EP3452045A1

EP3452045A1 - Methods of treatment and combination therapies using gcase activator heterobicyclic and related compounds

Info

Publication number: EP3452045A1
Application number: EP17793335.5A
Authority: EP
Inventors: Renato T. Skerlj; Peter T. Lansbury; Elyse Marie Josee BOURQUE; Andrew C. Good
Original assignee: Lysosomal Therapeutics Inc
Current assignee: Lysosomal Therapeutics Inc
Priority date: 2016-05-04
Filing date: 2017-05-04
Publication date: 2019-03-13
Also published as: WO2017192841A1

Abstract

The invention provides methods of treatment and combination therapies using heterobicyclic and related compounds that activate Gcase, such as in the treatment of endometriosis and Parkinson's disease. An exemplary heterobicyclic compound that activates Gcase is a substituted pyrrolo[1,2-a]pyrimidine compound, such as substituted 2,4-dimethyl-N-phenylpyrrolo[1,2-a]pyrimidine-8-carboxarnide compounds and variants thereof.

Description

METHODS OF TREATMENT AND COMBINATION THERAPIES USING GCASE ACTIVATOR HETEROBICYCLIC AND RELATED COMPOUNDS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 62/331,539, filed May 4, 2016, the contents of which are hereby incorporated by reference.

FIELD OF THE INVENTION

[0002] The invention provides methods of treatment and combination therapies using heterobicyclic and related compounds that activate glucocerebrosidase (Gcase), such as in the treatment of endometriosis and Parkinson's disease.

BACKGROUND

[0003] Mutations in the gene encoding glucocerebrosidase are 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 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 frequently involves use of levodopa and dopamine agonists. However, these drugs can produce significant side effects such as hallucinations, insomnia, nausea, and constipation. Further, patients often develop tolerance to these drugs such that the drugs become ineffective at treating the symptoms of the disease, while sometimes also producing a movement disorder side effect called dyskinesia. Diffuse Lewy Body disease is a dementia that is sometimes confused with Alzheimer's disease.

[0004] Endometriosis is a condition of severe dysmenorrhea, which is often accompanied by severe pain, bleeding into the endometrial masses or peritoneal cavity and can lead to infertility. The cause of the symptoms of this condition can be ectopic endometrial growths which respond inappropriately to normal hormonal control and are located in inappropriate tissues. Because of the inappropriate locations for endometrial growth, the tissue may initiate local inflammatory -like responses causing macrophage infiltration and a cascade of events leading to initiation of a painful response. Existing treatments for endometriosis include use of low-dose estrogen to suppress endometrial growth through a negative feedback effect on central gonadotropin release and subsequent ovarian production of estrogen; however, it is sometimes necessary to use continuous estrogen to control the symptons. Such use of estrogen can lead to undersirable side effects and potentially elevated risk of endometrial cancer.

[0005] Accordingly, the need exists for new therapeutic methods for treating Parkinson's disease, endometriosis, and other medical disorders. The present invention addresses this need and provides other related advantages.

SUMMARY [0006] The invention provides methods of treatment and combination therapies using heterobicyclic and related compounds that activate glucocerebrosidase (Gcase), such as in the treatment of endometriosis and Parkinson's disease. Methods for treating endometriosis comprise administering to a patient a therapeutically effective amount of a heterobicyclic or related compound described herein that activates Gcase. The combination therapies for use in treating Parkinson's disease comprise administering to a patient a therapeutically effective amount of a heterobicyclic or related compound described herein that activates Gcase and a second therapeutic agent selected from the group consisting of a glucosylceramide synthase inhibitor, an acid ceramidase inhibitor, and an acid sphingomyelinase activator. Various aspects and embodiments of the invention are described in further detail below.

[0007] Accordingly, one aspect of the invention provides a method of treating

endometriosis in a patient. The method comprises administering to a patient in need thereof a therapeutically effective amount of a Gcase activator compound described herein (e.g., a compound of any one Formulae A-l, B-l, B-IIa, B-III, or C-l) treat the endometriosis.

[0008] Another aspect of the invention provides a method of treating Parkinson's disease in a patient. The method comprises administering to a patient in need thereof a therapeutically effective amount of (i) a Gcase activator compound described herein (e.g., a compound of any one Formulae A-l, B-l, B-IIa, B-III, or C-l) and (ii) a second therapeutic agent selected from the group consisting of a glucosylceramide synthase inhibitor, an acid ceramidase inhibitor, and an acid sphingomyelinase activator, in order treat the Parkinson's disease. [0009] Another aspect of the invention provides a method of treating a disorder selected from the group consisting of Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, major depression, and open angle glaucoma in a patient. The method comprises administering to a patient in need thereof a therapeutically effective amount of (i) a Gcase activator compound described herein (e.g., a compound of any one Formulae A-l, B-l, B-IIa, B-III, or C-l) and (ii) an acid ceramidase inhibitor, in order to treat the disorder.

DETAILED DESCRIPTION

[0010] The invention provides methods of treatment and combination therapies using heterobicyclic and related compounds that activate Gcase, such as in the treatment of endometriosis and Parkinson's disease. Methods for treating endometriosis comprise administering to a patient a therapeutically effective amount of a heterobicyclic or related compound described herein that activates Gcase. The combination therapies for use in treating Parkinson's disease comprise administering to a patient a therapeutically effective amount of a heterobicyclic or related compound described herein that activates Gcase and a second therapeutic agent selected from the group consisting of a glucosylceramide synthase inhibitor, an acid ceramidase inhibitor, and an acid sphingomyelinase activator. 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 herein incorporated by reference in its entirety. Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section.

I. DEFINITIONS

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

[0012] The terms "a" and "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 straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as Ci-Ci₂alkyl, Ci-Cioalkyl, and Ci-Cealkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methy 1-1 -propyl, 2-methyl-2- propyl, 2-methy 1-1 -butyl, 3 -methyl- 1 -butyl, 2-methy 1-3 -butyl, 2,2-dimethy 1-1 -propyl, 2- methyl-l-pentyl, 3-methyl-l-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethy 1-1 -butyl, 3,3-dimethyl-l-butyl, 2-ethy 1-1 -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 with 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 with a heteroatom (e.g., an O, N, or S atom). The heteroalkyl may be, for example, an -O-Ci-Cioalkyl group, an -Ci-Cealkylene-O-Ci-Cealkyl group, or a C1-C6 alkylene-OH group. In certain embodiments, the "heteroalkyl" may be 2-8 membered heteroalkyl, indicating that the heteroalkyl contains from 2 to 8 atoms selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. In yet other embodiments, the heteroalkyl may be a 2-6 membered, 4-8 membered, or a 5-8 membered heteroalkyl group (which may contain for example 1 or 2 heteroatoms selected from the group oxygen and nitrogen). One type of heteroalkyl group is an "alkoxyl" group.

[0017] The term "alkenyl" as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C_2-Ci₂alkenyl, C_2-Cioalkenyl, and C_2-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 straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C_2-Ci₂alkynyl, C_2-Cioalkynyl, and C_2- Cealkynyl, respectively. Exemplary alkynyl groups include ethynyl, prop-l -yn-l-yl, and but-1 - yn-l-yl.

[0019] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as "C4-₈cycloalkyl," derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes. Unless specified otherwise, 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, phosphonato, phosphinato, 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 not substituted, i.e., it is unsubstituted.

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

[0021] The term "partially unsaturated carbocyclyl" refers to a monovalent cyclic hydrocarbon that contains at least one double bond between ring atoms where at least one ring of the carbocyclyl is not aromatic. The partially unsaturated carbocyclyl may be characterized according to the number of ring carbon atoms. For example, the partially unsaturated carbocyclyl may contain 5-14, 5-12, 5-8, or 5-6 ring carbon atoms, and accordingly be referred to as a 5-14, 5-12, 5-8, or 5-6 membered partially unsaturated carbocyclyl, respectively. The partially unsaturated carbocyclyl may be in the form of a monocyclic carbocycle, bicyclic carbocycle, tricyclic carbocycle, bridged carbocycle, spirocyclic carbocycle, or other carbocyclic ring system. Exemplary partially unsaturated carbocyclyl groups include cycloalkenyl groups and bicyclic carbocyclyl groups that are partially unsaturated. Unless specified otherwise, partially unsaturated carbocyclyl 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, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. In certain embodiments, the partially unsaturated carbocyclyl is not substituted, i.e., it is unsubstituted.

[0022] 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 one carbon-carbon double bond, referred to herein, e.g., as "C4- gcycloalkenyl," derived from a cycloalkane. Exemplary cycloalkenyl groups include, but are not limited to, cyclohexenes, cyclopentenes, and cyclobutenes. Unless specified otherwise, 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, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. In certain embodiments, the cycloalkenyl group is not substituted, i.e., it is unsubstituted.

[0023] The term "aryl" is art-recognized and refers to a carbocyclic aromatic group.

Representative aryl groups include phenyl, naphthyl, anthracenyl, and the like. The term "aryl" includes poly cyclic ring systems having two or more carbocyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic and, e.g., the other ring(s) may be cycloalkyls, cycloalkenyls,

cycloalkynyls, and/or aryls. Unless specified otherwise, 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, sulfhydryl, imino, amido, carboxylic acid, - C(0)alkyl, -C0₂alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moieties, -CF₃, -CN, or the like. 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, i.e., it is unsubstituted. In certain embodiments, the aryl group is a 6-10 membered ring structure.

[0024] The term "aralkyl" refers to an alkyl group substituted with an aryl group.

[0025] The term "bicyclic carbocyclyl that is partially unsaturated" refers to a bicyclic carbocyclic group containing at least one double bond between ring atoms and at least one ring in the bicyclic carbocyclic group is not aromatic. Representative examples of a bicyclic carbocyclyl that is partially unsaturated include, for example:

[0026] The terms ortho, meta and para are art-recognized 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.

[0027] The terms "heterocyclyl" and "heterocyclic group" are art-recognized and refer to saturated, partially unsaturated, or aromatic 3- to 10-membered ring structures, alternatively 3- to 7-membered rings, whose ring structures include one to four heteroatoms, such as nitrogen, oxygen, and sulfur. The number of ring atoms in the heterocyclyl group can be specified using C_x-C_x nomenclature where x is an integer specifying the number of ring atoms. For example, a C3-Cvheterocyclyl 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 from 3 to 7 ring atoms, inclusive of any heteroatoms that occupy a ring atom position. One example of a

C₃heterocyclyl is aziridinyl. Heterocycles may 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 may be fused to one or more aryl, partially unsaturated, or saturated 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, thiopyranyl, xanthenyl, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. Unless specified otherwise, 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, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl. In certain embodiments, the heterocyclyl group is not substituted, i.e., it is unsubstituted.

[0028] 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:

In certain embodiments, the bicyclic heterocyclyl is an carbocyclic ring fused to partially unsaturated heterocyclic ring, that together form a bicyclic ring structure having 8-10 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 art-recognized and refers to a saturated heterocyclyl group as defined above. In certain embodiments, the "heterocycloalkyl" is a 3- to 10- membered ring structures, alternatively a 3- to 7-membered rings, whose ring structures include one to four heteroatoms, such as nitrogen, oxygen, and sulfur.

[0030] The term "heterocycloalkylene" of a heterocycloalkyl group.

An exemplary heterocycloalkylene group is heterocycloalkylene may contain, for example, 3-6 ring atom (i.e., a 3-6 membered heterocycloalkylene). In certain embodiments, the heterocycloalkylene is a 3-6 membered heterocycloalkylene containing 1, 2, or 3 three heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur.

[0031] The term "heteroaryl" is art-recognized and refers to aromatic groups that include at least one ring heteroatom. In certain instances, 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 specified otherwise, the heteroaryl ring may be substituted at one or more ring positions with, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, carboxylic acid, -C(0)alkyl, -CC^alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moieties, -CF₃, -CN, or the like. The term "heteroaryl" also includes poly cyclic ring systems having two or more rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls. In certain embodiments, the heteroaryl ring is substituted at one or more ring positions with halogen, alkyl, hydroxyl, or alkoxyl. In certain other embodiments, the heteroaryl ring is not substituted, i.e., 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, whose 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 art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety represented by the general formula -N(R⁵⁰)(R⁵¹), wherein R⁵⁰ and R⁵¹ each independently represent hydrogen, alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl, aralkyl, or -(CH₂)_m-R⁶¹; or R⁵⁰ and R⁵¹, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R⁶¹ represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a poly cycle; 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 "alkoxyl" or "alkoxy" are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -0-(CH₂)_m-R₆i, where m and R₆i are described above.

[0035] The term "carbamate" as used herein refers to a radical of the form

-RgOC(0)N(Rh)-, -RgOC(0)N(Rh)Ri_, or -OC(0)NRhRi, wherein R_g R¾ and R[ 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. Exemplary carbamates include arylcarbamates and heteroaryl carbamates, e.g., wherein at least one of Rg R^ and R[ are independently aryl or heteroaryl, such as phenyl and pyridinyl.

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

[0037] The term "carboxamido" as used herein refers to the radical -C(0)NRR', where R and R' may be the same or different. R and R' may be independently alkyl, aryl, arylalkyl, cycloalkyl, formyl, haloalkyl, heteroaryl, or heterocyclyl.

[0038] The term "carboxy" as used herein refers to the radical -COOH or its corresponding salts, e.g. -COONa, etc.

[0039] The term "amide" or "amido" as used herein refers to a radical of the form

-R_aC(0)N(R_b)-, -R_aC(0)N(R_b)R_c-, -C(0)NR_bR_c, or -C(0)NH₂, wherein R_a, R_b and R_c 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 attached to another group through the carbon, the nitrogen, R , R_c, or R_a. The amide also may be cyclic, for example R_b and R_c, R_a and R_b, or R_a and R_c may be joined to form a 3- to 12-membered ring, such as a 3- to 10-membered ring or a 5- to 6-membered ring.

[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 herein refers to a radical -O-CO-alkyl.

[0042] The term "oxo" is art-recognized and refers to a "=0" substituent. For example, a cyclopentane susbsituted with an oxo group is cyclopentanone.

[0043] The term "sulfonamide" or "sulfonamido" as used herein refers to a radical having the structure -N(R_r)-S(0)2-R_s- or -S(0)2-N(R_r)R_s, where R_r, and R_s can be, for example, hydrogen, alkyl, aryl, cycloalkyl, and heterocyclyl. Exemplary sulfonamides include alkylsulfonamides (e.g., where R_s is alkyl), arylsulfonamides (e.g., where R_s is aryl), cycloalkyl sulfonamides (e.g., where R_s is cycloalkyl), and heterocyclyl sulfonamides (e.g., where R_s is heterocyclyl), etc. [0044] The term "sulfonyl" as used herein refers to a radical having the structure R_US02-, where R_u can be alkyl, aryl, cycloalkyl, and heterocyclyl, e.g., alkylsulfonyl. The term

"alkylsulfonyl" as used herein refers to an alkyl group attached to a sulfonyl group.

[0045] The symbol " -~>~ " indicates a point of attachment. [0046] The compounds of the disclosure 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 consist 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 denote a chiral center implicitly. It is understood that graphical depictions of chemical structures, e.g., generic chemical structures, encompass all stereoisomeric forms of the specified compounds, unless indicated otherwise.

[0047] Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, or (3) direct separation of the mixture of optical enantiomers on 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 as a chiral salt complex, or crystallizing the compound in a chiral solvent. Further, enantiomers can be separated using supercritical fluid chromatographic (SFC) techniques described in the literature. Still further, stereoisomers can be obtained from stereomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods. [0048] Geometric isomers can also exist in the compounds of the present invention. The symbol denotes a bond that may be a single, double or triple bond as described herein. The present invention encompasses the 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 configuration wherein the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E" and "Z" isomers.

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

[0050] The invention also embraces isotopically labeled compounds of the invention which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, H, ¹ C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷0, ¹P, ²P, ⁵S, ¹⁸F, and ⁶C1, respectively.

[0051] Certain isotopically-labeled disclosed compounds (e.g., those labeled with H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., H) and carbon- 14 (i.e., ¹⁴C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in, e.g., the Examples 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., murines, simians, equines, bovines, porcines, canines, felines, and the like), and more preferably humans.

[0053] As used herein, the term "effective amount" refers to the amount of a compound (e.g. , a compound of the present invention) sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term "treating" includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating 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 a phosphate buffered saline solution, water, emulsions (e.g. , such as an oil/water or water/oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see Martin, Remington's Pharmaceutical Sciences, 15th 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 which, upon administration to a subject, is capable of providing a compound of this invention or an active metabolite or residue thereof. As is known to those of skill in the art, "salts" of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, gly colic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene- 2-sulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may 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 (e.g., sodium) hydroxides, alkaline earth metal (e.g. , magnesium) hydroxides, ammonia, and compounds of formula NW^~4⁺, wherein W is C_1-4 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, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate,

flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy ethanesulfonate, 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 NW^~4⁺ (wherein W is a C_1-4 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 0-(7-azabenzotriazol-l-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)₂0); dimethylsulfoxide (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, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0062] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

II. THERAPEUTIC APPLICATIONS ~ TREATMENT OF ENDOMETROSIS

[0063] One aspect of the invention provides a method of treating endometriosis in a patient. The method comprises administering to a patient in need thereof a therapeutically effective amount of a Gcase activator compound described herein (e.g., a compound of any one

Formulae A-1, B-1, B-IIa, B-III, or C-l) treat the endometriosis.

Medical Use and Preparation of Medicament

[0064] Another aspect of the invention relates to compounds and compositions described herein for use in treating endometriosis. Another aspect of the invention pertains to use of a compound or composition described herein in the preparation of a medicament for treating endometriosis.

