2.83 (m, 2H), 2.76 (s, 3H ), 2.70 (s, 3H), 2.53-2.57 (m, 2H). ES-MS m/z 339.20 (M+H)+. HPLC purity 99.5%. Example 45 - Preparation of N-(4-azidophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00275] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide 5 (50 mg, 0.13 mmol), CuI (2 mg, 0.01 mmol), NaN3 (17 mg, 0.26 mmol) and sodium ascorbate (2 mg, 0.01 mmol) in EtOH:H2O (2 mL) was degassed with argon for 15 minutes. N,N-dimethyl ethylenediamine (0.002 mL, 0.02 mmol) was added and the mixture was heated at 100°C for 50 minutes in a microwave. The reaction mixture was diluted with water (2 mL), extracted with ethyl acetate (3 silica 2-ethyl pyridine; Dimensions: size 30 X 250mm, 5μ; Method: mobile phase A - CO2, mobile phase B - 5mM ammonium formate in MeOH; give the title compound as a brown solid (24 mg, 62%). 1H NMR (400 MHz, CDCl3) δ 10.08 (br s, 1H), 8.62 (s, 1H), 7.68 (d, J=8.0 Hz, 2H), 6.96 (d, J=8.1 Hz, 2H), 6.70 (s, 1H), 2.75 (s, 3H), 2.65 (s, 3H). ES-MS m/z 308.05 (M+H)+. HPLC purity 95.9%. Example 46 - Preparation of 5,7-dimethyl-N-(4-(thiophen-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00276] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide 5 (100 mg, 0.25 mmol) in DMF (2 mL) was charged with 4,4,5,5-tetramethyl-2-(thiophen-2-iL)-1,3,2-dioxaborolane (64 mg, 0.31 mmol), K2CO3 (105 mg, 0.76 mmol), and Pd (PPh3)4 (29 mg, 0.025 mmol), and the reaction mixture was degassed with argon for 30 minutes and heated at 100 ° C for 30 hours. Then, the reaction mixture was filtered through a celite pad and washed with ethyl acetate (10 mL). The filtrate was washed with ice water (10 mL) and brine (10 mL) and concentrated in vacuo to provide a crude compound which was then purified by FCC (eluent, 5 to 10% methanol in DCM) to give the compound of titer as a brown solid (40 mg, 45%). 1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 8.63 (s, 1H), 7.70 (d, J=8.6 Hz, 2H), 7.54 (d, J =8.5 Hz, 2H), 7.21 (d, J= 3.5 Hz, 1H), 7.17 (d, J= 5.1 Hz, 1H), 7.00 (dd, J=3 .6, 5.0 Hz, 1H), 6.69 (s, 1H), 2.75 (s, 3H), 2.65 (s, 3H). ES-MS m/z 349.10 (M+H)+. HPLC purity 98.9%. Example 47 - Preparation of 5,7-dimethyl-N-(2-methyl-1H-indol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00277] To a stirred solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.26 mmol), HATU (148 mg, 0.39 mmol), and DIPEA (0.09 mL, 0.52 mmol) into 1 mL of DMF was added 2-methyl-1H-indole-5-amine (45 mg, 0.31 mmol). The reaction mixture was stirred at room temperature for 16 hours until the reaction was complete. The resulting crude product was purified by preparative HPLC (MeCN/10 mM NH4HCO3) to provide the title compound as a yellow solid (13.1 mg, 15.6%). 1H NMR (400 MHz, DMSO) δ 10.87 (s, 1H), 10.04 (s, 1H), 8.61 (s, 1H), 7.86(s, 1H), 7.25 (d , J = 1.2 Hz, 2H), 7.19 (s, 1H), 6.12 (s, 1H), 2.78 (s, 3H), 2.72 (s, 3H), 2.38 (s, 3H). ES-MS m/z: 320 [M+H]+. LC-MS purity (214 nm): >99%; tR= 1.71 min. Example 48 - Preparation of N -(1H-indazol-5-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00278] To a stirred solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.26 mmol), HATU (57 mg, 0.39 mmol) in DMF/ NMM (1 mL/0.1 mL) 1H-indazol-5-amine (42 mg, 0.314 mmol) was added. The reaction was stirred at room temperature for 12 hours. Then, the reaction mixture was quenched with water (2 mL), stirred at room temperature for 0.5 hour and then filtered. The solid was washed with water (1 mL), DCM (2 mL), Et2O (2 mL) and dried to provide the title compound (20 mg, 25.0%) as a white solid. 1H NMR (400 MHz, DMSO) δ 13.03 (s, 1H), 10.20 (s, 1H), 8.64 (s, 1H), 8.28 (s, 1H), 8.07 (d , J = 1.1 Hz, 1H), 7.56 (s, 2H), 7.19 (s, 1H), 2.77 (s, 3H), 2.72 (s, 3H). ES-MS m/z: 307.2 [M+H]+. LC-MS purity (254 nm): >98%; tR= 1.54 min. Example 49 - Preparation of N -(1H-Indazol-6-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00279] To a stirred solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (70 mg, 0.37 mmol), HATU (209 mg, 0.55 mmol), and DIPEA (0.13 mL, 0.74 mmol) into 1 mL of DMF was added 1H-indazol-6-amine (59 mg, 0.44 mmol). The reaction was stirred at room temperature for 16 hours until the reaction was complete. The solid was collected by filtration, washed with H2O, DCM and diethyl ether to provide the title compound (51 mg, 63.7%) as a brown solid. 1H NMR (400 MHz, DMSO) δ 12.96 (s, 1H), 10.36 (s, 1H), 8.65 (s, 1H), 8.34 (s, 1H), 8.00 (s , 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.19 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 2.75 (s , 3H), 2.72 (s, 3H). ES-MS m/z: 307.1 [M+H]+. LC-MS purity (214 nm): >97%; tR = 1.45 min. Example 50 - Preparation of N-(2H-1,3-benzodioxol-5-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00280] To a stirred solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.26 mmol), HATU (148 mg, 0.39 mmol), and DIPEA (0.09 mL, 0.52 mmol) into 1 mL of DMF was added 2H-1,3-benzodioxol-5-amine (42 mg, 0.31 mmol). The reaction was stirred at room temperature for 16 hours. The reaction mixture was purified by preparative HPLC (MeCN/NH4HCO3) to provide the title compound as a white solid (16.8 mg, 23%). 1H NMR (400 MHz, DMSO) δ 10.07 (s, 1H), 8.61 (s, 1H), 7.51(d, J = 2.4 Hz, 1H), 7.19 (d, J = 0.8 Hz, 1H), 7.07 (dd, J = 2.4 Hz, J = 1.6 Hz, 1H), 6.92 (d, J = 4.4 Hz, 1 H), 6 .03 (s, 2H), 2.77 (s, 3H), 2.70 (s, 3H). ES-MS m/z: 311.0 [M+H]+. LC-MS purity (214 nm): >99%; tR= 1.72 min. Example 51 - Preparation of N-(2-methyl-1,3-benzodioxol-6-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00281] To a stirred solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.262 mmol), 2-methyl-1,3-benzoxazol-6-amine (47 mg, 0.314 mmol) and HATU (149 mg, 0.393 mmol) in DMF (1 mL), DIPEA (0.1 mL, 0.524 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours until the reaction was complete. complete. The suspension was diluted with H2O (3 mL), and the precipitated solid was collected by filtration, washed with minimal DCM and Et2O, and dried in vacuo to provide the title compound (60 mg, 71%) as a white solid. . 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.66 (s, 1H), 8.31 (d, J = 2.0 Hz, 1H), 7.64 (d , J = 8.4 Hz, 1H), 7.47 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.21 (s, 1H), 2.78 (s, 3H), 2.73 (s, 3H), 2.60 (s, 3H). ES-MS m/z: 322.0 [M+H]+. LC-MS purity (254 nm): >99%; tR = 1.74 min. Example 52- Preparation of 5,7-dimethyl-N-(2-methyl-1H-1,3-benzodiazol-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00282] To a stirred solution of 5,7-dimethylpyrazolo[1,5- a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.262 mmol), 2-methyl-1H-1,3-benzodiazol-6-amine (57 mg, 0.314 mmol) and HATU (149 mg, 0.393 mmol) in DMF (1 mL) DIPEA (0.14 mL, 0.786 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours until reaction is complete. The suspension was diluted with H2O (3 mL), and the precipitated solid was collected by filtration, washed with minimal DCM and Et2O, and purified by preparative HPLC (MeCN/10 mM NH4HCO3) to provide the title compound (28 mg, 33%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 10.18 (d, J = 31.2 Hz, 1H), 8.63 (s, 1H), 8.09 (d , J = 53.2 Hz, 1H), 7.49-7.16 (m, 3H), 2.78 (s, 3H), 2.72 (s, 3H), 2.49 (s, 3H) . ES-MS m/z: 321.1 [M+H]+. LC-MS purity (254 nm): 99%; tR = 1.46 min. Example 53 - Preparation of 5,7-Dimethyl-N -(1,2,3,4-tetrahydroisoquinolin-6-iL)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00283] To a mixture of 6-nitro-1,2,3,4-tetrahydroquinoline (200 mg, 0.772 mmol) and TEA (156 mg, 1.544 mmol) in 6 mL of dioxane and 1 mL of H2O was added Boc2O (168 mg, 0.772 mmol), and the reaction mixture was stirred at room temperature for two hours and concentrated in vacuo. Saturated sodium bicarbonate was added to the residue, and the mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Mg2SO4 and concentrated to provide crude tert-butyl 6-nitro-1,2,3,4-tetrahydroquinoline-2-carboxylate (220 mg, 100% ) which was used directly in the next step. ES-MS m/z: 223 (M-55)+. LC-MS purity (254 nm): > 98%; tR = 2.00 min.