Combination Therapy

[0065] The invention embraces combination therapy, which includes the administration of a Gcase activator compound described herein (e.g., a compound of any one Formulae A-1, B-1, B-IIa, B-III, or C-l) and a second therapeutic agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination may include pharmacokinetic or pharmacodynamic co- action resulting from the combination of therapeutic agents.

[0066] Exemplary second agents for use in treating endometriosis include, for example, progesterone, progestin, a gonadotropin-releasing hormone (GnRH) agonist, and danazol. III. THERAPEUTIC APPLICATIONS ~ COMBINATION THERAPY FOR TREATING

PARKINSON'S DISEASE AND OTHER DISORDERS

[0067] One aspect of the invention provides a method of treating Parkinson's disease in a patient. The method comprises administering to a patient in need thereof a therapeutically effective amount of (i) a Gcase activator compound described herein (e.g., a compound of any one Formulae A-l, B-l, B-IIa, B-III, or C-l) and (ii) a second therapeutic agent selected from the group consisting of a glucosylceramide synthase inhibitor, an acid ceramidase inhibitor, and an acid sphingomyelinase activator, in order treat the Parkinson's disease.

[0068] Another aspect of the invention provides a method of treating a disorder selected from the group consisting of Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, major depression, and open angle glaucoma in a patient. The method comprises administering to a patient in need thereof a therapeutically effective amount of (i) a Gcase activator compound described herein (e.g., a compound of any one Formulae A-l, B-l, B-IIa, B-III, or C-l) and (ii) an acid ceramidase inhibitor, in order to treat the disorder.

[0069] Each therapeutic agent in a combination therapy of the invention may be administered simultaneously (i.e., in the same medicament), concurrently (i.e., in separate medicaments administered one right after the other in any order) or sequentially in any order. Sequential administration is particularly useful when the therapeutic agents in the combination therapy are in different dosage forms (e.g., one agent is a tablet or capsule and another agent is a sterile liquid) and/or are administered on different dosing schedules, e.g., a Gcase activator compound that is administered at least every other day and a second therapeutic agent that is administered less frequently, such as once weekly, once every two weeks, or once every three weeks. In certain embodiments, the Gcase activator compound is administered before administration of the second therapeutic agent, while in other embodiments, the Gcase activator compound is administered after administration of the second therapeutic agent.

[0070] In certain embodiments, the patient is a human, such as an adult human or pediatric human.

Medical Use and Preparation of Medicament

[0071] Another aspect of the invention relates to compounds and compositions described herein for use in treating a disorder described herein. Another aspect of the invention pertains to use of a compound or composition described herein in the preparation of a medicament for treating a disorder described herein. Exemplary Benefits of the Combination Therapy

[0072] The methods and compositions are contemplated to provide various benefits. The beneficial effect of the combination may include pharmacokinetic or pharmacodynamic co- action resulting from the combination of therapeutic agents.

[0073] One contemplated benefit is improved efficacy in treating the disorder when a Gcase activator compound is administered with a second therapeutic agent compared to the efficacy observed when the Gcase activator compound is administered alone. In certain embodiments, the improvement may be a 5%, 10%, 20%, 30%, 50%, 75%, 100%, or greater improvement in efficacy in treating the disorder when the Gcase activator compound is administered with a second therapeutic agent compared to the efficacy observed when the Gcase activator compound is administered alone.

[0074] Another contemplated benefit is a reduction in side effects associated with administration of a Gcase activator compound and/or a second therapeutic agent. In certain embodiments, the reduction in side effects may be a 5%, 10%, 20%, 30%, 50%, 75%, 100%, or greater reduction in side effects in a human subject when the Gcase activator compound is administered with the second therapeutic agent compared to the side effects observed when the Gcase activator and/or a second therapeutic agent is administered alone at a dosage necessary to achieve a similar therapeutic effect.

[0075] The administration of a Gcase activator and/or a second therapeutic agent may result in a synergistic effect, e.g., a synergistic improvement in efficacy in treating a disorder described herein. In certain embodiments, the synergistic improvement in efficacy is at least a 5%, 10%, 15%, 20%, 25%, 30%, or greater improvement in efficacy compared to the additive improvement in efficacy associated with administration of the Gcase activator compound and the second therapeutic agent together.

IV. Heterobicyclic Compounds for Activation of Gcase for Use in Therapeutic Methods

[0076] Exemplary heterobicyclic compounds for activation of Gcase contemplated for use in the therapeutic methods are provided below. In certain embodiments, the heterobicyclic compound is a substituted pyrrolo[l,2-a]pyrimidine or related organic compound. In certain embodiments, the heterobicyclic compound is a substituted pyrazolo[l,5-a]pyrimidine or related organic compound. In certain embodiments, the heterobicyclic compound is a substituted imidazo[l,5-a]pyrimidine or related organic compound.

Part A: SUBSTITUTED PYRROLO[l,2-a]PYRiMiDiNE AND RELATED ORGANIC COMPOUNDS

[0077] In certain embodiments, the heterobicyclic compound for activation of Gcase is a substituted pyrrolo[l,2-a]pyrimidine or related organic compound, such as a substituted pyrrolo[l,2-a]pyrimidine or related organic compound embraced by Formula A-I:

(A-I)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R² each represent independently for each occurrence hydrogen, deuterium, C alkyl, Ci^ haloalkyl, C1-4 deuteroalkyl, C_1-4 alkoxyl, -(C 1-4 alky lene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, halogen, hydroxyl, or -N(R⁴)₂;

R³ represents independently for each occurrence hydrogen, C_1-6 alkyl, or C3-6

cycloalkyl;

R⁴ represents independently for each occurrence hydrogen, C_1-4 alkyl, cyclopropyl, or

-C(0)R³;

R⁵ represents independently for each occurrence C_1-4 alkyl or C3-6 cycloalkyl;

X¹ is one of the following:

(a) a carbonyl-containing linker selected from -C(0)N(H)-v|/, -C(0)N(H)(Ci_-6 and -C(0)-(3-6 membered heterocycloalkylene containing at least one ring -N(H)- group)-v|/; where ψ is a bond to A¹; or

(b) an amine-containing linker selected from -(C_1-4 alkylene)-N(H)-v|/ and -(C_1-4 alkylene)-N(H)-(Ci-4 alkylene)-v|/;

A¹ is a cyclic group selected from:

· C3-1₀ cycloalkyl, phenyl, naphthyl, or 5-6 membered heteroaryl, each of which is substituted by 1 or 2 occurrences of Y¹ and 0, 1, 2, or 3 occurrences of Y ; • a 5-14 membered partially unsaturated carbocyclyl, or a 3-16 membered heterocyclyl, each of which is substituted by 0, 1, or 2 occurrences of Y¹ and 0, 1, 2, or 3 occurrences of Y²; and

• phenyl substituted with 0, 1, 2, or 3 occurrences of Y²;

Y¹ represents, independently for each occurrence, one of the following:

• 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl, a 3-

10 membered heterocyclyl, or C3-6 halocycloalkyl;

• 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -O-C3-7 cycloalkyl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -O- (C2-6 alkynyl);

• C₂-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C_2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl; or

• Ci-6 haloalkyl, Ci_-6 alkyl, halogen, cyano, -C0₂R³, -C(0)R⁵, -S(0)₂R⁵, -C(0)N(R⁵)₂, -C(0)N(R )₂, -N(R )C(0)R⁵, or -0-(Ci_-8 haloalkyl);

Y² represents, independently for each occurrence, deuterium, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, C ₁-6 hydroxy alkyl, hydroxyl, Ci-₆ alkoxyl, cyano, azido, -N(R )₂, -(Ci-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C0₂R³, or Ci-₆ haloalkyl-substituted C3-6 cycloalkyl;

m is 1 or 2;

n is 1, 2, or 3; and

provided that at least one occurrence of R¹ or R² is other than hydrogen when (i) A¹ is an unsubstituted heterocyclyl, (ii) A¹ is an unsubstituted phenyl or a phenyl substituted only by halogen, or (iii) Y² is halogen.

[0078] Definitions of the variables in Formula A-I above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where X¹ is A¹ is phenyl or 5-6 membered heteroaryl, and Y¹ is 2-8 membered heteroalkyl. [0079] Accordingly, in certain embodiments, R¹ represents independently for each occurrence C_1-4 alkyl, Ci^ haloalkyl, -(C_1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, halogen, or -N(R⁴)₂. In certain embodiments, R¹ represents independently for each occurrence Ci-4 alkyl, Ci^ haloalkyl, C_1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R¹ represents independently for each occurrence C_1-4 alkyl, C_1-4 haloalkyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R¹ is methyl. In certain embodiments, the R¹ groups are located at the 2 and 4 positions of the pyrrolo[l,2- a]pyrimidinyl.

[0080] In certain embodiments, n is 2. In certain other embodiments, n is 1.

[0081] In certain embodiments, m is 1. In certain other embodiments, m is 2.

[0082] 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.

[0083] In certain embodiments, R³ and R⁴ each represent independently for each occurrence hydrogen, methyl, or ethyl. In certain embodiments, R³ is hydrogen. In certain embodiments, R⁴ is hydrogen.

[0084] In certain embodiments, X¹ is -0(Ο)Ν(Η)-ψ. In certain embodiments, X¹ is

or -C(0)-(3-6 membered heterocycloalkylene containing at least

[0085] In certain embodiments, A¹ is a cyclic group selected from:

• phenyl, 5-6 membered heteroaryl, or C3-7 cycloalkyl, each of which is substituted by 1 or 2 occurrences of Y¹ and 0, 1, 2, or 3 occurrences of Y²; and

• a bicyclic carbocyclyl that is partially unsaturated or a mono-cyclic or bicyclic

heterocyclyl, each of which is substituted by 0, 1, or 2 occurrences of Y¹ and 0, 1, 2, or 3 occurrences of Y².

[0086] In certain embodiments, A¹ is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y¹ and 0, 1, or 2 occurrences of Y². In certain embodiments, A¹ is phenyl substituted once by Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is a 5-6 membered heteroaryl substituted once by Y¹ and 0-1 occurrences of Y². In certain

embodiments, A¹ is pyridinyl substituted once by Y¹ and 0-1 occurrences of Y . [0087] In certain embodiments, A is C5-10 cycloalkyl substituted once by Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is C3-7 cycloalkyl substituted once by Y¹ and 0- 1 occurrences of Y². In certain embodiments, A¹ is a cyclopentyl or cyclohexyl, each of which is substituted once by Y¹ and 0-1 occurrences of Y .

[0088] In certain embodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y¹ and 0, 1, or I occurrences of Y². In certain embodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y² selected from the group consisting of Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, hydroxyl, and Ci-6 alkoxyl.

[0089] In certain embodiments, A¹ is (^Y )m _or (Y )m ; wherein m is 0, 1, or 2; and Y² represents independently for each occurrence Ci-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxy or cyano. In certain embodiments, A¹

is ^J ( )m or wherein m is 0, 1, or 2; and Y² represents independently for each occurrence C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, hydroxyl, or C_1-6 alkoxyl.

[0090] In certain embodiments, any occurrence of Y² is independently C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, or hydroxyl. In certain embodiments, any occurrence of Y² is independently C_1-3 alkyl. In certain embodiments, Y² is cyclopropyl.

[0091] In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl, furanyl, or pyridinyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl. [0092] In certain embodiments, Y¹ is -0-(Ci_7 alkyl). In certain embodiments, Y¹ is -O- butyl, -O-pentyl, or -O-hexyl. In certain embodiments, Y¹ is -(C_1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y¹ is -CH₂-0-(5-6 membered heteroaryl). In certain embodiments, Y¹ is -CH₂-0-(5-6 membered heteroaryl), wherein the 5-6 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, C ₁-6 hydroxy alkyl, hydroxyl, Ci-₆ alkoxyl, cyano, -N(R⁴)₂, amide, and

[0093] In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e 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 heterocycloalkyl. In certain embodiments, Y¹ is 5-membered heteroaryl. In certain embodiments, Y¹ is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C3-7 cycloalkyl, halogen, Ci-₆ haloalkyl, C ₁-6 hydroxy alkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R⁴)2, amide, and -CO2H. In certain embodiments, Y¹ is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, hydroxyl, and C_1-6 alkoxyl.

[0094] 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, Ci-₆ hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H.

[0095] 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 consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, Ci-₆ hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H.

[0096] In certain embodiments, Y¹ is C_2-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C2-4 alkynylene)-(5-6 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 -C≡C-(Ci_6 alkylene)-OR⁴. In certain embodiments, Y¹ is -C≡C-(Ci_6 alky lene)-0-(C 1-2 alkyl). In certain embodiments, Y¹ is -C≡C-CH₂-0-CH₃.

[0097] The description above describes multiple embodiments relating to compounds of Formula A-I. The patent application specifically contemplates all combinations of the embodiments. For example, the invention contemplates a compound of Formula A-I wherein X¹ is A¹ is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y¹ and 0, 1, or 2 occurrences of Y², and Y¹ is 2-8 membered heteroalkyl.

[0098] In certain embodiments, the compound is a compound of Formula A-I-l :

(A-I-l)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R² each represent independently for each occurrence hydrogen, C1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro;

R³ represents independently for each occurrence hydrogen or C_1-4 alkyl;

R⁴ represents independently for each occurrence hydrogen, C_1-4 alkyl, or -C(0)R³;

X¹ is one of the following:

(a) a carbonyl-containing linker selected from -C(0)N(H)(Ci_-6

and -C(0)-(3-6 membered heterocycloalkylene containing at least one ring -N(H)- where ψ is a bond to A ; or

(b) an amine-containing linker selected from -(C_1-4 and -(C_1-4 alkylene)-N(H)-(Ci-4 alkylene)-\|/; A¹ is a cyclic group selected from:

• a bicyclic carbocyclyl that is partially unsaturated or a mono-cyclic or bicyclic heterocyclyl, each of which is substituted 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:

• 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl;

· 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -0-(3-6

membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl); or

• C₂-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C_2-4 alkynylene)-(5-6 membered heteroaryl), or C2-₆ alkenyl;

Y² represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, hydroxyl, Ci-6 alkoxyl, cyano, azido, -N(R )2, -(Ci-6 alkylene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R³, or Ci-6 haloalkyl-substituted C3-6 cycloalkyl;

m is 1 or 2;

n is 1, 2, or 3; and

provided that at least one occurrence of R¹ or R² is other than hydrogen when (i) A¹ is an unsubstituted heterocyclyl or (ii) Y² is halogen.

[0099] Definitions of the variables in Formula A-I-l above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where X¹ is A¹ is phenyl or 5-6 membered heteroaryl, and Y¹ is 2-8 membered heteroalkyl.

[00100] Accordingly, in certain embodiments, R¹ represents independently for each occurrence C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R¹ represents independently for each occurrence C1-4 alkyl, C 1-4 haloalkyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R¹ is methyl. In certain embodiments, the R¹ groups are located at the 2 and 4 positions of the pyrrolo[l,2- ajpyrimidinyl.

[00101] In certain embodiments, n is 2. In certain other embodiments, n is 1.

[00102] In certain embodiments, m is 1. In certain other embodiments, m is 2.

[00103] 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.

[00104] In certain embodiments, R³ and R⁴ each represent independently for each occurrence hydrogen, methyl, or ethyl. In certain embodiments, R³ is hydrogen. In certain embodiments, R⁴ is hydrogen.

[00105] In certain embodiments, X¹ is In certain embodiments, X¹ is

or -C(0)-(3-6 membered heterocycloalkylene containing at least

[00106] In certain embodiments, A¹ is a cyclic group selected from:

[00107] In certain embodiments, A¹ is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y¹ and 0, 1, or 2 occurrences of Y². In certain embodiments, A¹ is phenyl substituted once by Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is a 5-6 membered heteroaryl substituted once by Y¹ and 0-1 occurrences of Y². In certain

embodiments, A¹ is pyridinyl substituted once by Y¹ and 0-1 occurrences of Y .

[00108] In certain embodiments, A¹ is C3-7 cycloalkyl substituted once by Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is a cyclopentyl or cyclohexyl, each of which is substituted once by Y¹ and 0-1 occurrences of Y . [00109] In certain embodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y¹ and 0, 1, or I occurrences of Y². In certain embodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y² selected from the group consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, hydroxyl, and C_1-6 alkoxyl.

[00110] In certain embodiments, A¹ is wherein m is 0, 1, or 2; and Y² represents independently for each occurrence C_1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, C_1-6 alkoxyl, or cyano. In certain embodiments, A¹

is ^i^^ (^Y )m or (^Y )m ; wherein m is 0, 1, or 2; and Y² represents independently for each occurrence C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, hydroxyl, or C_1-6 alkoxyl.

[00111] In certain embodiments, any occurrence of Y² is independently C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, or hydroxyl. In certain embodiments, any occurrence of Y² is independently Ci-3 alkyl. In certain embodiments, Y² is cyclopropyl.

[00112] In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl, furanyl, or pyridinyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl.

[00113] In certain embodiments, Y¹ is -0-(C_1-7 alkyl). In certain embodiments, Y¹ is -O- butyl, -O-pentyl, or -O-hexyl. In certain embodiments, Y¹ is -(C_1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y¹ is -CH₂-0-(5-6 membered heteroaryl). In certain embodiments, Y¹ is -CH₂-0-(5-6 membered heteroaryl), wherein the 5-6 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci-₆ alkoxyl, cyano, -N(R⁴)₂, amide, and

[00114] In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e 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 heterocycloalkyl. In certain embodiments, Y¹ is 5-membered heteroaryl. In certain embodiments, Y¹ is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C3-7 cycloalkyl, halogen, Ci-₆ haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H. In certain embodiments, Y¹ is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, hydroxyl, and C_1-6 alkoxyl.

[00115] 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, Ci-₆ hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H.

[00116] 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 consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, Ci-₆ hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H.