[00284] A suspension of tert-butyl 6-nitro-1,2,3,4-tetrahydroquinoline-2-carboxylate (220 mg, 0.772 mmol) and NH4Cl (330 mg, 6.176 mmols) in 6 mL of EtOH and 4 mL of H2O were added Fe powder (173 mg, 3.088 mmols) in portions. The reaction mixture was stirred at 70°C for two hours, cooled to room temperature and then filtered through Celite. The filter mass was washed with ethanol. The orange solution was concentrated, and the residue was purified by preparative HPLC (MeCN/10 mM NH4HCO3) to provide tert-butyl 6-amino-1,2,3,4-tetrahydroquinoline-2-carboxylate as an oil. (150 mg, 78% 2 steps). 1H NMR (400 MHz, CDCl3) δ 6.89 (d, J = 8.0 Hz, 1H), 6.54 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 6.47 ( s, 1H), 6.45 (s, 2H), 3.60-3.58 (m, 4H), 2.73 (t, J = 5.6 Hz, 2H), 1.48 (s, 9H ).

[00285] To a stirred solution of 5,7-dimethylpyrazolo[1,5- a]pyrimidine-3-carboxylic acid 2 (65 mg, 0.340 mmol), 6-amino-1,2,3,4-tetrahydroquinoline tert-Butyl-2-carboxylate (84 mg, 0.340 mmol) and HATU (155 mg, 0.408 mmol) in DMF (1.5 mL) was added DIPEA (0.12 mL, 0.680 mmol), and the reaction mixture was stirred at room temperature for 16 hours until the reaction was complete. The crude product was purified by preparative HPLC (MeCN/10 mM NH4HCO3) to provide boc-protected derivative of the title compound (64 mg, 47%) as a white solid. ES-MS m/z: 422.0 [M+H]+. LC-MS purity (254 nm): 96%; tR = 1.93 min. This boc-protected derivative of the title compound was converted to the title compound using the procedure below.

[00286] TFA (0.5 mL) was added to the boc-protected derivative of the title compound from the above procedure (64 mg, 0.152 mmol) at 0°C. The mixture was stirred at room temperature for two hours, diluted with DCM, and basified to pH ~8 with saturated NaHCO3. The resulting mixture was separated, and the aqueous phase was extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, and concentrated in vacuo to provide a residue which was then purified by preparative HPLC (MeCN/10 mM NH4HCO3) to provide the title compound (24 mg, 51%) as a white solid. . 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.60 (s, 1H), 8.46-8.44 (m, 2H), 7.18 (s, 1H) , 7.00 (d, J = 8.0 Hz, 1H), 3.81 (s, 2H), 2.94 (t, J = 5.6 Hz, 2H), 2.76 (s, 3H) , 2.70-2.69 (m, 5H). ES-MS m/z: 322.0 [M+H]+. LC-MS purity (254 nm): 99%; tR = 1.51 min. Example 54 - Preparation of N -(1,2-Benzoxazol-5-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00287] To an ice-cold stirred solution of SnCl4 (1.828 g, 7.02 mmols) in 12 M HCl (0.5 mL) was added 5-nitro-1,2-benzoxazole (140 mg, 0.86 mmol) in one portion at 0°C. 5 minutes later, a solution of SnCl2.2H2O (792 mg, 3.51 mmols) in 12 M HCl (0.5 mL) was added dropwise at 0°C, followed by the addition of another 1.0 mL of 12 M HCl. Then the reaction mixture was stirred at room temperature for 3 hours, and extracted with Et2O. The aqueous layer was basified to pH ~ 8 with saturated NaHCO3, and extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4, filtered, concentrated and dried in vacuo to provide 1,2-benzoxazol-5-amine as a colorless solid (110 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 6.94 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H) ES-MS m/z: 135.1 [M+H]+. LC-MS purity (214 nm): 90%; tR = 1.32 min.

[00288] To a solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (100 mg, 0.524 mmol) and HATU (259 mg, 0.681 mmol) in DMF (1 mL) was added DIPEA (136 mg, 1.048 mmol), and the reaction mixture was stirred at room temperature for two hours until the reaction was complete. The suspension was diluted with H2O (3 mL), and the precipitated solid was collected by filtration, washed with minimal DCM and Et2O, and dried in vacuum to provide the ester compound (105 mg, 65%) as a white solid. ESMS m/z: 310.0 [M+H]+. LC-MS purity (254 nm): 88%; tR = 1.61 min. The ester compound was used in the procedure below.

[00289] To a suspension of the ester compound from the above procedure (105 mg, 0.340 mmol) in DMF (0.5 mL) was added a solution of 1,2-benoxazol-5-amine (46 mg, 0.340 mmol) in DMF (0.5 mL). The reaction mixture was stirred at room temperature for two hours until the reaction was complete, and quenched with the addition of TFA (5 drops). The precipitated solid was collected by filtration, suspended in DCM, basified with saturated NaHCO3 to pH ~8. The aqueous layer was extracted with DCM, dried over anhydrous Na2SO4, filtered and concentrated to provide a residue. The residue was purified by preparative HPLC (MeCN/H2O) to provide the title compound (40 mg, 38%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 8.72-8.71 (m, 2H), 8.45 (d, J = 1.6 Hz, 1H), 7.67 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.60 (d, J = 9.2 Hz, 1H), 6.79 (s, 1H), 2.84 (s, 3H ), 2.74 (s, 3H). ES-MS m/z: 308.0 [M+H]+. HPLC purity (214 nm): 98%; tR = 9.36 min. Example 55 - Preparation of N-[2-(Furan-2-iL)-1H-1,3-benzodiazol-5-iL]-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00290] A mixture of 4-nitrobenzene-1,2-diamine (1.53 g, 10 mmols), furan-2-carbaldehyde (1.22 g, 13.0 mmols), p-benzoquinone (1.19 g , 11 mmols) and 2-propanol (15 mL) in a sealed tube was refluxed for two hours. The reaction was diluted with water, filtered and dried in vacuo to give 2-(furan-2-iL)-5-nitro-1H-1,3-benzodiazole as a yellow solid (1.2 g, 52%). LC-MS m/z: 234 (M+H) +. LC-MS purity (214 nm): >90%.