[00117] In certain embodiments, Y¹ is C_2-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C2-4 alkynylene)-(5-6 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 -C=C-(Ci_6 alkylene)-OR⁴. In certain embodiments, Y¹ is -C=C-(Ci_6 alky lene)-0-(C 1-2 alkyl). In certain embodiments, Y¹ is -C≡C-CH₂-0-CH₃.

[00118] The description above describes multiple embodiments relating to compounds of Formula A-I-1. The patent application specifically contemplates all combinations of the embodiments. For example, the invention contemplates a compound of Formula A-I wherein X¹ is A¹ is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y¹ and 0, 1, or 2 occurrences of Y², and Y¹ is 2-8 membered heteroalkyl.

[00119] In certain embodiments, the compound is a compound of Formula A-I-la:

(A-I-la)

or a pharmaceutically acceptable salt thereof, wherein:

R represents independently for each occurrence C1-4 alkyl;

R² and R³ each represent independently for each occurrence hydrogen or C1-4 alkyl; R⁴ represents independently for each occurrence hydrogen, C1-4 alkyl, or -C(0)R³; X¹ is one of the following:

(a) a carbonyl-containing linker selected from -C(0)N(H)(Ci_-6

(b) an amine-containing linker selected from -(C1-4 and -(C1-4 alkylene)-N(H)-(Ci-4

A¹ is a cyclic group selected from:

phenyl, 5-6 membered heteroaryl, or C3-7 cycloalkyl, each of which is substituted by 1 or 2 occurrences of Y¹ and 0, 1, 2, or 3 occurrences of Y ;

• a bicyclic carbocyclyl that is partially unsaturated or a mono-cyclic or bicyclic heterocyclyl, each of which is substituted 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:

• 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C_2-6 alkynyl); or

• C₂-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C_2-4 alkynylene)-(5-6 membered heteroaryl), or C_2-6 alkenyl;

Y² represents, independently for each occurrence, Ci_6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, C ₁-6 hydroxy alkyl, hydroxyl, Ci-₆ alkoxyl, cyano, azido, -N(R )₂, -(C ₁-6 alky lene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C0₂R³, or Ci-₆ haloalkyl-substituted C3-6 cycloalkyl; and

n is 1, 2, or 3.

[00120] Definitions of the variables in Formula A-I-la above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where X¹ is A¹ is phenyl or 5-6 membered heteroaryl, and Y¹ is 2-8 membered heteroalkyl.

[00121] In certain embodiments, the compound is a compound of Formula A-I-A:

(A-I-A)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is independently methyl, isopropyl, cyclopropyl, Ci_-2 haloalkyl, -(CH₂)i_-2-0-(Ci-3 alkyl), chloro, fluoro, or -N(R⁴)₂;

R² is hydrogen; R³ and R⁴ each represent independently for each occurrence hydrogen or C1-4 alkyl; A¹ is a cyclic group selected from:

• C3-10 cycloalkyl, phenyl, or 5-6 membered heteroaryl, each of which is substituted by 1 occurrence ofY¹ and 0, 1, or 2 occurrences of Y²; and

· a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y¹ and 0, 1, or I

occurrences ofY²;

Y¹ represents, independently for each occurrence, one of the following:

• 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-6 alkynyl); or

• C2-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl;

Y² represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen,

Ci-₆ haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci-₆ alkoxyl, cyano, azido, -N(R )₂, -(Ci-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R³, or Ci-6

haloalkyl-substituted C3-6 cycloalkyl.

[00122] Definitions of the variables in Formula A-I-A above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where A¹ is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y¹, where Y¹ is a 2-8 membered heteroalkyl.

[00123] Accordingly, in certain embodiments, A¹ is C3-7 cycloalkyl substituted once by Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is phenyl substituted once by Y¹ and 0- 1 occurrences of Y². In certain embodiments, A¹ is a 5-6 membered heteroaryl substituted once by Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is pyridinyl substituted by Y¹ and 0-1 occurrences of Y². [00124] In certain embodiments, any occurrence of Y² is independently C_1-3 alkyl, halogen, or Ci-3 haloalkyl.

[00125] In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is -0-(Ci_ 7 alkyl). In certain embodiments, Y¹ is -O-butyl, -O-pentyl, or -O-hexyl. In certain

embodiments, Y¹ is -(C_1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y¹ is -CH₂-0-(5-6 membered heteroaryl).

[00126] In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl). In certain embodiments, Y¹ is a 3-10 membered heterocyclyl. 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 heterocycloalkyl.

[00127] In certain embodiments, Y¹ is a 5-membered heteroaryl. In certain embodiments, Y¹ is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, Ci-₆ alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H. 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H.

[00128] 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H.

[00129] In certain embodiments, Y¹ is C_2-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2-₆ alkenyl. In certain embodiments, Y¹ is C₂-6 alkynyl. In certain embodiments, Y¹ is -C≡CH. In certain

[00130] In certain embodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y¹ and 0, 1, or I occurrences of Y². In certain embodiments, A¹ is an 8-12 membered bicyclic carbocyclyl that is partially unsaturated or an 8-12 membered bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y¹ and 0, 1, or 2 occurrences of Y². In certain embodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0, 1, or 2 occurrences of Y². In certain embodiments, A¹ is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl.

In certain embodiments, A¹ is or (^Y )m ; wherein m is 0, 1, or 2; and

Y² represents independently for each occurrence C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, hydroxyl, or Ci-₆ alkoxyl. In certain embodiments, A _or wherein m is 0, 1, or 2; and Y² represents independently for each occurrence Ci-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, hydroxyl, C_1-6 alkoxyl, or cyano.

[00131] In certain embodiments, R¹ is methyl. In certain embodiments, R¹ is further selected from halogen and halomethyl, such that R¹ may be methyl, halogen, or halomethyl.

[00132] In certain embodiments, R² is further selected from halogen, such that R² may be hydrogen or halogen.

[00133] The description above describes multiple embodiments relating to compounds of Formula A-I-A. The patent application specifically contemplates all combinations of the embodiments. For example, the invention contemplates a compound of Formula I-A wherein A is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y¹ and 0, 1, or 2 occurrences of Y², and Y¹ is 2-8 membered heteroalkyl. [00134] In certain embodiments, the compound is a compound of Formula A-I-Al :

(A-I-Al)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is independently methyl, cyclopropyl, or isopropyl;

R² is hydrogen;

R³ and R⁴ each represent independently for each occurrence hydrogen or C alkyl; A¹ is a cyclic group selected from:

• phenyl, 5-6 membered heteroaryl, or C₃-7 cycloalkyl, each of which is substituted by 1 occurrence ofY¹ and 0, 1, or 2 occurrences of Y²; and

• a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y¹ and 0, 1, or I occurrences ofY²;

Y¹ represents, independently for each occurrence, one of the following:

• 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C₂-6 alkynyl); or

• C₂-6 alkynyl, -C≡C-(d_-6 alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C_2-4 alkynylene)-(5-6 membered heteroaryl), or C₂-6 alkenyl;

Y² represents, independently for each occurrence, Ci-6 alkyl, C₃-6 cycloalkyl, halogen, Ci-₆ haloalkyl, C ₁-6 hydroxy alkyl, hydroxyl, Ci-₆ alkoxyl, cyano, azido, -N(R )₂, -(C ₁-6 alky lene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R³, or Ci-6 haloalkyl-substituted C3-6 cycloalkyl.

[00135] Definitions of the variables in Formula A-I-Al above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where A¹ is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y¹, where Y¹ is a 2-8 membered heteroalkyl.

[00136] Accordingly, in certain embodiments, A¹ is phenyl substituted once by Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is a 5-6 membered heteroaryl substituted once by Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is pyridinyl substituted by Y¹ and 0-1 occurrences of Y².

[00137] In certain embodiments, any occurrence of Y² is independently C_1-3 alkyl, halogen, or Ci-₃ haloalkyl.

[00138] In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is -0-(Ci_ 7 alkyl). In certain embodiments, Y¹ is -O-butyl, -O-pentyl, or -O-hexyl. In certain

[00139] In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl). In certain embodiments, Y¹ is a 3-10 membered heterocyclyl. 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 heterocycloalkyl.

[00140] In certain embodiments, Y¹ is a 5-membered heteroaryl. In certain embodiments, Y¹ is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R⁴)2, amide, and -CO2H. 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H. [00141] In certain embodiments, Y ¹ 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 C _{1 -6} alkyl, C3-6 cycloalkyl, halogen, C i-6 haloalkyl, C i-6 hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H.

[00142] In certain embodiments, Y ¹ is C_2-6 alkynyl, -C≡C-(C i_-6 alkylene)-OR⁴, -C≡C-(C i_-6 alkylene)-N(R )2, -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl. In certain embodiments, Y ¹ is C2-6 alkynyl. In certain embodiments, Y¹ is -C≡CH. In certain

embodiments, Y ¹ is -C≡C-(C i_6 alkylene)-OR⁴. In certain embodiments, Y¹ is -C≡C-(C i_6 alky lene)-0-(C 1-2 alkyl). In certain embodiments, Y¹ is -C≡C-CH₂-0-CH₃.

[00143] In certain embodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y ¹ and 0, 1, or 2 occurrences of Y². In certain embodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0, 1, or 2 occurrences of Y². In certain embodiments, A¹ is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, A¹ is or (^Y )m ; wherein m is 0, 1 , or 2; and Y² represents independently for each occurrence C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, hydroxyl, or C_1-6

alkoxyl. In certain embodiments, A¹ is ^/ (^Y )m or (^Y )m ; wherein m is 0, 1, or 2; and Y² represents independently for each occurrence C _{1 -6} alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, C_1-6 alkoxyl, or cyano.

[00144] In certain embodiments, R¹ is methyl. In certain embodiments, R¹ is further selected from halogen and halomethyl, such that R¹ may be methyl, halogen, or halomethyl.

[00145] In certain embodiments, R² is further selected from halogen, such that R² may be hydrogen or halogen. [00146] The description above describes multiple embodiments relating to compounds of Formula A-I-Al. The patent application specifically contemplates all combinations of the embodiments. For example, the invention contemplates a compound of Formula A-I-Al wherein A¹ is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y¹ and 0, 1, or 2 occurrences of Y², and Y¹ is 2-8 membered heteroalkyl.

[00147] In certain embodiments, the compound is a compound of Formula A-I-B:

(A-I-B)

or a pharmaceutically acceptable salt thereof, wherein:

A¹ is a cyclic group selected from phenyl, pyridinyl, cyclopentyl, or cyclohexyl, each of which is substituted by 1 occurrence of Y¹ and 0, 1, or 2 occurrences of Y :

Y¹ represents, independently for each occurrence, one of the following:

• 2-8 membered heteroalkyl optionally substituted by a 6 membered aryl or a 3-10 membered heterocyclyl;

· 3-10 membered heterocyclyl, a 6 membered aryl, -0-(3-6 membered heterocyclyl), or -0-(C2-e alkynyl); or

• -C≡C-H, -C≡C-(Ci-4 alkyl), or -C≡C-(Ci_-6 alkylene)-OR⁴;

Y² represents, independently for each occurrence, Ci_6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, or Ci-6 alkoxyl; and

R⁴ represents independently for each occurrence hydrogen or C1-4 alkyl.

[00148] Definitions of the variables in Formula A-I-B above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where A¹ is phenyl or pyridinyl, each of which is substituted once by Y¹, where Y¹ is 2-8 membered heteroalkyl. [00149] Accordingly, in certain embodiments, A¹ is phenyl substituted once by Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is pyridinyl substituted by Y¹ and 0-1 occurrences of Y².

[00150] In certain embodiments, any occurrence of Y² is independently C_1-3 alkyl, halogen, or Ci-₃ haloalkyl.

[00151] In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionally substituted by a 6 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is -0-(Ci_7 alkyl). In certain embodiments, Y¹ is -O-butyl, -O-pentyl, or -O-hexyl. In certain

[00152] In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6 membered aryl, or -0-(3-6 membered heterocyclyl). In certain embodiments, Y¹ is a 3-10 membered

heterocyclyl. 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 heterocycloalkyl.

[00153] In certain embodiments, Y¹ is a 5-membered heteroaryl. In certain embodiments, Y¹ is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, Ci-₆ alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H. 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, and C_1-6 alkoxyl.

[00154] 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H. [00155] The description above describes multiple embodiments relating to compounds of Formula A-I-B. The patent application specifically contemplates all combinations of the embodiments. For example, the invention contemplates a compound of Formula A-I-B wherein A¹ is phenyl or pyridinyl, each of which is substituted once by Y¹ and 0, 1, or I occurrences of Y², and Y¹ is 2-8 membered heteroalkyl.

[00156] In certain embodiments, the compound is a compound of Formula A-I-C:

(A-I-C)

or a pharmaceutically acceptable salt thereof, wherein:

A¹ is a bi cyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y¹ and 0, 1, or 2 occurrences of Y :

Y¹ represents, independently for each occurrence, one of the following:

· 3-10 membered heterocyclyl, a 6 membered aryl, -0-(3-6 membered heterocyclyl), or -0-(C2-6 alkynyl); or

• -C≡C-H, -C≡C-(Ci-4 alkyl), or -C≡C-(Ci_-6 alkylene)-OR⁴; and

R⁴ represents independently for each occurrence hydrogen or C1-4 alkyl.

[00157] Definitions of the variables in Formula A-I-C above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [00158] In certain embodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrences of Y².

[00159] In certain embodiments, any occurrence of Y² is independently C_1-3 alkyl, halogen, or Ci-3 haloalkyl.

[00160] 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.

Compound

^"""""""""11^""""""""""" K 1! m

I-l methyl methyl H

1-2 methyl methyl H

1-3 methyl methyl H

1-4 methyl methyl H

1-5 methyl methyl H

1-6 methyl methyl H

1-7 methyl methyl H -

methyl methyl H -C(0)N(H)(CH₂)₂-

1-9 methyl methyl H -C(0)N(H)(CH₂)₂-

1-74 methyl H F -C(0)N(H)CH₂-v|/

Where in Table 1, ψ is a bond

[00161] Methods for preparing compounds described herein are illustrated in the following synthetic schemes. These schemes are given for the purpose of illustrating the invention, and should not be regarded in any manner as limiting the scope or the spirit of the invention.

Starting materials shown in the schemes can be obtained from commercial sources or can be prepared based on procedures described in the literature.

[00162] The synthetic route illustrated in Scheme 1 depicts an exemplary procedure for preparing substituted pyrrolo[l,2-a]pyrimidine compounds. In the first step, 2-amino-lH- pyrrole-3-carboxamide (R -H) A is condensed with pentane-2,4-dione (R^u=R^lv=Me; R^m=H) in acetic acid at 80°C to afford 2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxarnide B.

Treatment of carboxamide B with phosphoryl chloride affords the intermediate nitrile which is hydrolyzed under acidic conditions and treated with ethanol to afford ethyl ester C. Hydrolysis of ethyl ester C under basic conditions provides 2,4-dimethylpyrrolo[l,2-a]pyrimidine-8- carboxylic acid D. SCHEME 1

[00163] The synthetic route illustrated in Scheme 2 depicts an exemplary procedure for preparing substituted pyrrolo[l,2-a]pyrimidine compounds. In the first step, coupling of carboxylic acid D with a variety of substituted aromatic or heteraromatic amines may be accomplished using standard peptide coupling procedures, such as HATU and/or HOBT in DMF in the presence of DIPEA to afford amide E. Alternatively, carboxylic ester C may be treated with Α1Μβ₃ to afford the intermediate Weinreb amide, which after reaction with an amine provides substituted amide E. In some cases, the reaction is performed in a stepwise manner where a bromo or iodo-substituted aromatic or heteraromatic amine is coupled with the Weinreb amide to form the iodo or bromo-substituted amide F. The bromo or iodo moiety may 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 E. SCHEME 2

[00164] The reaction procedures in Scheme 2 are contemplated to be amenable to preparing a wide variety of substituted pyrrolo[l,2-a]pyrimidine carboxamide compounds having different substituents at the A¹ and Y¹ positions. Furthermore, if a functional group that is part of the A¹ and/or Y¹ would not be amenable to a reaction condition described in Scheme 2, it is contemplated that the functional group can first be protected using standard protecting group chemistry and strategies, 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, 2^nd ed.; Wiley: New York, 1991, for further description of protecting chemistry and strategies. In certain other embodiments, a functional group in substituent A¹ and Y¹ can 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. , 1991 - 1992).

PART B: SUBSTITUTED PYRAzoLO[l,5-a]PYRiMiDiNE AND RELATED ORGANIC COMPOUNDS

[00165] In certain embodiments, the heterobicyclic compound for activation of Gcase is a substituted pyrazolo[l,5-a]pyrimidine or related organic compound, such as a substituted pyrazolo[l,5-a]pyrimidine or related organic compound embraced by Formula B-I:

(B-I)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R² each represent independently for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, Ci-₄ alkoxyl, -(Ci-₄ alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, chloro, fluoro, 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(0)R³;

X¹ is one of the following:

(a) a carbonyl-containing linker selected from and -C(0)N(H)(Ci_₆ where ψ is a bond to A¹; or

(b) an amine-containing linker selected from -(C₁-₄ and -(C₁-₄ alkylene)-N(H)-(Ci-4

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-lH-inden-l -yl, or 2,3-dihydro-lH- inden-2-yl, each of which is substituted 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:

o 4-8 membered heteroalkyl;

o 2-6 membered heteroalkyl substituted by a 5-10 membered heteroaryl; o -C≡C-(Ci-₆ alkylene)-OR⁴ or -(C₂-₄ alkynylene)-(5-6 membered heterocyclyl);

o -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), -0-(C2-e alkynyl), or azido; or

o 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;

Y¹ represents, independently for each occurrence, one of the following:

· 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a

3-10 membered heterocyclyl;

• 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl); or

• C₂-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C_2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl;

Y² represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci-₆ alkoxyl, C2-4 alkynyl, cyano, azido, -N(R )₂, -(Ci-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R³, or Ci-6

haloalkyl-substituted C3-6 cycloalkyl;

n is 1, 2, or 3.

[00166] Definitions of the variables in Formula B-I above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii) , e.g. , such as where R is CM alkyl or cyclopropyl, X¹ is -C(0)N(H)- ψ, and A¹ is phenyl substituted by 4-8 membered heteroalkyl.

[00167] In certain embodimnets, the compound is a compound of Formula B-I provided that:

• 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 Ci-4 alkoxyl, -(C1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, chloro, fluoro, 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(0)N(H)-\|/. [00168] In certain embodiments, R¹ represents independently for each occurrence C_1-4 alkyl, Ci-₄ haloalkyl, C_1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R¹ is methyl. In certain embodiments, the R¹ groups are located at the 5 and 7 positions of the pyrazolo[l,5-a]pyrimidinyl.

[00169] In certain embodiments, n is 2. In certain other embodiments, n is 1.

[00170] 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.

[00171] In certain embodiments, R³ and R⁴ each represent independently for each occurrence hydrogen, methyl, or ethyl. In certain embodiments, R³ is hydrogen. In certain embodiments, R⁴ is hydrogen.

[00172] In certain embodiments, X¹ is

[00173] In certain embodiments, any occurrence of Y² is independently C_1-6 alkyl, C3-₆ cycloalkyl, halogen, Ci-₆ haloalkyl, or hydroxyl. In certain embodiments, any occurrence of Y² is independently C_1-3 alkyl.

[00174] In certain embodiments, A¹ is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y² and (b) one of the following:

o 4-8 membered heteroalkyl;

o 2-6 membered heteroalkyl substituted by a 5-10 membered heteroaryl;

o -C≡C-(Ci-₆ alkylene)-OR⁴ or -(C_2-4 alkynylene)-(5-6 membered heterocyclyl); or o -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), -0-(C2-6 alkynyl), or azido.

[00175] In certain embodiments, A¹ is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y² and (b) one of the following:

(i) 4-8 membered heteroalkyl;

(ii) 2-6 membered heteroalkyl substituted by a 5-10 membered heteroaryl;

(iii) -C≡C-(Ci-₆ alkylene)-OR⁴ or -(C_2-4 alkynylene)-(5-6 membered heteroaryl); or

(iv) -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), -0-(C2-e alkynyl), or azido. [00176] In certain embodiments, A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) a 4-8 membered heteroalkyl. In certain embodiments, A¹ is phenyl substituted by -0-(Ci_7 alkyl). In certain embodiments, A¹ is phenyl substituted by -0-(C4_7 alkyl). In certain embodiments, A¹ is phenyl substituted by -O-butyl, -O-pentyl, or -O-hexyl. In certain embodiments, A¹ is phenyl substituted is -OCH2CH2OCH2CH2.

[00177] In certain embodiments, A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) a 2-6 membered heteroalkyl optionally substituted by a 5-10 membered heteroaryl. In certain embodiments, A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) a 2-6 membered heteroalkyl substituted by a 5-6 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, Ci-₆ hydroxyalkyl, hydroxyl, Ci-₆ alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H). In certain embodiments, A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) a 2-4 membered heteroalkyl substituted by pyridinyl.

[00178] In certain embodiments, A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) -C≡C-(Ci-6 alkylene)-OR⁴. In certain embodiments, A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) -C≡C-CH₂-0-CH₃. In certain embodiments, A¹ is phenyl substituted by -C≡C-CH₂-0-CH₃.

[00179] In certain embodiments, A¹ is C3-7 cycloalkyl substituted once by Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is C5-10 cycloalkyl that is substituted by 1 or 2 occurrences of Y¹ and 0, 1, 2, or 3 occurrences of Y².

[00180] In certain embodiments, A¹ is 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.

[00181] In certain embodiments, A¹ is 1,2,3,4-tetrahydronaphthalenyl substituted by 0, 1, 2, or 3 occurrences of Y².

[00182] In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl, furanyl, or pyridinyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl.

[00183] In certain embodiments, Y¹ is 2-8 membered heteroalkyl. In certain embodiments, Y¹ is -0-(Ci-7 alkyl). In certain embodiments, Y¹ is -O-but l, -O-pentyl, or -O-hexyl. In certain embodiments, Y¹ is -(C_1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y¹ is -CH₂-0-(5-6 membered heteroaryl). In certain embodiments, Y¹ is -CH₂- 0-(5-6 membered heteroaryl), wherein the 5-6 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, Ci-₆ alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H.

[00184] In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -O-(6-10 membered aryl), or -0-(C2-e 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 heterocycloalkyl. In certain embodiments, Y¹ is 5- membered heteroaryl. In certain embodiments, Y¹ is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C3-7 cycloalkyl, halogen, C_1-6 haloalkyl, Ci-6 hydroxyalkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R⁴)2, amide, and -CO2H. In certain embodiments, Y¹ is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, hydroxyl, and C_1-6 alkoxyl.

[00185] 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H.

[00186] 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 consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, Ci-₆ hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H.

[00187] In certain embodiments, Y¹ is C_2-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C2-4 alkynylene)-(5-6 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 -C≡C-(Ci-6 alkylene)-OR⁴. In certain embodiments, Y¹ is -C≡C-(Ci-6 alky lene)-0-(C 1-2 alkyl). In certain embodiments, Y¹ is -C≡C-CH₂-0-CH₃.

[00188] The description above describes multiple embodiments relating to compounds of Formula B-I. The patent application specifically contemplates all combinations of the embodiments. For example, the invention contemplates a compound of Formula I wherein X¹ is A¹ is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y² and (b) 4-8 membered heteroalkyl, and Y¹ is Ci-6 alkyl or halogen.

[00189] In certain embodiments, the compound is represented by Formula B-I-l :

(B-I-l) or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R² each represent independently for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro;

R³ represents independently for each occurrence hydrogen or C1-4 alkyl;

R⁴ represents independently for each occurrence hydrogen, C1-4 alkyl, or -C(0)R³;

X¹ is one of the following:

(a) a carbonyl-containing linker selected from and -C(0)N(H)(Ci-6 where ψ is a bond to A ; or

(b) an amine-containing linker selected from -(C1-4 and -(C1-4 alkylene)-N(H)-(Ci-4 alkylene)-\|/; A¹ is a cyclic group selected from:

following:

o 4-8 membered heteroalkyl;

o 2-6 membered heteroalkyl substituted by a 5-10 membered heteroaryl; o -C≡C-(Ci-₆ alkylene)-OR⁴ or -(C₂-₄ alkynylene)-(5-6 membered hetero heterocyclyl); or

o -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), -0-(C2-e alkynyl), or azido;

· C3-₇ cycloalkyl that is substituted by 1 or 2 occurrences ofY¹ and 0, 1, 2, or 3 occurrences of Y²; and

• 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 ofY²;

Y¹ represents, independently for each occurrence, one of the following:

• 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl); or · C₂-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C_2-4 alkynylene)-(5-6 membered heteroaryl), or C2-₆ alkenyl;

Y² represents, independently for each occurrence, Ci-₆ alkyl, C3-₆ cycloalkyl, halogen, Ci-₆ haloalkyl, C ₁-₆ hydroxy alkyl, hydroxyl, Ci-₆ alkoxyl, C₂-₄ alkynyl, cyano, azido, -N(R )₂, -(Ci-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R³, or Ci-6

haloalkyl-substituted C3-₆ cycloalkyl;

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.

[00190] Definitions of the variables in Formula B-I-1 above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii) , e.g. , such as where R is Ci_-4 alkyl or cyclopropyl, X¹ is -C(0)N(H)- ψ, and A¹ is phenyl substituted by 4-8 membered heteroalkyl.

[00191] Accordingly, in certain embodiments, R¹ represents independently for each occurrence C1-4 alkyl, Ci^ haloalkyl, C1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R¹ is methyl. In certain embodiments, the R¹ groups are located at the 5 and 7 positions of the pyrazolo[l,5-a]pyrimidinyl.

[00192] In certain embodiments, n is 2. In certain other embodiments, n is 1.

[00193] 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.

[00194] In certain embodiments, R³ and R⁴ each represent independently for each occurrence hydrogen, methyl, or ethyl. In certain embodiments, R³ is hydrogen. In certain embodiments, R⁴ is hydrogen.

[00195] In certain embodiments, X¹ is

[00196] In certain embodiments, any occurrence of Y² is independently Ci-₆ alkyl, C3-₆ cycloalkyl, halogen, Ci-₆ haloalkyl, or hydroxyl. In certain embodiments, any occurrence of Y² is independently C1-₃ alkyl.

[00197] In certain embodiments, A¹ is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y² and (b) one of the following:

o 4-8 membered heteroalkyl;

o 2-6 membered heteroalkyl substituted by a 5-10 membered heteroaryl;

o -C≡C-(Ci-₆ alkylene)-OR⁴ or -(C2-4 alkynylene)-(5-6 membered heterocyclyl); or o -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), -0-(C2-e alkynyl), or azido.

[00198] In certain embodiments, A¹ is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y² and (b) one of the following:

(v) 4-8 membered heteroalkyl; (vi) 2-6 membered heteroalkyl substituted by a 5-10 membered heteroaryl;

(vii) -C≡C-(Ci-6 alkylene)-OR⁴ or -(C2-4 alkynylene)-(5-6 membered heteroaryl); or

(viii) -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), -0-(C2-e alkynyl), or azido.

[00199] In certain embodiments, A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) a 4-8 membered heteroalkyl. In certain embodiments, A¹ is phenyl substituted by -0-(Ci-7 alkyl). In certain embodiments, A¹ is phenyl substituted by -0-(C4_7 alkyl). In certain embodiments, A¹ is phenyl substituted by -O-butyl, -O-pentyl, or -O-hexyl. In certain embodiments, A¹ is phenyl substituted is -OCH2CH2OCH2CH2.

[00200] In certain embodiments, A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) a 2-6 membered heteroalkyl optionally substituted by a 5-10 membered heteroaryl. In certain embodiments, A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) a 2-6 membered heteroalkyl substituted by a 5-6 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 Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, Ci-₆ hydroxyalkyl, hydroxyl, Ci-₆ alkoxyl, cyano, -N(R⁴)2, amide, and -CO2H). In certain embodiments, A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) a 2-4 membered heteroalkyl substituted by pyridinyl.

[00201] In certain embodiments, A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) -C≡C-(Ci-6 alkylene)-OR⁴. In certain embodiments, A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) -C≡C-CH₂-0-CH₃. In certain embodiments, A¹ is phenyl substituted by -C≡C-CH₂-0-CH₃.

[00202] In certain embodiments, A¹ is C3-7 cycloalkyl substituted once by Y¹ and 0-1 occurrences of Y².

[00203] In certain embodiments, A¹ is 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.

[00204] In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl, furanyl, or pyridinyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl.

[00205] In certain embodiments, Y¹ is -0-(Ci_7 alkyl). In certain embodiments, Y¹ is -O- butyl, -O-pentyl, or -O-hexyl. In certain embodiments, Y¹ is -(C_1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y¹ is -CH₂-0-(5-6 membered heteroaryl). In certain embodiments, Y¹ is -CH₂-0-(5-6 membered heteroaryl), wherein the 5-6 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C^ haloalkyl, C ₁-6 hydroxy alkyl, hydroxyl, Ci-₆ alkoxyl, cyano, -N(R⁴)₂, amide, and -CO₂H.

[00206] In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e 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 heterocycloalkyl. In certain embodiments, Y¹ is a 5- membered heteroaryl. In certain embodiments, Y¹ is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of Ci-6 alkyl, C3-7 cycloalkyl, halogen, Ci-₆ haloalkyl, Ci-₆ hydroxyalkyl, hydroxyl, Ci-₆ alkoxyl, cyano, -N(R⁴)₂, amide, and -CO₂H. In certain embodiments, Y¹ is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, hydroxyl, and C_1-6 alkoxyl.

[00207] 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, Ci-₆ hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO₂H. [00208] 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 consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, Ci-₆ hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H.

[00209] In certain embodiments, Y¹ is C_2-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )2, -(C2-4 alkynylene)-(5-6 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 -C≡C-(Ci_6 alkylene)-OR⁴. In certain embodiments, Y¹ is -C≡C-(Ci_6 alky lene)-0-(C 1-2 alkyl). In certain embodiments, Y¹ is -C≡C-CH₂-0-CH₃.

[00210] The description above describes multiple embodiments relating to compounds of Formula B-I-1. The patent application specifically contemplates all combinations of the embodiments. For example, the invention contemplates a compound of Formula B-I-1 wherein X¹ is -C(0)N(H)-v|/, A¹ is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y² and (b) 4-8 membered heteroalkyl, and Y¹ is C_1-6 alkyl or halogen.

[00211] In certain embodiments, the compound is a compound of Formula B-I-A:

(B-I-A)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is independently methyl, cyclopropyl, isopropyl, or -(C alkylene)-(2-6 membered heteroalkyl);

R² is hydrogen;

R³ and R⁴ each represent independently for each occurrence 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; Y¹ represents, independently for each occurrence, a 2-8 membered heteroalkyl;

Ci-₆ haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci-₆ alkoxyl, cyano, azido, -N(R )₂, -(C 1-6 alky lene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R³, or Ci-6 haloalkyl-substituted C3-6 cycloalkyl.

[00212] Definitions of the variables in Formula B-I-A above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).

[00213] Accordingly, in certain embodiments, any occurrence of Y² is independently C1-3 alkyl, halogen, or Ci^ haloalkyl.

[00214] In certain embodiments, A¹ is C3-1₀ cycloalkyl that is substituted 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.

[00215] In certain embodiments, R¹ is methyl. In certain embodiments, R¹ is further selected from halogen and halomethyl, such that R¹ may be methyl, halogen, or halomethyl.

[00216] In certain embodiments, R² is further selected from halogen, such that R² may be hydrogen or halogen.

[00217] The description above describes multiple embodiments relating to compounds of Formula B-I-A. The patent application specifically contemplates all combinations of the embodiments. For example, the invention contemplates a compound of Formula B-I-A wherein R¹ is methyl, and A¹ is phenyl substituted by (a) 0, 1 , 2, or 3 occurrences of Y² and (b) C4-8 alkoxyl. [00218] In certain embodiments, the compound is a compound of Formula B-I-Al :

(B-I-Al)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is independently methyl, cyclopropyl, or isopropyl;

R² is hydrogen;

R³ and R⁴ each represent independently for each occurrence hydrogen or C alkyl; A is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y² and (b) one of the following:

(i) C4-₈ alkoxyl;

(ii) 2-4 membered heteroalkyl substituted by a 5-10 membered heteroaryl; or

(iii) -C≡C-(Ci-6 alkylene)-OR⁴; and

Y² represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, azido, -N(R )₂, -(C_1-6 alkylene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R³, or Ci-6 haloalkyl-substituted C3-6 cycloalkyl.

[00219] Definitions of the variables in Formula B-I-Al above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where R¹ is methyl, and A¹ is phenyl substituted by C4-8 alkoxyl.

[00220] Accordingly, in certain embodiments, any occurrence of Y² is independently C_1-3 alkyl, halogen, or C_1-3 haloalkyl. [00221] In certain embodiments, A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) C4-8 alkoxyl. In certain embodiments, A¹ is phenyl substituted by -0-(C4_7 alkyl). In certain embodiments, A¹ is phenyl substituted by -0-(C4_7 alkyl) at 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 at the para-position of the phenyl group. In certain embodiments, A¹ is phenyl substituted is -OCH₂CH₂OCH₂CH₂.

[00222] In certain embodiments, A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) a 2-4 membered heteroalkyl substituted by a 5-6 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, Ci-₆ hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, and amide). In certain embodiments, A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) a 2-4 membered heteroalkyl substituted by pyridinyl.

[00223] In certain embodiments, A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) -C≡C-(Ci-6 alkylene)-OR⁴, where R⁴ is Ci-4 alkyl. In certain embodiments, A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) -C≡C-CH₂-0-CH₃. In certain embodiments, A¹ is phenyl substituted by -C≡C-CH₂-0-CH₃.

[00224] In certain embodiments, R¹ is methyl. In certain embodiments, R¹ is further selected from halogen and halomethyl, such that R¹ may be methyl, halogen, or halomethyl.

[00225] In certain embodiments, R² is further selected from halogen, such that R² may be hydrogen or halogen.

[00226] The description above describes multiple embodiments relating to compounds of Formula B-I-Al. The patent application specifically contemplates all combinations of the embodiments. For example, the invention contemplates a compound of Formula B-I-Al wherein R¹ is methyl, and A¹ is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y² and (b) C4-8 alkoxyl. [00227] In certain embodiments, the compound is a compound of Formula B-I-B:

(B-I-B) or a pharmaceutically acceptable salt thereof, wherein:

A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) C4-8 alkoxyl or -C≡C- (C1-6 alky lene)-0-(C 1-3 alkyl); and

Y² represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen, or Ci-6 haloalkyl.

[00228] Definitions of the variables in Formula B-I-B above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).

[00229] Another aspect of the invention provides a compound of Formula B-II:

(Β-Π)

or a pharmaceutically acceptable salt thereof, wherein:

R³ represents independently for each occurrence hydrogen or C1-4 alkyl;

X¹ is one of the following: (a) a carbonyl-containing linker selected from and -C(0)N(H)(Ci_6 where ψ is a bond to A¹; or

(b) an amine-containing linker selected from -(CM and -(C

alkylene)-N(H)-(Ci-4

A 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)-(5-6 membered heterocyclyl);

• a bi cyclic carbocyclyl that is partially unsaturated and substituted by (a) a 3-10 membered heterocyclyl, and (b) 0, 1, 2, or 3 occurrences of Y²;

• piperazinyl substituted by 0, 1, or 2 occurrences of Y²; or

• both Ci-6 alkoxyl and C2-4 alkynyl;

Y² represents, independently for each occurrence, C_1-6 alkyl, C₃-6 cycloalkyl, halogen, Ci-₆ haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, C_1-6 alkoxyl, cyano, azido, -N(R )₂, -(C 1-6 alky lene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R³, or Ci-6 haloalkyl-substituted C3-6 cycloalkyl; and

n is 1, 2, or 3.