[00291] A suspension of 2-(furan-2-iL)-5-nitro-1H-1,3-benzodiazole (1.2 g, 5.15 mmols) and 10% Pd/C (120 mg) in EtOH (10 mL) was stirred at room temperature under H2 for two hours. The mixture was filtered, and the filtrate was concentrated in vacuo to provide a residue. The residue was purified by silica gel column (MeOH/DCM = 1/10) to give 2-(furan-2-iL)-1H-1,3-benzodiazol-5-amine as a yellow solid (870 mg, 83%). 1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 7.85 (d, J = 1.2 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H ), 7.01 (d, J = 3.2 Hz, 1H), 6.67 (m, 2H), 6.53 (q, J = 2.0 Hz, 1H), 4.93 (s, 2H ). LC-MS m/z: 204 (M+H) +. LC-MS purity (214 nm): > 95%.

[00292] To a stirred solution of 5,7-dimethylpyrazolo[1,5- a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.262 mmol), 2-(furan-2-iL)-1H- 1,3 -benzodiazol-5-amine (57 mg, 0.314 mmol) and HATU (149 mg, 0.393 mmol) in DMF (1 mL) was added DIPEA (0.14 mL, 0.786 mmol), and the reaction mixture was stirred at temperature environment for 16 hours until the reaction is complete. The suspension was diluted with H2O (3 mL), and the precipitated solid was collected by filtration, washed with minimal DCM and Et2O, and dried in vacuo to provide the title compound (73 mg, 75%) as a white solid. . 1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 10.26 (d, J = 2.8 Hz, 1H), 8.65 (s, 1H), 8.23 (d , J = 46.8 Hz, 1H), 7.94 (d, J = 0.8 Hz, 1H), 7.60-7.17 (m, 4H), 6.73 (dd, J = 3, 6Hz, 2.0Hz, 1H), 2.77 (s, 3H), 2.73 (s, 3H). ES-MS m/z: 373.0 [M+H] +. LC-MS purity (254 nm): 96%; tR = 1.62 min. Example 56 - Preparation of N-(2-methyl-1,3-benzothiazol-6-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00293] To a stirred solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.262 mmol), 2-methyl-1,3-benzothiazol-6-amine (51 mg, 0.314 mmol) and HATU (149 mg, 0.393 mmol) in DMF (1 mL), DIPEA (0.1 mL, 0.524 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours until the reaction was complete. complete. The suspension was diluted with H2O (3 mL), and the precipitated solid was collected by filtration, washed with minimal DCM and Et2O, and dried in vacuo to provide the title compound as a white solid (53 mg, 60%) . 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.66 (s, 1H), 8.54 (d, J = 1.2 Hz, 1H), 7.90 (d , J = 8.8 Hz, 1H), 7.74 (dd, J = 8.8 Hz, 1.2 Hz, 1H), 7.21 (s, 1H), 2.78 (s, 6H), 2.74 (s, 3H). ES-MS m/z: 338.1 [M+H]+. LC-MS purity (254 nm): 99%; tR = 1.75 min. Example 57 - Preparation of N-(2-3-Dihydro-1H-inden-5-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00294] To a stirred solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.262 mmol), 2,3-dihydro-1H-inden-5-amine (42 mg, 0.314 mmol) and HATU (149 mg, 0.393 mmol) in DMF (1 mL) DIPEA (0.1 mL, 0.524 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours until reaction is complete. The reaction mixture was purified by reverse phase chromatography (MeCN/10 mM NH4HCO3) to provide the title compound (37 mg, 46%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.62 (s, 1H), 7.66 (s, 1H), 7.46 (dd, J = 8.0 Hz , 2.0 Hz, 1H), 7.22-7.19 (m, 2H), 2.90-2.82 (m, 4H), 2.77 (s, 3H), 2.71 (s, 3H), 2.07-1.99 (m, 2H). ES-MS m/z: 307.2 [M+H]+. LC-MS purity (254 nm): >99%; tR = 1.98 min. Example 58- Preparation of N-{4-Chloro-3-[(pyridin-3-yloxy)methyl]phenyl}-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00295] 2-Chloro-5-nitrobenzaldehyde (10 g, mmol) was dissolved in 150 ml of methanol and cooled to 0°C. A solution of NaBH4 (3.33 g, mmol) in 30 ml of water was then added dropwise over 90 minutes while maintaining the temperature below 10°C. The resulting reaction mixture was then stirred for one hour, acidified with 2N HCl and allowed to stir overnight. The mixture was concentrated in vacuo, and the resulting solids were filtered then washed with water and dried in vacuo to provide (2-chloro-5-nitrophenyl)methanol (9.3 g, 92%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 2.8 Hz, 1H), 8.14 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 7, 73 (d, J = 8.8 Hz, 1H), 5.81 (bs, 1H), 4.63 (s, 2H). LC-MS purity (254 nm): > 98%; tR= 1.60 min.

[00296] To an ice-cold solution of (2-chloro-5-nitrophenyl)methanol (1.82 g, 9.8 mmols) in DCM (60 mL) was added triphenylphosphine (2.62 g, 10 mmols), followed by CBr4 (3.26 g, 9.8 mmols). The reaction mixture was stirred at room temperature for 24 hours, and then diluted with DCM, washed with water and saturated brine. The organic layer was separated, dried (MgSO4), filtered, and concentrated in vacuo to provide a residue. The residue was purified by silica gel column (EA/PE: 1/10) to give 2-(bromomethyl)-1-chloro-4-nitrobenzene (1.56 g, 64%). 1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 2.8 Hz, 1H), 8.13 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 7, 59 (d, J = 8.8 Hz, 1H), 4.62 (s, 2H). LC-MS purity (254 nm): > 80%; tR = 1.95 min.

[00297] To an ice-cold suspension of NaH (60%, 110 mg, 2.75 mmols) in anhydrous DMF (1 mL) was added dropwise a solution of 3-hydroxypyridine (250 mg, 2.65 mmols) in DMF (2 mL. After a mixture was stirred at 0°C for 15 minutes, a solution of 2-(bromomethyl)-1-chloro-4-nitrobenzene (610 mg, 2.45 mmols) in DMF (4 mL) was added dropwise. The reaction mixture was stirred at 0°C for another hour, quenched with water, and then partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over (MgSO4). ) anhydrous, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel column (EA/PE: 1/1) to give 3-[(2-chloro-5-nitrophenyl)methoxy ]pyridine (350 mg, 54%) as a cream solid. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 2.8 Hz, 1H), 8.45 (d, J = 2 .8 Hz, 1H), 8.32 (dd, J = 4.8 Hz, 1.2 Hz, 1H), 8.18 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 7 .61 (d, J = 8.8 Hz, 1H), 7.36-7.33 (m, 1H), 7.30-7.26 (m, 1H), 5.26 (s, 2H). ES-MS m/z: 265 (M+H)+. LC-MS purity (254 nm): > 97%; tR= 1.80 min.

[00298] To a suspension of 3-[(2-chloro-5-nitrophenyl)methoxy]pyridine (320 mg, 1.212 mmol) and NH4Cl (513 mg, 9.696 mmols) in 9 mL of EtOH and 6 mL of H2O was added Fe powder (272 mg, 4.85 mmols) in portions. The reaction mixture was stirred at 80°C for 3 hours, cooled to room temperature and then filtered through Celite. The filter mass was washed with ethanol. The orange solution was concentrated in vacuo, and the residue was dissolved in DCM, washed with saturated NaHCO3. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (EA/PE: 3/1) to give 4-chloro-3-[(pyridin-3-yloxy)methyl)]aniline (167 mg, 59%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.41 (dd, J = 2.8 Hz, 0.8 Hz, 1H), 8.25 (d, J = 4.4 Hz, 2.0 Hz , 1H), 7.26-7.23 (m, 2H), 7.26 (d, J = 8.4 Hz, 1H), 6.59 (dd, J = 8.4 Hz, 2.8 Hz , 1H), 5.13 (s, 2H), 3.71 (bs, 2H).