[00230] Definitions of the variables in Formula B-II above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where R¹ is C M alkyl or cyclopropyl, X¹ is

and A¹ is phenyl substituted by phenyl.

[00231] Accordingly, in certain embodiments, R¹ represents independently for each occurrence hydrogen, CM alkyl, Ci^ haloalkyl, CM alkoxyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R¹ is methyl. In certain embodiments, the R¹ groups are located at the 5 and 7 positions of the pyrazolo[l,5-a]pyrimidinyl.

[00232] In certain embodiments, n is 2. In certain other embodiments, n is 1. [00233] 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.

[00234] In certain embodiments, R³ and R⁴ each represent independently for each occurrence hydrogen, methyl, or ethyl. In certain embodiments, R³ is hydrogen. In certain embodiments, R⁴ is hydrogen.

[00235] In certain embodiments, X¹ is

[00236] In certain embodiments, any occurrence of Y² is independently C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, or hydroxyl. In certain embodiments, any occurrence of Y² is independently C_1-3 alkyl.

[00237] The description above describes multiple embodiments relating to compounds of Formula B-II. The patent application specifically contemplates all combinations of the embodiments. For example, the invention contemplates a compound of Formula B-II wherein X¹ is and A¹ is phenyl substituted by (a) 0, 1 , 2, or 3 occurrences of Y² and (b) phenyl.

[00238] Another aspect of the invention provides a compound of Formula B-IIa:

(B-IIa) or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R² each represent independently for each occurrence hydrogen, C1-4 alkyl, C_1-4 haloalkyl, Ci-4 alkoxyl, -(Ci-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, chloro, or fluoro;

R³ represents independently for each occurrence hydrogen or C_1-4 alkyl;

R⁴ represents independently for each occurrence hydrogen, C_1-4 alkyl, or -C(0)R³; X¹ is one of the following:

(a) a carbonyl-containing linker selected from -0(Ο)Ν(Η)-ψ and -C(0)N(H)(Ci-6 where ψ is a bond to A¹; or (b) an amine-containing linker selected from -(CM and -(C alkylene)-N(H)-(Ci-4

A¹ is one of the following:

• C₃-10 cycloalkyl that is substituted by (a) 1, 2, or 3 halogen and (b) 0, 1, 2, or 3 occurrences of Y²;

• phenyl substituted by (a) halogen or C_1-6 alkoxyl and (b) 0, 1, 2, or 3 occurrences of Y²; or

following:

o phenyl substituted by 0, 1, 2, or 3 occurrences of Y²;

o 4-pyridinyl substituted by 0, 1, 2, or 3 occurrences of Y²;

o -C≡C-(Ci-₆ alkylene)-(5-6 membered heterocyclyl);

o a bicyclic carbocyclyl that is partially unsaturated and substituted by (a) a 3-10 membered heterocyclyl, and (b) 0, 1, 2, or 3 occurrences ofY²;

o piperazinyl substituted by 0, 1, or 2 occurrences of Y²; or o both Ci-₆ alkoxyl and C₂-4 alkynyl;

Y² represents, independently for each occurrence, C_1-6 alkyl, C₃-₆ cycloalkyl, halogen, Ci-₆ haloalkyl, C 1-₆ hydroxy alkyl, hydroxyl, C_1-6 alkoxyl, cyano, azido, -N(R )₂, -(C 1-₆ alky lene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R³, or C_1-6 haloalkyl-substituted C3-6 cycloalkyl; and

n is 1, 2, or 3;

provided that if X¹ is optionally substituted halophenyl or -phenyl-methoxy, then X¹ is -C(0)N(H)(C₂-6 branched alkylene)-v|/.

[00239] Definitions of the variables in Formula B-IIa above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where R¹ is CM alkyl or cyclopropyl, X¹ is

and A¹ is phenyl substituted by phenyl. [00240] Accordingly, in certain embodiments, R¹ represents independently for each occurrence C_1-4 alkyl, Ci^ haloalkyl, C_1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R¹ is methyl.

[00241] In certain embodiments, n is 2.

[00242] In certain embodiments, R¹ groups are located at the 5 and 7 positions of the pyrazolo[l,5-a]pyrimidinyl.

[00243] In certain embodiments, X¹ is

[00244] Another aspect of the invention provides a compound of Formula B-III:

(B-III) or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R² each represent independently for each occurrence hydrogen, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxyl, -(C_1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, chloro, or fluoro;

R³ represents independently for each occurrence hydrogen or C_1-4 alkyl;

X¹ is one of the following:

(a) a carbonyl-containing linker selected from -0(Ο)Ν(Η)-ψ and -C(0)N(H)(Ci-₆ where ψ is a bond to A¹; or

(b) an amine-containing linker selected from -(C_1-4 alkylene)-N(H)-v|/ and -(C_1-4 alkylene)-N(H)-(Ci-4

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:

o a 5-membered heteroaryl substituted by 0, 1, 2, or 3 occurrences of Y²; o -(Ci_-6 alkylene)-C0₂R³; or

o C 1-₆ hydroxy alkyl; • 5-6 membered heteroaryl substituted by 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:

• 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl); or

Ci-₆ haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci-₆ alkoxyl, cyano, azido, -N(R )₂, -(C 1-6 alky lene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R³, or Ci-6 haloalkyl-substituted C3-6 cycloalkyl; and

n is 1, 2, or 3. [00245] Definitions of the variables in Formula B-III above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii) , e.g. , such as where R¹ is C1-4 alkyl or cyclopropyl, X¹ is -C(0)N(H)- ψ, and A¹ is phenyl substituted by a 5 -membered heteroaryl.

[00246] Accordingly, in certain embodiments, R¹ represents independently for each occurrence C1-4 alkyl, Ci^ haloalkyl, C1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R¹ is methyl. In certain embodiments, the R¹ groups are located at the 5 and 7 positions of the pyrazolo[l ,5-a]pyrimidinyl.

[00247] In certain embodiments, n is 2. In certain other embodiments, n is 1.

[00248] 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. [00249] In certain embodiments, R³ and R⁴ each represent independently for each occurrence hydrogen, methyl, or ethyl. In certain embodiments, R³ is hydrogen. In certain embodiments, R⁴ is hydrogen.

[00250] In certain embodiments, X¹ is

[00251] In certain embodiments, any occurrence of Y² is independently C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, or hydroxyl. In certain embodiments, any occurrence of Y² is independently C_1-3 alkyl.

[00252] In certain embodiments, A¹ is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y² and (b) a 5-membered heteroaryl substituted by 0, 1, 2, or 3 occurrences of Y². In certain embodiments, A¹ is phenyl substituted by (a) C_1-6 alkyl or halogen and (b) a 5-membered heteroaryl selected from the group consisting of furanyl, thiophenyl, or oxazolyl.

[00253] In certain embodiments, A¹ is phenyl substituted by Ci-₆ hydroxyalkyl.

[00254] In certain embodiments, A¹ is 5-6 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 a 5-membered heteroaryl selected from the group consisting of furanyl, thiophenyl, or oxazolyl.

[00255] In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl, furanyl, or pyridinyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl.

[00256] In certain embodiments, Y¹ is -0-(Ci_7 alkyl). In certain embodiments, Y¹ is -O- butyl, -O-pentyl, or -O-hexyl. In certain embodiments, Y¹ is -(C_1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y¹ is -CH₂-0-(5-6 membered heteroaryl). In certain embodiments, Y¹ is -CH₂-0-(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, or pyridinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, C ₁-6 hydroxy alkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R⁴)₂, and amide.

[00257] In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C_2-6 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 heterocycloalkyl. In certain embodiments, Y¹ is 5-membered heteroaryl. In certain embodiments, Y¹ is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R⁴)₂, and amide. In certain embodiments, Y¹ is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, hydroxyl, and C_1-6 alkoxyl.

[00258] 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, Ci-₆ hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, and amide.

[00259] 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R⁴)₂, and amide.

[00260] In certain embodiments, Y¹ is C_2-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C_2-4 alkynylene)-(5-6 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 -C≡C-(Ci_6 alkylene)-OR⁴. In certain embodiments, Y¹ is -C≡C-(Ci_6 alkylene)-0-(Ci_-2 alkyl). In certain embodiments, Y¹ is -C≡C-CH₂-0-CH₃. [00261] The description above describes multiple embodiments relating to compounds of Formula B-III. The patent application specifically contemplates all combinations of the embodiments. For example, the invention contemplates a compound of Formula B-III wherein R¹ is methyl, X¹ is A¹ is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y² and (b) a 5-membered heteroaryl.

[00262] In certain embodiments, the compound is a compound of Formula B-III-A:

(B-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) C_1-6 alkyl or halogen and (b) a 5-membered heteroaryl selected from the group consisting of furanyl, thiophenyl, or oxazolyl C4-8 alkoxyl, each of which is optionally substituted by 1 or substituents independently selected from the group consisting of alkyl, halogen, and haloalkyl.

[00263] Definitions of the variables in Formula B-III-A above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).

[00264] In certain other embodiments, the compound is one of the compounds listed in Table 3 or 4 below or a pharmaceutically acceptable salt thereof. TABLE 3.

1-74 methyl H F -C(0)N(H)CH₂-v|/

Where in Table 1 , ψ is a bond to A¹.

TABLE 4.

[00265] Methods for preparing compounds described herein are illustrated in the following synthetic schemes. These schemes are given for the purpose of illustrating the invention, and should not be regarded in any manner as limiting the scope or the spirit of the invention.

[00266] The synthetic route illustrated in Scheme 1-A depicts an exemplary procedure for preparing substituted pyrazolo[l,5-a]pyrimidine compounds. In the first step, ethyl 5-amino- lH-pyrazole-4-carboxylate (R -H) A is condensed with pentane-2,4-dione (R^u=R^ly=Me;

R^U1=H) in acetic acid at 80°C to afford 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3-carboxylic ester B. Hydrolysis of ethyl ester B under basic conditions provides 5,7-dimethylpyrazolo[l,5- a]pyrimidine-3-carboxylic acid C.

SCHEME 1-A

[00267] The synthetic route illustrated in Scheme 2- A depicts an exemplary procedure for preparing substituted pyrazolo[l,5-a]pyrimidine compounds. In the first step, coupling of carboxylic acid C with a variety of substituted aromatic or heteraromatic amines may be accomplished using standard peptide coupling procedures, such as HATU and/or HOBT in DMF in the presence of DIPEA. Alternatively, carboxylic ester B may be treated with Α1Μβ₃ to afford the intermediate Weinreb amide, which after reaction with an amine provides substituted amide D. In some cases, the reaction is performed in a stepwise manner where a bromo or iodo-substituted aromatic or heteraromatic amine is coupled with the Weinreb amide to form the iodo or bromo-substituted amide E. The bromo or iodo moiety may 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.

[00268] The reaction procedures in Scheme 2- A are contemplated to be amenable to preparing a wide variety of substituted pyrazolo[l,5-a]pyrimidine carboxamide compounds having different substituents at the A¹ and Y¹ positions. Furthermore, if a functional group that is part of the A¹ and/or Y¹ would not be amenable to a reaction condition described in Scheme 2-A, it is contemplated that the functional group can first be protected using standard protecting group chemistry and strategies, 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, 2^nd ed.; Wiley: New York, 1991, for further description of protecting chemistry and strategies. In certain other embodiments, a functional group in substituent A¹ and Y¹ can 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., 1991-1992).

PART C: SUBSTITUTED lMiDAzo[l,5-a]PYRiMiDiNES AND RELATED ORGANIC COMPOUNDS

[00269] In certain embodiments, the heterobicyclic compound for activation of Gcase is a substituted imidazo[l,5-a]pyrimidine or related organic compound, such as a substituted imidazo[l,5-a]pyrimidine or related organic compound embraced by Formula C-I:

(C-I)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ represents independently for each occurrence hydrogen, Ci-₄ alkyl, Ci^ haloalkyl, Ci.

4 alkoxyl, -(C alky lene)-(C 1-4 alkoxyl), cyclopropyl, cyano, chloro, or fluoro;

R² is hydrogen, C_1-4 alkyl, Ci^ haloalkyl, C_1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro;

R³ represents independently for each occurrence hydrogen or C_1-4 alkyl;

X¹ is one of the following:

(a) a carbonyl-containing linker selected from -C(0)N(H)-v|/, -C(0)N(H)(Ci_-6

and -C(0)-(3-6 membered heterocycloalkylene containing at least one ring -N(H)- group)-v|/; where ψ is a bond to A¹; or

A¹ is a cyclic group selected from:

• C₃-10 cycloalkyl, phenyl, or 5-6 membered heteroaryl, each of which is

substituted by 1 or 2 occurrences of Y¹ and 0, 1, 2, or 3 occurrences of Y²; and

• a bicyclic carbocyclyl that is partially unsaturated or a mono-cyclic or bicyclic heterocyclyl, each of which is substituted 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:

• 3-10 membered heterocyclyl, 6-10 membered aryl, C₃-7 cycloalkyl, -O-C₃-7 cycloalkyl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -O- (C₂-6 alkynyl); • C₂-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C_2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl; or

• halogen or cyano;

Y² represents, independently for each occurrence, deuterium, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci-₆ alkoxyl, cyano, azido, -N(R )₂, -(Ci-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C0₂R³, or Ci-₆ haloalkyl-substituted C3-6 cycloalkyl; and

n is 1, 2, or 3.

[00270] Definitions of the variables in Formula C-I above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where X¹ is A¹ is phenyl or 5-6 membered heteroaryl, and Y¹ is 2-8 membered heteroalkyl.

[00271] Accordingly, in certain embodiments, R¹ represents independently for each occurrence C1-4 alkyl, Ci^ haloalkyl, C1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R¹ represents independently for each occurrence C1-4 alkyl, Ci^ haloalkyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R¹ is methyl. In certain embodiments, the R¹ groups are located at the 2 and 4 positions of the imidazo[l,5- a]pyrimidinyl.

[00272] In certain embodiments, n is 2. In certain other embodiments, n is 1.

[00273] In certain embodiments, R¹ represents independently for each occurrence hydrogen, Ci-4 alkyl, Ci^ haloalkyl, C1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro; and n is 1.

[00274] 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.

[00275] In certain embodiments, R³ and R⁴ each represent independently for each occurrence hydrogen, methyl, or ethyl. In certain embodiments, R³ is hydrogen. In certain embodiments, R⁴ is hydrogen. [00276] In certain embodiments, X¹ is In certain embodiments, X¹ is

or -C(0)-(3-6 membered heterocycloalkylene containing at least

[00277] In certain embodiments, A¹ is a cyclic group selected from:

phenyl, 5-6 membered heteroaryl, or C3-7 cycloalkyl, each of which is substituted by 1 or 2 occurrences of Y¹ and 0, 1, 2, or 3 occurrences of Y²; and

a bicyclic carbocyclyl that is partially unsaturated or a mono-cyclic or bicyclic heterocyclyl, each of which is substituted by 0, 1, or 2 occurrences of Y¹ and 0, 1, 2, or 3 occurrences of Y².

[00278] In certain embodiments, A¹ is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y¹ and 0, 1, or 2 occurrences ofY². In certain embodiments, A¹ is phenyl substituted once by Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is a 5-6 membered heteroaryl substituted once by Y¹ and 0-1 occurrences of Y². In certain

[00279] In certain embodiments, A is C5-10 cycloalkyl substituted once by Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is C3-7 cycloalkyl substituted once by Y¹ and 0- 1 occurrences of Y². In certain embodiments, A¹ is a cyclopentyl or cyclohexyl, each of which is substituted once by Y¹ and 0-1 occurrences of Y .

[00280] In certain embodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y¹ and 0, 1, or I occurrences of Y². In certain embodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y² selected from the group consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, hydroxyl, and C_1-6 alkoxyl.

[00281] In certain embodiments, A¹ is or ; wherein m is 0, 1, or 2; and Y² represents independently for each occurrence C_1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, C_1-6 alkoxyl, or cyano. In certain embodiments, A¹ is ^ ^^""--/ (^Y )m or (^Y )m ; wherein m is 0, 1, or 2; and Y² represents independently for each occurrence C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, hydroxyl, or C_1-6 alkoxyl.

[00282] In certain embodiments, any occurrence of Y² is independently C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, or hydroxyl. In certain embodiments, any occurrence of Y² is independently C_1-3 alkyl.

[00283] In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl, furanyl, or pyridinyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl. In certain embodiments, R¹ is -OCH2CH2OCH2CH2.

[00284] In certain embodiments, Y¹ is -0-(C_1-7 alkyl). In certain embodiments, Y¹ is -O- butyl, -O-pentyl, or -O-hexyl. In certain embodiments, Y¹ is -(C_1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y¹ is -CH₂-0-(5-6 membered heteroaryl). In certain embodiments, Y¹ is -CH₂-0-(5-6 membered heteroaryl), wherein the 5-6 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C^ haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and

[00285] In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(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 heterocycloalkyl. In certain embodiments, Y¹ is 5-membered heteroaryl. In certain embodiments, Y¹ is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C3-7 cycloalkyl, halogen, Ci-₆ haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H. In certain embodiments, Y¹ is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, hydroxyl, and C_1-6 alkoxyl.

[00286] 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, Ci-6 hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)2, amide, and -CO2H.

[00287] 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 consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, Ci-₆ hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H.