[00299] To a stirred solution of 5,7-dimethylpyrazolo[1,5- a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.262 mmol), 4-chloro-3-[(pyridin-3-yloxy)methyl )]aniline (73 mg, 0.314 mmol) and HATU (149 mg, 0.393 mmol) in DMF (1 mL) DIPEA (0.1 mL, 0.524 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours, 45°C for two hours and 60°C for two hours until the reaction is complete. The suspension was diluted with H2O (3 mL), and the precipitated solid was collected by filtration, washed with minimal DCM and Et2O, and dried in vacuo to provide the title compound (57 mg, 53%) as a white solid. pale. 1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.64 (s, 1H), 8.41 (d, J = 3.2 Hz, 1H), 8.22 (dd , J = 4.8 Hz, 1.6 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.81 (dd, J = 8.8 Hz, 3.2 Hz, 1H), 7.54-7.51 (m, 2H), 7.38 (dd, J = 8.8 Hz, 4.8 Hz, 1H), 7.20 (s, 1H), 5.26 ( s, 2H), 2.76 (s, 3H), 2.69 (s, 3H). ES-MS m/z: 409.1 [M+H]+. LC-MS purity (254 nm): 99%; tR = 1.89 min. Example 59 - Preparation of 5,7-dimethyl-N-{4-methyl-3-(1,3-oxazol-2-yl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00300] A suspension of 3-bromo-4-methylaniline (184 mg, 1.0 mmol), 2-(tributylstanyl)-1,3-oxazole (430 mg, 1.2 mmol), CuO (8 mg, 0 .1 mmol) and Pd(PPh3)4 (115 mg, 0.1 mmol) in dioxane (2 mL) was stirred at 100 ° C for 3 hours under argon atmosphere in a microwave synthesizer to provide a crude product. The crude product was purified by preparative HPLC (MeCN/10 mM NH4HCO3) to provide 4-methyl-3-(1,3-oxazol-2-yl)aniline (92 mg, 52%) as an oil. ES-MS m/z: 175.2 [M + H]+. LC-MS purity (254 nm): > 99%; tR = 1.31 min.

[00301] A mixture of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.26 mmol), 4-methyl-3-(1,3-oxazol-2- iL)aniline (55 mg, 0.314 mmol) and HATU (57 mg, 0.39 mmol) in DMF/NMM (1 mL/0.1 mL) was stirred at room temperature for 12 hours. The reaction mixture was added with water (2 mL), stirred at room temperature for 0.5 hour and then filtered. The resulting solid was washed with water (1 mL), DCM (2 mL), Et2O (2 mL) and dried in vacuo to provide the title compound (62 mg, 68.0%) as a white solid. 1H NMR (400 MHz, DMSO) δ 10.22 (s, 1H), 8.64 (s, 1H), 8.45 (s, 1H), 8.27(s, 1H), 7.66 (s , 1H), 7.45 (m, 1H), 7.36-7.39 (m, 1H), 7.21 (s, 1H), 2.77 (s, 3H), 2.72 (s, 3H), 2.61 (s, 3H). ES-MS m/z: 348.1 [M+H]+. LC-MS purity (254 nm): >99%; tR= 1.91 min. Example 60 - Preparation of 5,7-dimethyl-N-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00302] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide 5 (100 mg, 0.25 mmol) in DMF (2 mL) was charged with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-iL)- 1H-pyrazole (64 mg, 0.31 mmol), K2CO3 (105 mg, 0. 76 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol) and the mixture was degassed with argon for 30 minutes and heated at 100°C for 30 hours. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (10 mL). The filtrate was washed with ice water (10 mL) and brine (10 mL) and concentrated in vacuo to provide a crude compound. The crude compound was purified by FCC (eluent, 5 to 10% methanol in DCM) to give the title compound as an off-white solid (35 mg, 39%). 1H NMR (400 MHz, CDCl3) δ 10.29 (s, 1H), 10.08 (s, 1H), 8.63 (s, 1H), 7.69 (d, J=7.1 Hz, 2H ), 7.54 (s, 1H), 7.40 (d, J=8.4 Hz, 2H), 6.70 (s, 1H), 3.90 (s, 3H), 2.75 (s , 3H), 2.65 (s, 3H). ES-MS m/z 347.20 (M+H)+. HPLC purity 91.1%. Example 61 - Preparation of N-(4-(furan-2-yl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00303] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide 5 (100 mg, 0.25 mmol) in DMF (2 mL) was charged with furan-2-iLboronic acid (34 mg, 0.31 mmol), K2CO3 (105 mg, 0.76 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol) and the reaction mixture was degassed with argon for 30 minutes and heated at 100°C for 30 hours. The reaction mixture was filtered through a celite pad and washed with ethyl acetate (10 mL). The filtrate was washed with ice water (10mL) and brine (10mL) and concentrated in vacuo to obtain crude compound which was purified by FCC (eluent, 5 to 10% methanol in DCM) to give the title compound as a yellow solid (30 mg, 35%). 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.61 (s, 1H), 7.70 (d, J=8.6 Hz, 2H), 7.59 (d, J =8.6 Hz, 2H), 7.38 (d, J=1.2 Hz, 1H), 6.68 (s, 1H), 6.52 (d, J=3.3 Hz, 1H), 6.40 (dd, J=1.8, 3.3 Hz, 1H), 2.73 (s, 3H), 2.64 (s, 3H). ES-MS m/z 333.10 (M+H)+. HPLC purity 99.0%. Example 62 - Preparation of 5,7-dimethyl-N -(4-(pyridin-4-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

[00304] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide 5 (100 mg, 0.25 mmol) in DMF (2 mL) was charged with pyridin-4-iLboronic acid (37 mg, 0.31 mmol), K2CO3 (105 mg, 0.76 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol) and the reaction mixture was degassed with argon for 30 minutes and heated at 100°C for 30 hours. Then, the reaction mixture was filtered through a celite pad and washed with ethyl acetate (10 mL). The filtrate was washed with ice water (10mL) and brine (10mL) and concentrated in vacuo to obtain crude compound which was purified by FCC (eluent, 5 to 10% methanol in DCM) to give the title compound as a white solid (40 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 10.26 (s, 1H), 8.64 (s, 1H), 8.58 (d, J=6.1 Hz, 2H), 7.85 (d, J =8.6 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H), 7.55 (d, J=6.1 Hz, 2H), 6.73 (s, 1H), 2.77 (s, 3H), 2.68 (s, 3H). ES-MS m/z 344.15 (M+H)+. HPLC purity 92.4%. Example 63 - Preparation of additional pyrazolo[1,5-a]pyrimidine-3-carboxamides

[00305] Additional pyrazolo[1,5-a]pyrimidine-3-carboxamide compounds were prepared based on the general procedures described in Part I below. Exemplary procedures for preparing specific amine compounds used in preparing certain compounds are provided in Part II below. Exemplary procedures for preparing specific carboxylic acid compounds used in the preparation of certain compounds are provided in Part III below. Specific pyrazolo[1,5-a]pyrimidine-3-carboxamide compounds prepared according to general procedures are provided in Part IV below.

Part I - General Procedures General Procedure A: Preparation of amide by coupling a carboxylic acid compound with an amine compound

[00306] A stirred solution of carboxylic acid compound (1.0 equivalent), HATU (1.5 equivalent), and DIPEA (3.75 equivalent) in DCM or DMF (~4 mL/0.2 mmol) was amine compound (1.25 - 2.0 equivalents) added. The reaction mixture was stirred at room temperature for 4 to 16 hours, and then washed with saturated aqueous NaHCO3 solution (5 mL/0.2 mmol), aqueous citric acid solution (5 mL/0.2 mmol) and saline (5 mL/0.2 mmol). The combined extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude material was purified by silica gel column chromatography or preparatory HPLC to provide the amide compound.

General Procedure B: Conversion of Carboxylic Ester Compound to Carboxylic Acid Compound

[00307] To a solution of carboxylic ester (1.0 equivalent) in EtOH (5.0 mL/1.0 mmol) and water (0 to 3.0 mL/1.0 mmol) was added NaOH (2.0 to 5.0 equivalents) and the mixture was heated at 80°C for two hours and then concentrated. To the concentrate, 6N HCl solution was added to adjust the pH to 5~6 and then the mixture was stirred for 10 minutes and subsequently filtered. The resulting solid was collected and dried to provide the carboxylic acid compound.