[00288] In certain embodiments, Y¹ is C₂-₆ alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl. In certain embodiments, Y¹ is C2-6 alkynyl. In certain embodiments, Y¹ is -C≡CH. In certain

[00289] The description above describes multiple embodiments relating to compounds of Formula C-I. The patent application specifically contemplates all combinations of the embodiments. For example, the invention contemplates a compound of Formula C-I wherein X¹ is A¹ is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y¹ and 0, 1, or 2 occurrences of Y², and Y¹ is 2-8 membered heteroalkyl. In certain embodiments, the compound is a compound of Formula

(C-I-l)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ represents independently for each occurrence hydrogen, Ci-4 alkyl, Ci^ haloalkyl, Ci_ 4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro;

R² is hydrogen, C1-4 alkyl, Ci^ haloalkyl, C1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro;

R³ represents independently for each occurrence hydrogen or C1-4 alkyl;

X¹ is one of the following:

(a) a carbonyl-containing linker selected from -C(0)N(H)(Ci_-6

and -C(0)-(3-6 membered heterocycloalkylene containing at least one ring -N(H)- where ψ is a bond to A¹; or

A¹ is a cyclic group selected from:

• phenyl, 5-6 membered heteroaryl, or C3-7 cycloalkyl, each of which is

Y¹ represents, independently for each occurrence, one of the following:

• 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl); or • C₂-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C_2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl;

Y² represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci-6 alkoxyl, cyano, azido, -N(R )2, -(C 1-6 alky lene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R³, or Ci-6 haloalkyl-substituted C3-6 cycloalkyl; and

n is 1, 2, or 3.

[00291] Definitions of the variables in Formula C-I-l above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where X¹ is A¹ is phenyl or 5-6 membered heteroaryl, and Y¹ is 2-8 membered heteroalkyl.

[00292] Accordingly, in certain embodiments, R¹ represents independently for each occurrence C1-4 alkyl, Ci-4 haloalkyl, C1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R¹ represents independently for each occurrence C1-4 alkyl, Ci^ haloalkyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R¹ is methyl. In certain embodiments, the R¹ groups are located at the 2 and 4 positions of the imidazo[l,5- a]pyrimidinyl.

[00293] In certain embodiments, n is 2. In certain other embodiments, n is 1.

[00294] In certain embodiments, R¹ represents independently for each occurrence hydrogen, Ci-4 alkyl, Ci-4 haloalkyl, C1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro; and n is 1.

[00295] 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.

[00296] In certain embodiments, R³ and R⁴ each represent independently for each occurrence hydrogen, methyl, or ethyl. In certain embodiments, R³ is hydrogen. In certain embodiments, R⁴ is hydrogen. [00297] In certain embodiments, X¹ is In certain embodiments, X¹ is

or -C(0)-(3-6 membered heterocycloalkylene containing at least

[00298] In certain embodiments, A¹ is a cyclic group selected from:

[00299] In certain embodiments, A¹ is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y¹ and 0, 1, or 2 occurrences of Y². In certain embodiments, A¹ is phenyl substituted once by Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is a 5-6 membered heteroaryl substituted once by Y¹ and 0-1 occurrences of Y². In certain

[00300] In certain embodiments, A is C5-10 cycloalkyl substituted once by Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is C3-7 cycloalkyl substituted once by Y¹ and 0- 1 occurrences of Y². In certain embodiments, A¹ is a cyclopentyl or cyclohexyl, each of which is substituted once by Y¹ and 0-1 occurrences of Y .

[00301] In certain embodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y¹ and 0, 1, or I occurrences of Y². In certain embodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y² selected from the group consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, hydroxyl, and C_1-6 alkoxyl.

[00302] In certain embodiments, A¹ is or ; wherein m is 0, 1, or 2; and Y² represents independently for each occurrence C_1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, C_1-6 alkoxyl, or cyano. In certain embodiments, A¹ is ^ ^^""--/ (^Y )m or (^Y )m ; wherein m is 0, 1, or 2; and Y² represents independently for each occurrence C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, hydroxyl, or C_1-6 alkoxyl.

[00303] In certain embodiments, any occurrence of Y² is independently C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, or hydroxyl. In certain embodiments, any occurrence of Y² is independently C_1-3 alkyl.

[00304] In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl, furanyl, or pyridinyl. In certain embodiments, Y¹ is a 2-8 membered heteroalkyl. In certain embodiments, R¹ is -OCH2CH2OCH2CH2.

[00305] In certain embodiments, Y¹ is -0-(C_1-7 alkyl). In certain embodiments, Y¹ is -O- butyl, -O-pentyl, or -O-hexyl. In certain embodiments, Y¹ is -(C_1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y¹ is -CH₂-0-(5-6 membered heteroaryl). In certain embodiments, Y¹ is -CH₂-0-(5-6 membered heteroaryl), wherein the 5-6 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C^ haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and

[00306] In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(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 heterocycloalkyl. In certain embodiments, Y¹ is a 5-membered heteroaryl. In certain embodiments, Y¹ is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C3-7 cycloalkyl, halogen, Ci-₆ haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H. In certain embodiments, Y¹ is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, hydroxyl, and C_1-6 alkoxyl.

[00307] 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, Ci-6 hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)2, amide, and -CO2H.

[00308] 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 consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, Ci-₆ hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H.

[00309] In certain embodiments, Y¹ is C₂-₆ alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C2-4 alkynylene)-(5-6 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 -C≡C-(Ci_6 alkylene)-OR⁴. In certain embodiments, Y¹ is -C≡C-(Ci_6 alky lene)-0-(C 1-2 alkyl). In certain embodiments, Y¹ is -C≡C-CH₂-0-CH₃.

[00310] The description above describes multiple embodiments relating to compounds of Formula C-I-l . The patent application specifically contemplates all combinations of the embodiments. For example, the invention contemplates a compound of Formula I wherein X¹ is A¹ is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y¹ and 0, 1, or 2 occurrences of Y², and Y¹ is 2-8 membered heteroalkyl. In certain embodiments, the compound is a compound of Formula C-I-la:

(C-I-la)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ represents independently for each occurrence C_M alkyl;

R² and R³ each represent independently for each occurrence hydrogen or C alkyl; R⁴ represents independently for each occurrence hydrogen, C alkyl, or -C(0)R³; X¹ is one of the following:

(a) a carbonyl-containing linker selected from -C(0)N(H)(Ci_-6 and -C(0)-(3-6 membered heterocycloalkylene containing at least one ring -N(H)- where ψ is a bond to A¹; or

(b) an amine-containing linker selected from -(C and -(C_M alkylene)-N(H)-(Ci-4

A¹ is a cyclic group selected from:

• phenyl, 5-6 membered heteroaryl, or C3-7 cycloalkyl, each of which is

Y¹ represents, independently for each occurrence, one of the following:

• 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered

heterocyclyl), -0(6-10 membered aryl), or -0-(C_2-6 alkynyl); or

• C₂-6 alkynyl, -C≡C-(d_-6 alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C_2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl; Y² represents, independently for each occurrence, C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci-₆ alkoxyl, cyano, azido, -N(R )₂, -(C 1-6 alky lene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R³, or Ci-6 haloalkyl-substituted C3-6 cycloalkyl; and

n is 1, 2, or 3.

[00312] Definitions of the variables in Formula C-I- la above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g., such as where X¹ is A¹ is phenyl or 5-6 membered heteroaryl, and Y¹ is 2-8 membered heteroalkyl.

[00313] In certain embodiments, the compound is a compound of Formula C-I-A:

(C-I-A)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is independently methyl, cyclopropyl, isopropyl, or -(C alkylene)-(Ci-4 alkoxyl); R² is hydrogen;

R³ and R⁴ each represent independently for each occurrence hydrogen or C1-4 alkyl; A¹ is a cyclic group selected from:

• a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y¹ and 0, 1, or 2 occurrences ofY²;

Y¹ represents, independently for each occurrence, one of the following: • 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl;

• 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl); or · C₂-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2-₆ alkenyl;

Y² represents, independently for each occurrence, C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci-₆ alkoxyl, cyano, azido, -N(R )₂, -(C_1-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R³, or C_1-6

haloalkyl-substituted C3-6 cycloalkyl.

[00314] Definitions of the variables in Formula C-I-A above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where A¹ is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y¹, where Y¹ is a 2-8 membered heteroalkyl.

[00315] Accordingly, in certain embodiments, A¹ is phenyl substituted once by Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is a 5-6 membered heteroaryl substituted once by Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is pyridinyl substituted by Y¹ and 0-1 occurrences of Y².

[00316] In certain embodiments, any occurrence of Y² is independently C_1-3 alkyl, halogen, or Ci-3 haloalkyl.

[00317] In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is -0-(Ci_ 7 alkyl). In certain embodiments, Y¹ is -O-butyl, -O-pentyl, or -O-hexyl. In certain

[00318] In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-6 alkynyl). In certain embodiments, Y¹ is a 3-10 membered heterocyclyl. 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 heterocycloalkyl.

[00319] In certain embodiments, Y¹ is a 5-membered heteroaryl. In certain embodiments, Y¹ is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, Ci-₆ alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H. 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H.

[00320] 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H.

[00321] In certain embodiments, Y¹ is C_2-6 alkynyl, -C≡C-(C_W alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl. In certain embodiments, Y¹ is C2-6 alkynyl. In certain embodiments, Y¹ is -C≡CH. In certain

[00322] In certain embodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y¹ and 0, 1, or 2 occurrences of Y². In certain embodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0, 1, or 2 occurrences of Y². In certain embodiments, A¹ is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, A¹ is \^^{^}--^/ (^γ )m or (^Y )m ; wherein m is 0, 1, or 2; and Y² represents independently for each occurrence C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, hydroxyl, or C_1-6

alkoxyl. In certain embodiments, A¹ is or ; wherein m is 0, 1, or 2; and Y² represents independently for each occurrence Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, hydroxyl, C_1-6 alkoxyl, or cyano.

[00323] The description above describes multiple embodiments relating to compounds of Formula I-A. The patent application specifically contemplates all combinations of the embodiments. For example, the invention contemplates a compound of Formula I-A wherein A is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y¹ and 0, 1, or 2 occurrences of Y², and Y¹ is 2-8 membered heteroalkyl.

[00324] In certain embodiments, R¹ is methyl. In certain embodiments, R¹ is further selected from halogen and halomethyl, such that R¹ may be methyl, halogen, or halomethyl.

[00325] In certain embodiments, R² is further selected from halogen, such that R² may be hydrogen or halogen.

[00326] In certain embodiments, the compound is a compound of Formula C-I-Al :

(C-I-Al) or a pharmaceutically acceptable salt thereof, wherein:

R is independently methyl, cyclopropyl, or isopropyl;

R² is hydrogen;

• phenyl, 5-6 membered heteroaryl, or C3-7 cycloalkyl, each of which is substituted by 1 occurrence ofY¹ and 0, 1, or 2 occurrences of Y²; and

Y¹ represents, independently for each occurrence, one of the following:

· 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C_2-6 alkynyl); or

Y² represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, hydroxyl, Ci-6 alkoxyl, cyano, azido, -N(R )2, -(Ci-6 alkylene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R³, or Ci-6 haloalkyl-substituted C3-6 cycloalkyl.

[00327] Definitions of the variables in Formula C-I-Al above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where A¹ is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y¹, where Y¹ is a 2-8 membered heteroalkyl.

[00328] Accordingly, in certain embodiments, A¹ is phenyl substituted once by Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is a 5-6 membered heteroaryl substituted once by Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is pyridinyl substituted by Y¹ and 0-1 occurrences of Y².

[00329] In certain embodiments, any occurrence of Y² is independently C1-3 alkyl, halogen, or C 1-3 haloalkyl. [00330] In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is -0-(Ci_ 7 alkyl). In certain embodiments, Y¹ is -O-butyl, -O-pentyl, or -O-hexyl. In certain

[00331] In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl). In certain embodiments, Y¹ is a 3-10 membered heterocyclyl. 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 heterocycloalkyl.

[00332] In certain embodiments, Y¹ is a 5-membered heteroaryl. In certain embodiments, Y¹ is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, Ci-₆ alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H. 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H.

[00333] 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H.

[00334] In certain embodiments, Y¹ is C_2-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C2-4 alkynylene)-(5-6 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 -C≡C-(Ci_6 alkylene)-OR⁴. In certain embodiments, Y¹ is -C≡C-(Ci_6 alky lene)-0-(C 1-2 alkyl). In certain embodiments, Y¹ is -C≡C-CH₂-0-CH₃. [00335] In certain embodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y¹ and 0, 1, or I occurrences of Y². In certain embodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0, 1, or 2 occurrences of Y². In certain embodiments, A¹ is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, A¹ is or (^γ' )m · wherein m is 0, 1 , or 2; and Y² represents independently for each occurrence C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, hydroxyl, or C_1-6

alkoxyl. In certain embodiments, A¹ is ^i^^ (^Y )m or (^Y )m ; wherein m is 0, 1, or 2; and Y² represents independently for each occurrence C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, hydroxyl, C_1-6 alkoxyl, or cyano.

[00336] The description above describes multiple embodiments relating to compounds of Formula C-I-A. The patent application specifically contemplates all combinations of the embodiments. For example, the invention contemplates a compound of Formula C-I-A wherein A¹ is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y¹ and 0, 1, or 2 occurrences of Y², and Y¹ is 2-8 membered heteroalkyl.

[00337] In certain embodiments, R¹ is methyl. In certain embodiments, R¹ is further selected from halogen and halomethyl, such that R¹ may be methyl, halogen, or halomethyl.

[00338] In certain embodiments, R² is further selected from halogen, such that R² may be hydrogen or halogen. [00339] In certain embodiments, the compound is a compound of Formula C-I-B:

(C-I-B)

or a pharmaceutically acceptable salt thereof, wherein:

Y¹ represents, independently for each occurrence, one of the following:

• -C≡C-H, -C≡C-(Ci-4 alkyl), or -C≡C-(Ci_-6 alkylene)-OR⁴;

Y² represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, or Ci-6 alkoxyl; and

R⁴ represents independently for each occurrence hydrogen or C1-4 alkyl.

[00340] Definitions of the variables in Formula C-I-B above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g. , such as where A¹ is phenyl or pyridinyl, each of which is substituted once by Y¹, where Y¹ is 2-8 membered heteroalkyl.

[00341] Accordingly, in certain embodiments, A¹ is phenyl substituted once by Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is pyridinyl substituted by Y¹ and 0-1 occurrences of Y².

[00342] In certain embodiments, any occurrence of Y² is independently C1-3 alkyl, halogen, or Ci-3 haloalkyl. [00343] In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionally substituted by a 6 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y¹ is -0-(Ci_7 alkyl). In certain embodiments, Y¹ is -O-butyl, -O-pentyl, or -O-hexyl. In certain

[00344] In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6 membered aryl, or -0-(3-6 membered heterocyclyl). In certain embodiments, Y¹ is a 3-10 membered

[00345] In certain embodiments, Y¹ is a 5-membered heteroaryl. In certain embodiments, Y¹ is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, Ci-₆ alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H. 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, and C_1-6 alkoxyl.

[00346] 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 C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, -N(R⁴)₂, amide, and -CO2H.

[00347] The description above describes multiple embodiments relating to compounds of Formula C-I-B. The patent application specifically contemplates all combinations of the embodiments. For example, the invention contemplates a compound of Formula I-B wherein A is phenyl or pyridinyl, each of which is substituted once by Y¹ and 0, 1, or 2 occurrences of Y², and Y¹ is 2-8 membered heteroalkyl. [00348] In certain embodiments, the compound is a compound of Formula C-I-C:

(C-I-C)

or a pharmaceutically acceptable salt thereof, wherein:

A¹ is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y¹ and 0, 1, or 2 occurrences of Y :

Y¹ represents, independently for each occurrence, one of the following:

• -C≡C-H, -C≡C-(Ci-4 alkyl), or -C≡C-(Ci_-6 alkylene)-OR⁴; and

Y² represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, C ₁-6 hydroxy alkyl, hydroxyl, or Ci-6 alkoxyl; and

R⁴ represents independently for each occurrence hydrogen or C₁-4 alkyl.

[00349] Definitions of the variables in Formula C-I-C above encompass 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 set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).

[00350] In certain embodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrences of Y².

[00351] In certain embodiments, any occurrence of Y² is independently C₁-3 alkyl, halogen, or Ci-₃ haloalkyl. [00352] In certain other embodiments, the compound is one of the compounds listed in Table 5 or 6 below or a pharmaceutically acceptable salt thereof.

TABLE 5.

Compound

^"""""""""11^""""""""""" K K m

I-l methyl methyl H

1-2 methyl methyl H

1-3 methyl methyl H

1-4 methyl methyl H

1-5 methyl methyl H

1-6 methyl methyl H

1-7 methyl methyl H -

methyl methyl H -C(0)N(H)(CH₂)₂- O'

1-9 methyl methyl H -C(0)N(H)(CH₂)₂-

1-10 methyl methyl H -C(0)N(H)(CH₂)₂-

0-

I-l 1 methyl methyl H -C(0)N(H)(CH₂)₂- V

1-74 methyl H -C(0)N(H)CH₂-\|/

Where in Table 1, ψ is a bond

TABLE 6.

No. ( ompoiind Sli in iii-e No. ( ompoiind StiiicUiiv

II- 1 II-6

H 0 H

II-2 II-7

0 H

II-3 II-8

H

II-4 II-9

O H

[00353] Methods for preparing compounds described herein are illustrated in the following synthetic schemes. These schemes are given for the purpose of illustrating the invention, and should not be regarded in any manner as limiting the scope or the spirit of the invention. Starting materials shown in the schemes can be obtained from commercial sources or can be prepared based on procedures described in the literature.

[00354] The synthetic route illustrated in Scheme 1-B depicts an exemplary procedure for preparing substituted imidazo[l,5-a]pyrimidine compounds. In the first step, 5-amino-lH- imidazole-4-carboxamide (R -H) A is condensed with pentane-2,4-dione (R^u=R^ly=Me; R^m=H) in acetic acid at 80°C to afford 2,4-dimethylimidazo[l,5-a]pyrimidine-8-carboxarnide B. Treatment of carboxamide B with phosphoryl chloride affords the intermediate nitrile which is hydrolyzed under acidic conditions and isolated as ethyl ester C. Hydrolysis of ethyl ester C under basic conditions provides 2,4-dimethylimidazo[l,5-a]pyrimidine-8-carboxylic acid D.

SCHEME 1-B

hydrolysis

[00355] The synthetic route illustrated in Scheme 2-B depicts an exemplary procedure for preparing substituted imidazo[l,5-a]pyrimidine compounds. In the first step, coupling of carboxylic acid D with a variety of substituted aromatic or heteraromatic amines may be accomplished using standard peptide coupling procedures, such as HATU and/or HOBT in DMF in the presence of DIPEA. Alternatively, carboxylic ester C may be treated with Α1Μβ₃ to afford the intermediate Weinreb amide, which after reaction with an amine provides substituted amide E. In some cases, the reaction is performed in a stepwise manner where a bromo or iodo-substituted aromatic or heteraromatic amine is coupled with the Weinreb amide to form the iodo or bromo-substituted amide F. The bromo or iodo moiety may 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 E.

SCHEME 2-B

[00356] The reaction procedures in Scheme 2-B are contemplated to be amenable to preparing a wide variety of substituted imidazo[l,5-a]pyrimidine carboxamide compounds having different substituents at the A¹ and Y¹ positions. Furthermore, if a functional group that is part of the A¹ and/or Y¹ would not be amenable to a reaction condition described in Scheme 2-B, it is contemplated that the functional group can first be protected using standard protecting group chemistry and strategies, 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, 2^nd ed.; Wiley: New York, 1991, for further description of protecting chemistry and strategies. In certain other embodiments, a functional group in substituent A¹ and Y¹ can 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., 1991-1992).

IV. PHARMACEUTICAL COMPOSITIONS

[00357] The invention provides pharmaceutical compositions Gcase activator compound described herein (e.g., a compound of any one Formulae A-l, B-l, B-IIa, B-III, or C-l). In certain embodiments, the pharmaceutical compositions preferably comprise a therapeutically - effective amount of one or more of Gcase activator compounds described herein (e.g., a compound of any one Formulae A-l, B-l, B-IIa, B-III, or C-l) described above, formulated together with one or more pharmaceutically acceptable carriers. 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, drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., those targeted for buccal, sublingual, and/or systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration by, for example, subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a 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.

[00358] The phrase "therapeutically-effective amount" as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.

[00359] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, 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. [00360] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[00361] 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 hydroxy toluene (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.

[00362] 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 which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.

[00363] The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 0.1 per cent to about ninety -nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[00364] In certain embodiments, a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present invention.

[00365] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the 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.

[00366] Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes 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.

[00367] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches 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, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-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 non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (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-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[00368] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[00369] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating 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 a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[00370] 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, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[00371] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[00372] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, poly oxy ethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydr oxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[00373] Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers 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, therefore, will melt in the rectum or vaginal cavity and release the active compound.

[00374] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[00375] Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches 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.

[00376] The 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.

[00377] Powders and sprays can 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 can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[00378] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[00379] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.

[00380] 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 nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[00381] Examples of suitable aqueous and nonaqueous carriers which may 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. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[00382] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may 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 into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

[00383] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be

accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[00384] Injectable depot forms are made by forming microencapsule 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 which are compatible with body tissue.

[00385] When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[00386] The preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.

[00387] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal,

subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.

[00388] The phrases "systemic administration," "administered systemically," "peripheral administration" and "administered peripherally" 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, thus, is subject to metabolism and other like processes, for example, subcutaneous administration. [00389] These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.

[00390] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.

[00391] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[00392] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide 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 the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[00393] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[00394] In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Preferably, the compounds are administered 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.

[00395] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.

V. KITS FOR USE IN MEDICAL APPLICATIONS

[00396] Another aspect of the invention provides a kit for treating a disorder. The kit comprises: i) instructions for treating a medical disorder described herein, such as Parkinson's disease, Lewy body disease, dementia, or multiple system atrophy; and ii) a Gcase activator compound described herein (e.g., a compound of any one Formulae A-1, B-1, B-IIa, B-III, or C-l). The kit may comprise one or more unit dosage forms containing an amount of a Gcase activator compound described herein (e.g., a compound of any one Formulae A-1, B-1, B-IIa, B-III, or C-l), that is effective for treating said medical disorder. In certain embodiments, the kit may further comprise a second therapeutic agent described herein.

[00397] The description above describes multiple aspects and embodiments of the invention, including Gcase activator compounds (e.g., a compound of any one Formulae A-1, B-1, B-IIa, B-III, or C-l), compositions comprising a Gcase activator compound, methods of using the Gcase activator compounds, and kits. The patent application specifically contemplates all combinations and permutations of the aspects and embodiments.

EXAMPLES

[00398] The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention. EXAMPLE 1 - PREPARATION OF SUBSTITUTED PYRROLO[1,2-A]PYRIMIDINE AND RELATED ORGANIC COMPOUNDS

PART 1 - PREPARATION OF ETHYL 2- AMINO- lH-p YRROLE-3-C ARBOX YLATE (1)

[00399] A solution of ethyl 3-amino-3-iminopropanoate (500 g, 3.0 mmol) and tri ethyl amine (0.5 mL, 3.60 mmol) in ethyl acetate (20 mL) was charged with anhydrous 2- chloroacetaldehyde (0.32 mL, 1.65 mmol) at room temperature. The resulting solution was heated to 80°C for 2h. The reaction mixture was cooled to room temperature and filtered. The solid residue obtained was suspended in ethyl acetate (2 X 20 mL) and filtered. The combined filtrate was concentrated in vacuo to afford the title compound 1 as a viscous oil (100 mg,

39%). Ti NMR (400 MHz, CDC1₃) δ 8.21 (br s, 1H), 6.25 (d, J=7.5 Hz, 1H), 6.18 (d, J=7.5 Hz, 1H), 5.04 (br s, 2H), 4.35 (q, J=7.1 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H).

PART 2 - PREPARATION OF ETHYL 2,4-DiMETHYLPYRROLO[l,2-a]PYRiMiDiNE-8-

CARBOXYLATE (2)

[00400] A solution of ethyl 2-amino-lH-pyrrole-3-carboxylate 1 (90 mg, 0.58 mmol) in acetic acid (3 mL) was charged with pentane-2,4-dione (0.07 mL, 0.64 mmol) and heated to reflux at 110°C for 16 h. The reaction mixture was concentrated to dryness in vacuo to obtain a crude residue which was dissolved in ethyl acetate (50 mL) and diluted with saturated NaHCCb solution (50 mL) and stirred for 15 mins. The organic layer was separated and dried over

Na₂SC>4 and concentrated in vacuo to obtain crude compound 2 as a light brown solid (71 mg, 56%). ^XH NMR (400 MHz, CDC1₃) δ 7.40 (d, J=2.8 Hz, 1H), 7.01 (d, J=2.0 Hz, 1H), 6.53 (s, 1H), 4.41 (q, J=7.1 Hz, 2H), 2.63 (s, 3H), 2.57 (s, 3H), 1.42 (t, J=7.1 Hz, 3H). ES-MS m/z 219.05 (M+H)⁺. PREPARATION OF 2,4-DIMETHYLPYRROLO[l,2-a]PYRIMIDINE-8-CARBOXYLIC ACID

[00401] A solution of ethyl 2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxylate 2 (200 mg, 0.92 mmol) in MeOH (10 mL) was charged with NaOH (110 mg, 2.76 mmol) at room temperature. The reaction mixture was heated to reflux at 60°C for 4 h. Then, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The separated aqueous layer was acidified (pH=5) with acetic acid and extracted with 10% MeOH in DCM (3 x 10 mL). The combined organic layer was dried over Na₂SC>4 and the solvent removed under vacuum to afford the title compound 3 as an off-white solid (95 mg, 54%). ^XH NMR (400 MHz, DMSO-c¾) δ 11.65 (br s, IH), 7.40 (d, J=3.1 Hz, IH), 7.26 (d, J=3.1 Hz, IH), 6.84 (s, IH), 2.69 (s, 3H), 2.59 (s, 3H).

PART 4 - PREPARATION OF 2,4-DIMETHYL-/V-(4-(OXAZOL-4-YL)PHENYL)PYRROLO[1,2- A]PYRIMIDINE-8-CARBOXAMIDE

[00402] A solution of 4-(4-nitrophenyl)oxazole (500 mg, 2.60 mmol) in MeOH:THF (6 mL; 1 : 1 mixture) was added 10% Pd/C (50 mg, 10% wt) under N2 atmosphere at room temperature. The reaction mixture was stirred under hydrogen atmosphere at room temperature for 16h. Then, the reaction mixture was filtered over a pad of celite and the filtrate was concentrated under vacuum to afford crude compound. The crude compound was purified by FCC (eluent, 30% ethyl acetate in hexane) to afford 4-(oxazol-4-yl)aniline as a light brown viscous oil (260 mg, 62%). ^lH NMR (400 MHz, DMSO-c¾) 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)⁺. [00403] A solution of 2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxylic acid 3 (90 mg, 0.47 mmol) in DMF (2 mL) at 0°C was charged with HATU (267 mg, 0.70 mmol), DIPEA (0.24 mL, 1.4 mmol) and 4-(oxazol-4-yl)aniline (90 mg, 0.56 mmol). The reaction mixture was warmed to room temperature and stirred for 24 h. Then, the reaction mixture was quenched with water (1 mL) resulting in a precipitate which was filtered and dried to obtain crude product. The crude product was purified by washing with MeOH to afford the title compound as a light yellow solid (40 mg, 25%). ^XH NMR (400 MHz, CDC1₃) δ 10.92 (s, 1H), 7.99 (dd, J=2.4, 8.6 Hz, 1H), 7.85 (dd, J=2.4, 8.6 Hz, 2H), 7.69(d, J=2.2 Hz, 1H), 7.60 (d, J=3.5 Hz, 1H), 7.10 (s, 1H), 7.52 (d, J=2.2 Hz, 1H), 7.04 (s, 1H), 6.50 (s, 1H), 2.58 (s, 3H), 2.54 (s, 3H). ES-MS m/z 333.35 (M+H)⁺. HPLC purity 99.7%.

PART 5 - PREPARATION OF A^-(4-ETHYNYLPHENYL)-2,4-DIMETHYLPYRROLO[1,2- A]PYRIMIDINE-8-CARBOXAMIDE

[00404] A solution of 2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxylic acid 3 (150 mg, 0.78 mmol) in DMF (3 mL) at 0°C was charged with HATU (444 mg, 1.17 mmol), DIPEA (0.4 mL, 2.30 mmol) and 4-((trimethylsilyl)ethynyl)aniline (149 mg, 0.78 mmol). The reaction mixture was warmed to room temperature and stirred for 16 h. 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 Na₂SC>4 and concentrated in vacuo to afford crude product which was purified by FCC (eluent, 20-25% ethyl acetate in hexane) to provide 2,4-dimethyl-N-(4- ((trimethylsilyl)ethynyl)phenyl)pyrrolo[l,2-a]pyrinddine-8-carboxamide as a brown solid (75mg, 26%). ES-MS m/z 362.40 (M+H)⁺.

[00405] A solution of 2,4-dimethyl-N-(4-((trimethylsilyl)ethynyl)phenyl)pyrrolo[l,2- a]pyrimidine-8-carboxamide (75 mg, 0.20 mmol) in MeOH (30 mL) was charged with K₂CO₃ (86 mg, 0.62 mmol) and stirred at room temperature for 2h. Then, the reaction mixture was concentrated in vacuo to obtain crude product which was suspended in water and stirred for 30 min. The resulting solid was filtered and washed with water followed by n-hexane to afford the title compound as a brown solid (25 mg, 42%). ^l NMR (400 MHz, CDC1₃) δ 10.80 (br s, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.50 (s, 1H), 7.41 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.2 Hz, 1H), 6.53 (d, J=8.2 Hz, 1H), 3.03 (s, 1H), 2.63 (s, 3H), 2.59 (s, 3H). ES-MS m/z 298.34 (M+H)⁺. HPLC purity 99.4%.

PART 6 - ADDITIONAL PYRROLO [l,2-a]PYRiMiDiNE-8-CARBOXAMiDE COMPOUNDS

[00406] Following the general procedures described in Part I below, the additional pyrrolo[l,2-a]pyrimidine-8-carboxarnide compounds listed in Part II below were prepared.

Part I - General Procedures

General Procedure A: Preparation of Amide by Coupling of a Carboxylic Acid Compound with an Amine Compound

[00407] To a stirred solution of carboxylic acid compound (1.0 equivalent), HATU (1.5 equivalents), and DIPEA (3.75 equivalents) in DCM or DMF (~4 mL/0.2 mmol) was added amine compound (1.25 - 2.0 equivalents). The reaction mixture was stirred at room

temperature for 4-16 hours, and then washed with saturated aqueous NaHCCb solution (5 mL/0.2 mmol), aqueous citric acid solution (5 mL/0.2 mmol) and brine (5 mL/0.2 mmol). The combined extracts were dried over anhydrous Na₂SC>4, filtered and concentrated in vacuo. The resulting crude material was purified by silica gel column chromatography or preparatory HPLC to give the amide compound.

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

Compound

[00408] To a solution of carboxylic ester (1.0 equivalent) in EtOH (5.0 mL/1.0 mmol) and water (0-3.0 mL/1.0 mmol) was added NaOH (2.0-5.0 equivalents) and the mixture was heated at 80 °C for 2 hours and then concentrated. To the concentrate, 6N HC1 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 give the carboxylic acid compound.

General Procedure C: Preparation of Amide from a Carboxylic Acid Compound and Amine Compound

[00409] 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 the addition of amine compound (5.0 equivalents) and triethylamine (2.0 equivalents). The reaction mixture was stirred at RT for 2 hours and then diluted with DCM (10 mL/0.5 mmol). The organic solution was washed sequentially with ¾() (10 mL/0.5 mmol) and brine (10 mL/0.5 mmol), then dried over anhydrous Na₂SC>4, and next filtered. The filtrate was concentrated in vacuo, and the resulting residue was purified by preparatory HPLC or silica gel chromatography to give the amide compound.

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

Compound

[00410] A solution of carboxylic ester compound (1.0 equivalent) and (Bu₃Sn)₂0 (1.6 equivalents) was refluxed in 10 mL of toluene for 1 week, cooled and concentrated in vacuo. The resulting residue was diluted by ethyl acetate (10 mL/mmol) and washed with saturated NaHC0₃ solution (5 mL * 3/mmol). The aqueous phases were neutralized to pH 4-5 with 3N HC1, and then extracted with DCM (10 mL * 3/mmol). The organic phases were dried over Na₂SC>4 and filtered. The filtrate was concentrated in vacuo to afford the carboxylic acid compound.

Part II - Compounds Prepared Following General Procedures

[00411] The following compounds were prepared based on the general procedures described in Part I above.

A/-((li?,4i?)-4-Butoxycvclohexyl)-2-(difluoromethyl)-4-methylpyrrolo[l,2-alpyrimidine-8- carboxamide

[00412] Following general procedure A, 2-(difluoromethyl)-4-methylpyrrolo[l,2- a]pyrimidine-8-carboxylic acid (25 mg, 0.13 mmol) and (li?,4i?)-4-butoxycyclohexan- afforded the title compound as a yellow solid (8.5 mg, 17%). ^XH NMR (500 MHz, CDC1₃): δ 8.36 (d, J = 7.0 Hz, 1H), 7.58 (d, J = 3.0 Hz, 1H), 7.28 (t, J = 1.5 Hz, 1H), 6.81 (s, 1H), 6.77 (t, J = 53.0 Hz, 1H), 4.06-4.03 (m, 1H), 3.47 (t, J = 7.0 Hz, 2H), 3.33-3.29 (m, 1H), 2.64 (s, 3H), 2.19-2.17 (m, 2H), 2.08-2.05 (m, 2H), 1.59-1.52 (m, 2H), 1.49-1.45 (m, 2H), 1.42-1.35 (m, 4H), 0.93 (t, J = 7.0 Hz, 3H). LC-MS m/z: 380.0 [M+H]⁺. HPLC Purity (214 nm): >99.5%; t_R = 10.85 minutes.

A/-((li?,4i?)-4-Butoxycvclohexyl)-4-(difluoromethyl)-2-methylpyrrolo[l,2-alpyrimidine-8- carboxamide

[00413] Following general procedure A, 4-(difluoromethyl)-2-methylpyrrolo[l,2- a]pyrimidine-8-carboxylic acid (50 mg, 0.26 mmol) and (li?,4i?)-4-butoxycyclohexan-l -amine afforded the title compound as a yellow solid (36 mg, 36%). ¹ H NMR (400 MHz, MeOD-c¾): 5 7.37 (s, 1H), 7.32 (d, J = 3.2 Hz, 1H), 7.09 (t, J = 52.4 Hz, 1H), 6.99 (s, 1H), 3.85-3.83 (m, 1H), 3.41 (t, J = 6.4 Hz, 2H), 3.29-3.26 (m, 1H), 3.52 (s, 3H), 2.05-1.98 (m, 4H), 1.48-1.40 (m, 2H), 1.37-1.25 (m, 6H), 0.84 (t, J= 7.2 Hz, 3H). LC-MS m/z: 380.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_R= 9.23 minutes.