General Procedure C: Preparation of amide from a carboxylic acid compound and amine compound

[00308] To a solution of carboxylic acid compound (1.0 equivalent) in DCM (3 mL/0.5 mmol) was added DMF (1 drop) and oxalyl chloride (2.0 equivalents). The solution was stirred at room temperature for 30 minutes and then concentrated in vacuo. The resulting residue was dissolved in DCM (1 mL/0.5 mmol) followed by addition of amine compound (5.0 equivalents) and triethylamine (2.0 equivalents). The reaction mixture was stirred at RT for two hours and then diluted with DCM (10 mL/0.5 mmol). The organic solution was washed sequentially with H2O (10 mL/0.5 mmol) and brine (10 mL/0.5 mmol), then dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated in vacuo, and the resulting residue was purified by preparatory HPLC or silica gel chromatography to provide the amide compound.

Part II - Preparation of Specific Amine Compounds

[00309] Exemplary procedures for preparing specific amine compounds used in the preparation of certain pyrazolo[1,5-a]pyrimidine-3-carboxamide compounds are provided below. 1 -(4,4-Difluorocyclohexyl)ethan-1-amine

[00310] A solution of 4,4-difluorocyclohexane-1-carboxylic acid (1.64 g, 10 mmols) and DIPEA (2.58 g, 20 mmols) in DMF (10 mL) at 0°C was HATU (5.7 g, 15 mmols) was added and the reaction mixture was stirred at 0°C for 30 minutes, followed by the addition of N,O-dimethylhydroxylamine hydrochloride (970 mg, 10 mmols). The reaction mixture was allowed to warm to RT and stirred overnight, then quenched with saturated NaHCO3 solution, and separated. The aqueous phase was extracted with EtOAc (100 mL x3), and the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (PE/EtOAc; 4:1) to give 4,4-difluoro-N-methoxy-oN-methylcyclohexane-1-carboxamide (880 mg, 42%) as a colorless oil. LC-MS m/z: 208.0 [M+H]+. LCMS: tR = 1.58 min.

[00311] To a solution of 4,4-difluoro-N-methoxy-oN-methylcyclohexane-1-carboxamide (880 mg, 4.25 mmols) in THF (12 mL) was added a solution of MeLi in 1. 2-diethoxyethane (3 mol/L, 2 mL) dropwise at 0°C. After addition was complete, the reaction mixture was allowed to warm to RT and stirred overnight, then quenched with saturated NH4Cl solution and separated. The aqueous phase was extracted with EtOAc (120 mL x 3), and the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (PE/EA = 4:1) to give 1-(4,4-difluorocyclohexyl)ethan-1-one (400mg, 43%) as a yellow oil Of course. 1H NMR (500 MHz, CDCl3) δ 2.44 (m, 1H), 2.19 (s, 3H), 2.13-2.16 (m, 2H), 1.96-1.98 (m, 2H), 1.74-1.83 (m, 4H).

[00312] A mixture of 1-(4,4-difluorocyclohexyl)ethan-1-one ((200 mg, 1.23 mmol), NH4OAc (1.9 g, 24.6 mmols) and NaBH3CN (388 mg , 6.15 mmols) in i-PrOH (15 mL) was stirred at RT for 4 hours and then at 90°C for two hours. Then, the reaction mixture was poured into water (15 mL), extracted with CH2Cl2. (30 ml, x3) and dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (EtOAc/MeOH; 10:1) to give 1-(4,4-difluorocyclo-). hexyl)ethan-1-amine as a colorless oil. LC-MS m/z: 164.1 [M+H]+. LCMS: tR = 1.13 min.

[00313] MgBrMe (3 M in THF, 5 mL, 15 mmols) was added dropwise at RT to a solution of 1-(4-chlorophenyl)ethan-1-one (1.54 g, 10 mols) in Et2O (60 mL). After the addition was complete the reaction mixture was stirred at RT for 12 hours and then quenched by careful addition of saturated NH4Cl solution (30 mL). The resulting mixture was stirred for one hour and then extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo, and purified by silica gel chromatography (PE/EtOAc; 5:1) to provide 2-(4-chlorophenyl)propan-2-ol (1.365 g, 80%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.42 (dd, J = 6.8 Hz, 2.0 Hz, 2H). 7.29 (dd, J = 6.8 Hz, 2.0 Hz, 2H), 1.78 (s, 1H), 1.56 (s, 6H).

[00314] A mixture of 2-(4-chlorophenyl)propan-2-ol (1.36 g, 8 mmols), TMSN3 (2.4 g, 16 mmols) and BF3-Et2O (16 mL) in CH2Cl2 (20 mL) was stirred at RT for two hours and quenched with saturated NaHCO3 solution. The resulting mixture was separated, and the aqueous phase was extracted with CH2Cl2 (30 mL x 3). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated in vacuum to give the target compound 1-(2-azidopropan-2-iL)-4-chlorobenzene as a colorless oil, which was used in the next step without further purification. LC-MS m/z: 153.0 [M - N3]+. LCMS: Purity (254 nm): 44%; tR= 1.44 min.

[00315] The crude azide from the previous step was dissolved in THF (15 mL) at RT and trimethylphosphine (16 mL, 1.0 M in THF) was added. After 15 minutes, 3 mL of water was added, and the resulting mixture was stirred at RT for two hours until the reaction was complete (monitored by LC/MS.) The solvent was removed in vacuo and the residue was diluted with water (75 mL), extracted with CH2Cl2, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the resulting residue was purified by reverse phase chromatography (0.05% TFA/MeCN) to provide the desired product 2-(4-chlorophenyl)propan-2-amine (200 mg, 57 % during two steps) as a pale oil. LC-MS m/z: 153.0 [M - NH2]+. LCMS: Purity (214 nm): 98%; tR = 1.71 min. Part III - Preparation of specific carboxylic acid compounds

[00316] Exemplary procedures for preparing specific carboxylic acid compounds used in the preparation of certain substituted pyrazolo[1,5-a]pyrimidine compounds are provided below. 7-Chloro-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid

[00317] To a solution of ethyl 3-amino-1H-pyrazol-4-carboxylate (10 g, 64.5 mmols) in HOAc (50 mL) was added 4-methyleneoxetan-2-one (27 g, 322. 5 mmols). The mixture was stirred at 110°C for two hours, cooled and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE/EA; 10:3) to give ethyl 7-hydroxy-o5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (8. 0 g, 57%) and ethyl 5-hydroxy-o7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (3.1 g, 21%) as white solids. 7-hydroxy product: LC-MS m/z: 221.0 [M+H]+, Purity (214 nm): >90%, tR = 1.26 min; 5-hydroxy product: LC-MS m/z: 221.0 [M+H]+, Purity (214 nm): >92%, tR = 1.46 min.

[00318] A solution of ethyl 7-hydroxy-o5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (4.4 g, 20 mmols) in POCl3 (30 mL) was stirred at 95°C for a hour and concentrated in vacuum. The residue was dissolved in EtOAc (20 mL) and basified with saturated NaHCO3 solution (20 mL) to pH ~ 7. The resulting mixture was separated, and the aqueous phase was extracted with EtOAc (15 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE/EA; 1:1) to provide 7-chloro-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate of ethyl (1.0 g, 21%) as a white solid. LC-MS m/z: 239.0 [M+H]+, Purity (254 nm): >82%, tR= 1.55 min.

[00319] To a solution of ethyl 7-chloro-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (1.0 g, 4.18 mmols) in toluene (10 mL) was added (Bu3Sn) 2O (5.0 g, 8.36 mmols). The reaction mixture was stirred at 120°C for 2 days, and concentrated in vacuo. The residue was dissolved in EtOAc (10 mL), and basified with saturated NaHCO3 solution (10 mL) to pH ~ 8 to 9. The aqueous phase was separated and acidified with 6 N HCl (10 mL) to pH ~ 5. The solution was extracted with EtOAc (10 mL x 3). The organic phases were dried over dry Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE/EA; 1:1) to provide 7-chloro-5-methylpyrazolo[1,5- a ]pyrimidine-3- acid carboxylic acid (230 mg, 26%) as a white solid. LC-MS m/z: 211.0 [M+H]+, Purity (214 nm): >97%, tR = 1.23min. 5-Chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid

[00320] A solution of ethyl 5-hydroxy-o7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (2.8 g, 12.6 mmols) in POCl3 (30 mL) was stirred at 70°C for two hours and concentrated in vacuum. The resulting residue was dissolved in EtOAc (20 mL) and basified with saturated NaHCO3 solution (15 mL) to pH ~ 7. The resulting mixture was separated, and the aqueous phase was extracted with EtOAc (10 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE/EA; 1:1) to provide 5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate of ethyl (2.7 g, 90%) as a white solid. LC-MS m/z: 239.0 [M+H]+, Purity (214 nm): >99%, tR = 1.74 min.

[00321] To a solution of ethyl 5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (1.0 g, 4.18 mmols) in toluene (10 mL) was added (Bu3Sn) 2O (5.0 g, 8.36 mmols). The reaction mixture was stirred at 120°C for 2 days, and concentrated in vacuo. The resulting residue was dissolved in EtOAc (10 mL), and basified with saturated NaHCO3 solution (10 mL) to pH ~ 8 to 9. The aqueous phase was separated and acidified with 6 N HCl (10 mL) to pH ~ 5 The solution was extracted with EtOAc (10 mL x 3). The organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE/EA; 1:1) to provide 5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3- acid. carboxylic acid (330 mg, 37%) as a white solid. LC-MS m/z: 211.0 [M+H]+, Purity (214 nm): >97%, tR = 1.28 min.

Part IV - Pyrazolo[1,5-a]pyrimidine-3-carboxamide compounds prepared following general procedures

[00322] The following compounds were prepared based on the general procedures described in Part I above. 5,7-Dimethyl-N -(1,2,3,4-tetrahydronaphthalen-1-iL)pyrazolo[1,5- a ]pyrimidine-3-carboxamide

[00323] Following general procedure A, 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40 mg, 0.21 mmol) and 1,2,3,4-tetrahydronaphthalen-1 -amine gave the title compound (37 mg, 55%) as a yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.68 (s, 1H),8.42 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 7.0 Hz, 1H) , 7,187.13 (m, 3H), 6.67 (s, 1H), 5.52-5.49 (m, 1H), 2.91-2.84 (m, 2H), 2.78 (s , 2H), 2.53 (s, 3H), 2.25-2.22 (m, 1H), 2.00-1.90 (m, 3H). LC-MS m/z: 321.2 [M+H]+. HPLC purity (214 nm): >99%; tR = 8.26 min. 5,7-Dimethyl-N -((1R, 4 R )-4-(pentyloxy)cyclohexyl)pyrazolo[1,5- a ]pyrimidine-3-carboxamide

[00324] Following general procedure A, 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (24 mg, 0.125 mmol) and (1R,4R)-4-(pentyloxy)cyclohexan- 1-amine gave the title compound (29 mg, 64%) as a white solid. 1H NMR (400 MHz, MeOD-d4): δ 8.37 (s, 1H), 8.27 (d, J = 7.6 Hz, 1H), 6.91 (s, 1H), 3.90 ( br, 1H), 3.47 (t, J = 6.8 Hz, 2H), 3.34 (br, 1H), 2.71 (s, 3H), 2.61 (s, 3H), 2, 10-2.06 (m, 4H), 1.55 (t, J = 6.4 Hz, 2H), 1.48-1.41 (m, 4H), 1.35-1.33 (m, 4H), 0.92 (t, J = 6.8 Hz, 3H). LC-MS m/z: 359.2 [M+H]+. HPLC purity (214nm): >99%; tR= 9.262 min. (S)-N-(1-(2-fluorophenyl)ethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00325] Following general procedure A, 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40 mg, 0.21 mmol) and (S)-1-(2-fluorophenyl)ethanol 1-amine gave the title compound (34.3 mg, 49%) as a white solid. 1H NMR (400 MHz, MeOD-d4) δ 9.02 (d, J = 7.5 Hz, 1H), 8.49 (s, 1H), 7.48-7.43 (m, 1H), 7 .34-7.28 (m, 1H), 7.19-7.10 (m, 2H), 7.03 (s, 1H), 5.52-5.47 (m, 1H), 2.79 (d, J = 0.4 Hz, 3H), 2.69 (s, 3H), 1.62 (d, J = 7.2 Hz, 3H). LC-MS m/z: 313.2 [M+H]+. HPLC: Purity (214 nm): >99%; tR = 9.85 min. (S)-N-(1-(2-methoxyphenyl)ethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00326] Following general procedure A, 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (25 mg, 0.13 mmol) and (S)- 1-(2-methoxyphenyl) ethane 1-amine gave the title compound (21.6 mg, 51%) as a yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.77 (d, J = 8.5 Hz, 1H), 8.61 (s, 1H), 7.36 (d, J = 6.0 Hz, 1H) , 7.23 (t, J = 8.0 Hz, 1H), 6.94-6.90 (m, 2H), 6.70 (s, 1H), 5.63-5.59 (m, 1H ), 3.93 (s, 3H), 2.78 (s, 3H), 2.67 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H). LC-MS m/z: 325.0 [M+H]+. HPLC: Purity (214 nm): >93%; tR = 9.82 min. (R)-N-(1-(2-methoxyphenyl)ethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00327] Following general procedure A, 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (30 mg, 0.15 mmol) and (R)- 1-(2-methoxyphenyl) ethane 1-amine gave the title compound (19.7 mg, 40%) as a pink solid. 1H NMR (500 MHz, DMSO-d6): δ 8.73 (d, J = 8.0 Hz, 1H), 8.48 (s, 1H), 7.31-7.25 (m, 2H), 7.14 (s, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.93 (t, J = 6.0 Hz, 1H), 5.43-5.39 (m , 1H), 3.91 (s, 3H), 2.74 (s, 3H), 2.66 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H). LC-MS m/z: 325.2 [M+H]+. HPLC: Purity (214 nm): >99%; tR = 9.82 min. (S)-N-(1-(3-chlorophenyl)ethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00328] Following general procedure A, 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40 mg, 0.21 mmol) and (S)- 1-(3-chlorophenyl) ethane 1-amine gave the title compound (26.1 mg, 38%) as a white solid. 1H NMR (400 MHz, MeOD-d4) δ 8.49 (s, 1H), 7.46 (s, 1H), 7.40-7.31 (m, 2H), 7.27 (dt, J = 6.8 Hz, 2.4 Hz, 1H), 7.03 (s, 1H), 5.24 (q, J = 7.0 Hz, 1H), 2.79 (s, 3H), 2.69 (s, 3H), 1.62 (d, J = 7.0 Hz, 3H). LC-MS m/z: 329.1 [M+H]+. HPLC: Purity (214 nm): >99%; tR= 10.24 min. (R)-N-(1-(4-chlorophenyl)ethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00329] Following general procedure A, 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (38 mg, 0.20 mmol) and (R)- 1-(4-chlorophenyl) ethane 1-amine gave the title compound (18 mg, 26%) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 8.49 (s, 1H), 8.47 (s, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.41 ( d, J = 8.5 Hz, 1H), 7.14 (s, 1H), 5.20-5.14 (m, 1H), 2.74 (s, 1H), 2.63 (s, 1H ), 1.51 (d, J = 6.0 Hz, 3H). LC-MS m/z: 329.1 [M+H]+. HPLC: Purity (214 nm): >99%; tR= 10.32 min. (R)-N-(1-(4-fluorophenyl)ethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00330] Following general procedure A, 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (30 mg, 0.16 mmol) and (R)- 1-(4-fluorophenyl) ethane 1-amine gave the title compound (26.7 mg, 53%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.63 (s, 1H), 8.49 (d, J = 7.5 Hz, 1H), 7.45-7.42 (m, 2H), 7, 07-7.03 (m, 2H), 6.73 (s, 1H), 5.39-5.37 (m, 1H), 2.81 (s, 3H), 2.65 (s, 3H) , 1.65 (s, 3H). LC-MS m/z: 313.2 [M+H]+. HPLC: Purity (214 nm): >99%; tR = 9.82 min. N-(1-(4,4-difluorocyclohexyl)ethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00331] Following general procedure A, 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (20 mg, 0.1 mmol) and 1-(4,4-difluorocyclohexyl)ethane- 1-amine gave the title compound (10 mg, 30%) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.63 (s, 1H), 8.14 (d, J = 8.5 Hz, 1H), 6.73 (s, 1H), 4.29-4.27 (m, 1H), 2.82 (s, 3H), 2.66 (s, 3H), 2.20-2.14 (m, 2H), 1.98-1.95 (m, 1H), 1.87-1.56 (m, 6H), 1.29 (d, J = 6.5 Hz, 3H). LC-MS m/z: 337.2 [M+H]+. HPLC: Purity (254 nm): >99%; tR = 7.95 min. N-(2-(4-chlorophenyl)propan-2-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00332] Following general procedure A, 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40 mg, 0.21 mmol) and 2-(4-chlorophenyl)propan-2-amine provided the title compound (23.5 mg, 33%) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 8.58 (s, 1H), 8.42 (s, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.36 ( d, J = 8.5 Hz, 2H), 7.16 (s, 1H), 2.76 (s, 3H), 2.63 (s, 3H), 1.73 (s, 6H). LC-MS m/z: 343.1 [M+H]+. HPLC: Purity (214 nm): >99%; tR = 8.99 min. 7-Chloro-N-(2-(4-chlorophenyl)propan-2-iL)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00333] Following general procedure C, 7-chloro-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (100 mg, 0.47 mmol) and 2-(4-chlorophenyl)propan-2- amine gave the title compound (40 mg, 23%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.44 (s, 1H), 7.60 (s, 1H), 7.44 (d, J = 9.0 Hz , 2H), 7.36(d, J =8.5 Hz, 2H), 2.65 (s, 3H), 1.73 (s, 6H). LC-MS m/z: 362.2 [M+H]+. HPLC purity (214 nm): >99%; tR= 9.02 min. 5-Chloro-N-(2-(4-chlorophenyl)propan-2-iL)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00334] Following general procedure C, 5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (100 mg, 0.47 mmol) and 2-(4-chlorophenyl)propan-2- amine gave the title compound (60 mg, 35%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.02 (s, 1H), 7.43 (t, J = 8.5 Hz, 3H), 7.35 (d , J = 8.5 Hz, 2H), 2.78 (s, 3H), 1.71 (s, 6H). LC-MS m/z: 363.2 [M+H]+. HPLC purity (214 nm): >97%; tR= 9.44 min. N-(2-(2,4-difluorophenyl)propan-2-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00335] Following general procedure A, 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (19 mg, 0.1 mmol) and 2-(2,4-difluorophenyl)propan-2- amine gave the title compound (20 mg, 58) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.66 (s, 1H), 8.56 (s, 1H), 7.49-7.44 (m, 1H), 6.86-6.82 (m, 1H), 6.76-6.73 (m, 1H), 6.74 (s, 1H), 2.81 (s, 3H), 2.67 (s, 3H), 1.92 (s, 6H ). LC-MS m/z: 345.1 [M+H]+. HPLC: Purity (254 nm): >99%; tR = 8.62 min. N-(2 -((1R,4R)-4-methoxycyclohexyl)propan-2-iL)-5,7-dimethylpyrazolo[1,5- a ]pyrimidine-3-carboxamide and N-(2 -( (1S,4S)-4-methoxycyclohexyl)propan-2-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

[00336] Following general procedure A, 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (50 mg, 0.26 mmol) and 2-(4-methoxycyclohexyl)propan-2- amine provided N-(2-((1R,4R)-4-methoxycyclohexyl)propan-2-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide (7.2 mg) and N-(2-((1S,4S)-4-methoxycyclohexyl)propan-2-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide (8.4 mg) as white solids.

[00337] N-(2 -((1R,4R)-4-methoxycyclohexyl)propan-2-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide: 1H NMR ( 500 MHz, MeOD-d4) δ 8.46 (s, 1H), 8.43 (s, 1H), 7.02 (s, 1H), 3.37 (s, 3H), 3,223.17 (m, 1H), 2.80 (s, 3H), 2.67 (s, 3H), 2.20-2.18 (m, 2H), 2.00-1.98 (m, 3H), 1.48 (s, 6H), 1.31-1.21 (m, 4H). LC-MS m/z: 345.2 [M+H]+. HPLC: Purity (214 nm): 99.52%; tR = 8.08 min.

[00338] N-(2-((1S,4S)-4-methoxycyclohexyl)propan-2-iL)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide: 1H NMR ( 500 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.44 (s, 1H), 7.02 (s, 1H), 3.51-3.50 (m, 1H), .3 .35 (s, 3H), 2.80 (s, 3H), 2.69 (s, 3H), 2.10-2.07 (m, 2H), 1.99-1.96 (m, 1H ), 1.87-1.66 (m, 2H), 1.54-1.48 (m, 6H), 1.48 (s, 6H), 0.87 (d, J = 7.0 Hz, 1H). LC-MS m/z: 345.2 [M+H]+. HPLC: Purity (214 nm): 95.63%; tR= 8.46 min. Example 64 - Preparation of additional pyrazolo[1,5-a]pyrimidine-3-carboxamides.

[00339] The following additional pyrazolo[1,5-a]pyrimidine-3-carboxamide compounds were prepared based on the procedures described above: Example 65 - ASSESSMENT OF BIOLOGICAL ACTIVITY

[00340] The ability of exemplary compounds to activate glucocerebrosidase (Gcase) was measured. Experimental Procedures and Results are provided below.

Part I: Test Procedure

[00341] A 484 μL aliquot of a 1.0 mg/mL solution of phosphatidylserine (PS) (Sigma P7769) in chloroform was evaporated under a stream of nitrogen for one hour. The lipid film was dissolved during 4 minutes of vigorous centrifugation in 40 mL of 176 mM K2HPO4/50 mM citric acid (pH 4.7) containing 7.5 μL of Triton X-100, resulting in a mixed micellar preparation with a composition of 0.32 mM Triton and 0.37 mol% PS. 4- Methylumbelliferyl-beta-D-glucopyranoside (ACROS-337025000) was dissolved in the micellar solution to a final concentration of 2 mM for use as the reaction substrate.

[00342] Test compounds were diluted to the desired concentrations with 10 mM dimethyl sulfoxide (DMSO) stocks, and 0.41 μL of the DMSO compound mixture was added to 100 μL of micellar solution containing 10 nM GCase and 100 nM saposin C (Enzo ALX-201-262-C050). Pre-incubation was allowed to occur for 30 minutes at room temperature, after which the reaction was initiated by combining 25 μL of substrate solution with 25 μL of compound/GCase/saposin mixture. The reaction continued for 15 minutes at room temperature and was stopped by adding 150 μL of 1M glycine, pH 12.5. The completion of the reaction was monitored by measuring the fluorescence intensity (excitation: 365 nm; emission: 440 nm) on a SpectraMax i3 instrument (Molecular Devices). Test compounds were analyzed at 1.0 and 0.1 μM final concentrations, and subsequent 8-point dose response curves were obtained using 3-fold dilutions of a maximum final concentration of 5 μM.

Part II: Results

[00343] Gcase activation values for the tested compounds are provided in Tables 3 and 4 below, along with cLogP, PSA, and Compound Solubility in Water. For experiments in which the test compound was used at a concentration of 1.0 μM, the "+" symbol indicates less than 30% Gcase activation; the symbol "++" indicates Gcase activation in the range of 30% to 60%; and the symbol "+++" indicates Gcase activation greater than 60%. For experiments in which the test compound was used at a concentration of 0.1 μM, the symbol "*" indicates less than 10% Gcase activation; the symbol "**" indicates Gcase activation in the range of 10% to 20%; and the symbol "***" indicates greater than 20% Gcase activation. TABLE 3. TABLE 4.

INCORPORATION BY RE FERÊN CIA

[00344] The entire description of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.

EQUIVALENTS

[00345] The invention can be represented in other specific ways without departing from the spirit or essential characteristics thereof. The foregoing embodiments should therefore be considered in all respects illustrative rather than limiting of the invention described herein. The scope of the invention is thus indicated by the appended claims, rather than by the preceding description, and all changes which fall within the meaning and range of equivalence of the claims are intended to be covered herein.

Claims (36)

1. Compound, characterized by the fact that it presents Formula I: or a pharmaceutically acceptable salt thereof, in which: R1 represents independently for each occurrence C14 alkyl, C1-4 haloalkyl, C1-4 alkoxy, cyclopropyl, cyano, chlorine or fluorine; R2 represents hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, -(C1-4 alkylene)-(2- to 6-membered heteroalkyl), cyclopropyl, cyano, chlorine, fluorine, or -N( H)(R3); R3 represents independently for each occurrence hydrogen or C1-4 alkyl; X1 is one of the following: (a) a carbonyl-containing ligand selected from -C(O)N(H)-ye -C(O)N(H)(CI-6 alkylene)-y; where y is a connection to A1; or (b) an amine-containing ligand selected from -(C1-4 alkylene)-N(H)-y and -(C1-4 alkylene)-N(H)-(C1-4 alkylene)-y; A1 is a C3-10 cycloalkyl that is substituted by 1 or 2 occurrences of Y1 and 0, 1, 2, or 3 occurrences of Y2; Y1 is -O-(CI-7 aquila); Y2 represents, independently for each occurrence, C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxyl, C2-4 alkynyl, cyano, azido, -N (R3)2, -(C1-6 alkylene)-(5-6 membered heterocyclyl), -(C1-6 alkylene)-CO2R3, or C3-6 cycloalkyl substituted by C1-6 haloalkyl; en is 1, 2, or 3. 2. Compound according to claim 1, characterized by the fact that R1 is methyl. 3. Compound, according to claim 1 or 2, characterized by the fact that n is 2. 4. Compound according to claim 3, characterized by the fact that the R1 groups are located in positions 5 and 7 of the pyrazolo[1,5-a]pyrimidinyl. 5. Compound according to any one of claims 1 to 4, characterized by the fact that R2 is hydrogen. 6. Compound according to any one of claims 1 to 5, characterized by the fact that R3 represents independently for each occurrence hydrogen, methyl, or ethyl. 7. Compound according to any one of claims 1 to 6, characterized by the fact that X1 is -C(O)N(H)-^. 8. Compound according to any one of claims 1 to 7, characterized by the fact that any occurrence of Y2 is independently C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, or hydroxyl. 9. Compound according to any one of claims 1 to 7, characterized by the fact that any occurrence of Y2 is independently C1-3 alkyl. 10. Compound according to any one of claims 1 to 9, characterized in that Y1 is -O-butyl, -O-pentyl, or -O-hexyl. 11. Compound according to any one of claims 1 to 10, characterized by the fact that A1 is C5-10 cycloalkyl that is substituted by 1 or 2 occurrences of Y1 and 0, 1, 2, or 3 occurrences of Y2 . 12. Compound according to any one of claims 1 to 11, characterized by the fact that A1 is C3-7 cycloalkyl replaced once by Y1 and 0 to 1 occurrences of Y2. 13. Compound, according to claim 1, characterized by the fact that the compound is represented by Formula IA: or a pharmaceutically acceptable salt thereof, in which: R1 is independently methyl, cyclopropyl or isopropyl; R2 is hydrogen; R3 represents independently for each occurrence hydrogen or C1-4 alkyl; A1 is C3-10 cycloalkyl that is substituted by 1 or 2 occurrences of Y1 and 0, 1, 2, or 3 occurrences of Y2; Y1 is -O-(C1-7alkyl); and Y2 represents, independently for each occurrence, C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, azido, -N(R3)2 , -(C1-6 alkylene)- (5- to 6-membered heterocyclyl), -(C1-6 alkylene)-CO2R3, or C3-6 cycloalkyl substituted by C1-6 haloalkyl. 14. Compound, according to claim i3, characterized by the fact that Ri is methyl. 15. Compound according to claim i3 or i4, characterized by the fact that any occurrence of Y2 is independently Ci-3 alkyl, halogen, or Ci-3 haloalkyl. 16. Compound, characterized by the fact that it presents Formula IIa: or a pharmaceutically acceptable salt thereof, in which: R1 and R2 each independently represent for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, -(C1-4 alkylene)-(2 to 6 members), cyclopropyl, cyano, chlorine, or fluorine; R3 represents independently for each occurrence hydrogen or C1-4 alkyl; X1 is one of the following: (a) a carbonyl-containing ligand selected from -C(O)N(H)-V and -C(O)N(H)(CI-6 alkylene)—v; where v is a connection to A1; or (b) an amine-containing ligand selected from -(C1-4 alkylene)-N(H)-ve -(C1-4 alkylene)-N(H)-(C1-4 alkylene)-v; A1 is C3-10 cycloalkyl that is substituted by (a) 1, 2, or 3 halogens and (b) 0, 1, 2, or 3 occurrences of Y2; Y2 represents, independently for each occurrence, C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, azido, -N(R3)2, -(C1-6 alkylene)- (5- to 6-membered heterocyclyl), -(C1-6 alkylene)-CO2R3, or C3-6 cycloalkyl substituted by C1-6 haloalkyl; en is 1, 2, or 3. 17. Compound according to claim 16, characterized by the fact that R1 independently represents for each occurrence C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, cyclopropyl, cyano, chlorine, or fluorine. 18. Compound, according to claim 16, characterized by the fact that R1 is methyl. 19. Compound according to any one of claims 16 to 18, characterized by the fact that n is 2. 20. Compound, according to claim 16, characterized by the fact that the R1 groups are located in positions 5 and 7 of the pyrazolo[1,5-a]pyrimidinyl. 21. Compound according to any one of claims 16 to 20, characterized by the fact that X1 is -C(O)N(H)-^. 22. Compound according to claim 1, characterized by the fact that the compound is selected from the group consisting of: It is , or a pharmaceutically acceptable salt thereof. 23. Compound according to claim 22, characterized in that the compound is: or a pharmaceutically acceptable salt thereof. 24. Compound, according to claim 22, characterized by the fact that the compound is: or a pharmaceutically acceptable salt thereof. 25. Compound, according to claim 22, characterized by the fact that the compound is: or a pharmaceutically acceptable salt thereof. 26. Compound, according to claim 22, characterized by the fact that the compound is: 27. Pharmaceutical composition, characterized by the fact that it comprises a compound, as defined in any one of claims 1 to 26, and a pharmaceutically acceptable carrier. 28. Pharmaceutical composition according to claim 27, characterized by the fact that the composition comprises the compound: or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 29. Pharmaceutical composition according to claim 27, characterized by the fact that the composition comprises the compound: and a pharmaceutically acceptable carrier. 30. Compound, according to any one of claims 1 to 26, or pharmaceutical composition, according to any one of claims 27 to 29, characterized by the fact that it is for use in the treatment of a selected disorder of the group consisting of Gaucher disease, Parkinson's disease, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, glaucoma open angle, multiple sclerosis, and multiple myeloma. 31. Compound or pharmaceutical composition, according to claim 30, characterized by the fact that the disorder is Gaucher disease, Parkinson's disease, Lewy body disease, dementia, or multiple system atrophy, preferably being disease Gaucher disease, Parkinson's disease or Lewy body disease. 32. Pharmaceutical compound or composition according to claim 30, characterized by the fact that the disorder is Parkinson's disease. 33. Use of a compound, as defined in any one of claims 1 to 26, or of a pharmaceutical composition, as defined in any one of claims 27 to 29, characterized by the fact that it is for the preparation of a medicament for the treatment of a disorder selected from the group consisting of Gaucher disease, Parkinson's disease, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, major depression, polycystic kidney disease, type 2 diabetes, open-angle glaucoma, multiple sclerosis, and multiple myeloma. 34. Use according to claim 33, characterized in that the disorder is Gaucher disease, Parkinson's disease, Lewy body disease, dementia, or multiple system atrophy, preferably Gaucher disease, Parkinson's disease or Lewy body disease. 35. Use according to claim 33, characterized by the fact that the disorder is Parkinson's disease. 36. Use according to claim 35, characterized in that the compound or pharmaceutical composition is for use in combination therapy with a second agent, such as levodopa, pramipexole, ropinirole, rotigotine or apomorphine.