PART 7 - ADDITIONAL COMPOUNDS

[00414] The following additional compounds were prepared based on procedures described above and in the detailed description:

2,4-Dimethyl-N-(6-(oxazol-4-yl)pyridin-3-yl)pyrrolo[l,2-a]pyrirnidine-8-carboxamide; N-(4- (3-Methoxyprop-l-yn-l-yl)phenyl)-2,4-dimethylpyrrolo[l,2-a]pyrirnidine-8-carboxamide; N- (6-Ethynylpyridin-3-yl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl- N-(4-(l,3-oxazol-2-yl)phenyl) pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(6- (thiophen-2-yl)pyridin-3-yl)pyrrolo[l,2-a]pyrirnidine-8-carboxarnide; 2,4-Dimethyl-N-(4- (pyridin-4-yl)phenyl)pyrrolo[l,2-a]pyrimidine-8-carboxarnide; N-(2-3-Dihydro-lH-inden-5- yl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxarnide; N-{4-Chloro-3-[(pyridin-3- yloxy)methyl]phenyl}-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(2H-1,3- Benzodioxol-5-yl)-2,4-dimethylpyrrolo[l,2-a]pyrirnidine-8-carboxarnide; 2,4-Dimethyl-N-(4- (piperidin-l-yl)phenyl)pyrrolo[l,2-a]pyrirnidine-8-carboxarnide; 2,4-dimethyl-N-(4- (pentyloxy)phenyl)pyrrolo[l,2-a]pyrimidine-8-carboxarnide; N-(4-(furan-2-yl)phenyl)-5,7- dimethylpyrrolo[l,2-a]pyrimidine-3-carboxarnide; 2,4-dimethyl-N-(4-(l -methyl- lH-pyrazol-4- yl)phenyl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; 2,4-dimethyl-N- {4-methyl-3-(l,3-oxazol-

2- yl)phenyl]pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-[6-(3-methoxyprop-l -yn-l -yl)pyridin

3- yl]-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-dimethyl-N-(6-(l-methyl-lH- pyrazol-4-yl)pyridin-3-yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Bis(difluoromethyl)-N (4-(oxazol-4-yl)phenyl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; 2,4-Bis(difluoromethyl)-N- (l,2,3,4 etrahydronaphthalen-l -yl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; 2,4- Bis(difluoromethyl)-N-((li?,4i?)-4-(pentyloxy)cyclohexyl)pyrrolo[l ,2-a]pyrimidine-8- carboxamide; N-((li?, 4i?)-4-Butoxycyclohexyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8- carboxamide; 4-(Difluoromethyl)-2-methyl-N-(4-(oxazol-4-yl)phenyl)pyrrolo[l ,2- a]pyrimidine-8-carboxamide; 4-(Difluoromethyl)-2-methyl-N-(l ,2,3,4-tetrahydronaphthalen-l- yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2-(Difluoromethyl)-4-methyl-N-(l,2,3,4- tetrahydronaphthalen-l-yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2-(Difluoromethyl)-4- methyl-N-(4-(oxazol-4-yl)phenyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2-Isopropyl-4- (methoxymethyl)-N-(l -methyl-l,2,3,4 etrahydroquinazolin-5-yl)pyrrolo[l,2-a]pyrimidine-8- carboxamide; 4-Isopropyl-2-(methoxymethyl)-N-(l -methyl-l,2,3,4-tetrahydroquinazolin-5- yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-((li?,4i?)-4-Butoxycyclohexyl)-4- (methoxymethyl)-2-methylpyrrolo[l,2-a]pyrimidine-8-carboxamide;

N-((li?, 4i?)-4-Butoxycyclohexyl)-2-(difluoromethyl)-4-(methoxymethyl)pyrrolo[l,2- a]pyrimidine-8-carboxamide; N-((li?, 4i?)-4-Butoxycyclohexyl)-4-(difluoromethyl)-2- (methoxymethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-((li?,4i?)-4-Butoxycyclohexyl)-2 isopropyl-4-(methoxymethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-((li?,4i?)-4- Butoxycyclohexyl)-4-isopropyl-2-(methoxymethyl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; 2-Chloro-4-methyl-N-(4-(oxazol-4-yl)phenyl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; 4- Chloro-2-methyl-N-(4-(oxazol-4-yl)phenyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2- Bromo-4-methyl-N-(4-(oxazol-4-yl)phenyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 4- Bromo-2-methyl-N-(4-(oxazol-4-yl)phenyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; (<S -2- (Methoxymethyl)-4-methyl-N-(l ,2,3,4-tetrahydronaphthalen-l -yl)pyrrolo[l,2-a]pyrimidine-8- carboxamide; (5)-2-((2-Methoxyethoxy)methyl)-4-methyl-N-(l ,2,3,4-tetrahydronaphthalen-l - yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-((li?,4i?)-4-Butoxycyclohexyl)-4-cyclopropyl- 2-methylpyrrolo[l ,2-a]pyrimidine-8-carboxamide; N-((li?,4i?)-4-Butoxycyclohexyl)-2- (methoxymethyl)-4-methylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 4-Cyclopropyl-2-methyl- N-((li?,4i?)-4-(4,4,4 rifluorobutoxy)cyclohexyl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; 4- Cyclopropyl-2-methyl-N-((li?, 4i?)-4-((5,5,5-trifluoropentyl)oxy)cyclohexyl)pyrrolo[l ,2- a]pyrimidine-8-carboxamide; 2-(Methoxymethyl)-4-methyl-N-(2-(4-(oxazol-4- yl)phenyl)propan-2-yl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; 4-(Methoxymethyl)-2-methyl- N-(2-(4-(oxazol-4-yl)phenyl)propan-2-yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2- (Methoxymethyl)-4-methyl-N-(4-(oxazol-4-yl)phenyl)pyrrolo[l ,2-a]pyrimidine-8- carboxamide; 4-Methoxy-2-methyl-N-(4-(oxazol-4-yl)phenyl)pyrrolo[l ,2-a]pyrimidine-8- carboxamide; 2-Methoxy-4-methyl-N-(4-(oxazol-4-yl)phenyl)pyrrolo[l ,2-a]pyrimidine-8- carboxamide; 4-Hydroxy-2-methyl-N-(4-(oxazol-4-yl)phenyl)pyrrolo[l ,2-a]pyrimidine-8- carboxamide; 4-Hydroxy-2-methyl-N-(l ,2,3,4-tetrahydronaphthalen-l-yl)pyrrolo[l ,2- a]pyrimidine-8-carboxamide; N-(6,7-Difluoro-4-methylchroman-4-yl)-2-(difluoromethyl)-4- (methoxymethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(6,7-Difluoro-4-methylchroman- 4-yl)-4-(difluoromethyl)-2-(methoxymethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(6,7- Difluorochroman-4-yl-4-ii)-2-isopropyl-4-(methoxymethyl)pyrrolo[l ,2-a]pyrimidine-8- carboxamide; N-(6,7-Difluorochroman-4-yl-4-<i)-4-isopropyl-2-(methoxymethyl)pyrrolo[l ,2- a]pyrimidine-8-carboxamide; N-(2-(4-Ethynylphenyl)propan-2-yl)-2-(methoxymethyl)-4- methylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(2-(4-Ethynylphenyl)propan-2-yl)-4- (methoxymethyl)-2-methylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(2-(3- Ethynylphenyl)propan-2-yl)-4-(methoxymethyl)-2-methylpyrrolo[l ,2-a]pyrimidine-8- carboxamide; N-(2-(3-Ethynylphenyl)propan-2-yl)-2-(methoxymethyl)-4-methylpyrrolo[ 1 ,2- a]pyrimidine-8-carboxamide; N-((li?,4i?)-4-Butoxycyclohexyl)-4-methyl-2- (methylamino)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2-Chloro-4-methyl-N-(l , 2,3,4- tetrahydro-l,3-methanonaphthalen-4-yl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; 4-Methyl-2- (methylamino)-N-(l ,2,3,4-tetrahy dro- 1 ,3-methanonaphthalen-4-yl)pyrrolo[ 1 ,2-a]pyrimidine-8- carboxamide; N-((lr,4r)-4-Isobutoxycyclohexyl)-4-methyl-2-(methylamino)pyrrolo[l,2- a]pyrimidine-8-carboxamide; N-((li?,4i?)-4-Butoxycyclohexyl)-2-fluoro-4-methylpyrrolo[l,2- a]pyrimidine-8-carboxamide; 2-Chloro-N-((li?,4i?)-4-isobutoxycyclohexyl)-4- methylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 2-Chloro-4-methyl-N-((lr,4r)-4- propoxycyclohexyl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; 2-Chloro-N-(2-((15',45 -4- methoxycyclohexyl)propan-2-yl)-4-methylpyrrolo[l ,2-a]pyrimidine-8-carboxamide; 2-Chloro- N-(2-((li?,4i?)-4-methoxycyclohexyl)propan-2-yl)-4-methylpyrrolo[l ,2-a]pyrimidine-8- carboxamide; 2,4-Dimethyl-N-(l-oxaspiro[5.5]undecan-8-yl)pyrrolo[l ,2-a]pyrimidine-8- carboxamide; 2,4-Dimethyl-N-(6-oxaspiro[4.5]decan-2-yl)pyrrolo[l,2-a]pyrimidine-8- carboxanude; N-(4-(lH-Imidazol-l-yl)phenyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8- carboxamide; N-(3-Methoxy-4-(oxazol-5-yl)phenyl)-2,4-dimethylpyrrolo[l,2-a]pyrirnidine-8- carboxamide; 2,4-Dimethyl-N-(2-methylbenzo[d]thiazol-6-yl)pyrrolo[l,2-a]pyrirnidine-8- carboxamide; N-((li?,4i?)-4-Methoxycyclohexyl)-2,4-dimethylpyrrolo[l,2-a]pyrirnidine-8- carboxamide; 2,4-Dimethyl-N-((li?,4i?)-4-(pyrirnidin-2-yloxy)cyclohexyl)pyrrolo[l,2- a]pyrirnidine-8-carboxamide; 2,4-Dimethyl-N-(2-phenylpropan-2-yl)pyrrolo[l,2-a]pyrirnidine- 8-carboxamide; N-(4,4-Difluorocyclohexyl)-2,4-dimethylpyrrolo[l,2-a]pyrirnidine-8- carboxamide; 2,4-Dimethyl-N-((li?,4i?)-4-(neopentyloxy)cyclohexyl)pyrrolo[l,2-a]pyrirnidine- 8-carboxamide; 2,4-Dimethyl-N-((15',45)-4-(neopentyloxy)cyclohexyl) pyrrolo[l,2- a]pyrirnidine-8-carboxamide; N-((li?,4i?)-4-((3,3-Difluorocyclobut l)methoxy)cyclohexyl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxarnide; 2,4-Dimethyl-N-(3-((5-methylisoxazol-3- yl)oxy)-2,3-dihydro-lH-inden-5-yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N- (3-(5-methyl-3-oxoisoxazol-2(3H)-yl)-2,3-dihydro-lH-inden-5-yl)pyrrolo[l,2-a]pyrimidine-8- carboxamide; N-(2-Methoxycyclohexyl)-2,4-dimethylpyrrolo[l,2-a]pyrirnidine-8-carboxamide; N-((li?,4i?)-4-Ethoxycyclohexyl)-2,4-dimethylpyrrolo[l,2-a]pyrirnidine-8-carboxamide; (S)- 2,4-Dimethyl-N-(l,2,3,4 etrahydronaphthalen-l-yl)pyrrolo[l,2-a]pyrirnidine-8-carboxainide N-((li?,4i?)-4-Cyclobutoxycyclohexyl)-2,4-dimethylpyrrolo[l,2-a]pyrirnidine-8-carboxamide; N-((li?,4i?)-4-(2-Ethoxyethoxy)cyclohexyl)-2,4-dimethylpyrrolo[l,2-a]pyrirnidine-8- carboxamide; N-(6-(2-Methoxyethoxy)-2,3-dihydro-lH-inden-l-yl)-2,4-dimethylpyrrolo[l,2- a]pyrirnidine-8-carboxamide; N-(7-(2-Methoxyethoxy)-l,2,3,4-tetrahydronaphthalen-l-yl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxarnide; N-((li?,4i?)-4-(2-(2-

Methoxyethoxy)ethoxy)cyclohexyl)-2,4-dimethylpyrrolo[l,2-a]pyrirnidine-8-carboxamide; N- ((li?,4i?)-4-Isopropoxycyclohexyl)-2,4-dimethylpyrrolo[l,2-a]pyrirnidine-8-carboxamide; N- ((li?,4i?)-4-(3-Methoxypropoxy)cyclohexyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8- carboxamide; N-(3-Methoxy-4-(oxazol-4-yl)phenyl)-2,4-dimethylpyrrolo[l,2-a]pyrirnidine-8- carboxamide; N-(2-Methoxy-4-(oxazol-4-yl)phenyl)-2,4-dimethylpyrrolo[l,2-a]pyrirnidine-8- carboxamide; N-(2-Methoxy-4-(oxazol-5-yl)phenyl)-2,4-dimethylpyrrolo[l,2-a]pyrirnidine-8- carboxamide; 2,4-Dimethyl-N-(2-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)pyrrolo[l,2- a]pyrirnidine-8-carboxamide; 2,4-Dimethyl-N-(l-oxaspiro[5.5]undecan-9-yl)pyrrolo[l,2- a]pyrirnidine-8-carboxamide; 2,4-Dimethyl-N-((li?,4i?)-4-

(propoxymethyl)cyclohexyl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(l - (thiophen-3-yl)piperidin-4-yl)pyrrolo[l,2-a]pyrirnidine-8-carboxamide; 2,4-Dimethyl-N-(5- (thiophen-2-yl)pyridin-2-yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(5-(Furan-2- yl)pyridin-2-yl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(5-Fluoro-4- methylchroman-4-yl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(3-Methoxy- 2,3-dihydro-lH-inden-5-yl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4- Dimethyl-N-(3-(pyridin-3-yloxy)-2,3-dihydro-lH-inden-5-yl)pyrrolo[l,2-a]pyrimidine-8- carboxamide; 2,4-Dimethyl-N-(3-(pyridin-2-yloxy)-2,3-dihydro-lH-inden-5-yl)pyrrolo[l,2- a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(7-(oxazol-4-yl)-l,2,3,4-tetrahydronaphthalen-l- yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(l-Oxaspiro[5.5]undecan-9-ylmethyl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; (i?)-2,4-Dimethyl-N-(l- phenylpropyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide;

N-((l<S,4i?)-4-((<S)-sec-butoxy)c clohexyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8- carboxamide; N-((li?,4i?)-3,4-dihy dro- 1 ,4-ethanonaphthalen- 1 (2H)-yl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(8-Hexanoyl-8-azabicyclo[3.2.1]octan-3- yl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(8-(2,2,2- trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(4- Ethynyl-2-methoxyphenyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4- Dimethyl-N-(6-(oxazol-4-yl)-2,3-dihydro-lH-inden-l-yl)pyrrolo[l,2-a]pyrimidine-8- carboxamide; D 1 -2,4-Dimethy l-N-( 1 ,2,3 ,4-tetrahy dronaphthalen- 1 -y l)py rrolo[ 1 ,2- a]pyrimidine-8-carboxamide; N-((li?,4i?)-4-(Cyclopentyloxy)cyclohexyl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(8-Fluoro-4-methylchroman-4-yl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(4-

(Cyclopropyl(methyl)carbamoyl)cyclohexyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8- carboxamide; 2,4-Dimethyl-N-(l,2,3,4-tetrahydro-l,3-methanonaphthalen-4-yl)pyrrolo[l,2- a]pyrimidine-8-carboxamide; Butyl 3-(2,4-dimethylpyrrolo[l,2-a]pyrimidine-8- carboxamido)azetidine- 1 -carboxy late; 2,4-Dimethy l-N-(6-oxaspiro [4.5] decan- 1 -y l)py rrolo[ 1 ,2- a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(3-oxaspiro[5.5]undecan-9-yl)pyrrolo[l,2- a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(l-oxaspiro[4.5]decan-8-yl)pyrrolo[l,2- a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(3',4,4',5-tetrahydro-2'H,3H-spiro[furan-2, - naphthalen]-4'-yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(4-(3-Hydroxypropyl)-l,2- dihydronaphthalen-l-yl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl- N-((li?,3i?)-3-(pentyloxy)cyclopentyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl- N-(l-oxaspiro[4.4]nonan-7-yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(2,3-Dihydro-lH- inden-5-yl)-2,4-dimethylpyrrolo[l ,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(4-methyl-

3- (oxazol-2-yl)phenyl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(2-methyl-4- (oxazol-2-yl)phenyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(5, 6,7,8- tetrahydroisoquinolin-5-yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(l - oxaspiro[5.5]imdecan-7-yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-((4,4- Difluorocyclohexyl)methyl)-2,4-dimethylpyrrolo[l ,2-a]pyrimidine-8-carboxamide; 2,4- Bis(methoxymethyl)-N-((lr,4r)-4-(pentyloxy)cyclohexyl)pyrrolo[l ,2-a]pyrimidine-8- carboxamide; N-(6,7-Difluoro-4-methylchroman-4-yl)-2,4-bis(methoxymethyl)pyrrolo[l ,2- a]pyrimidine-8-carboxamide; N-(2-(4-Ethynylphenyl)propan-2-yl)-2,4- bis(methoxymethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(2-(3-Ethynylphenyl)propan- 2-yl)-2,4-bis(methoxymethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; D8-2,4-Dimethyl-N-(4- (oxazol-4-yl)phenyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; D8-2,4-Dimethyl-N-(4- methylchroman-4-yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; D8-N-(2-(4- Fluorophenyl)propan-2-yl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; (S)-4- Cyclopropyl-N-(l,2,3,4-tetrahydronaphthalen-l -yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; (^-4-Isopropyl-N-(l,2,3,4-tetrahydronaphthalen-l-yl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; 2-Acetamido-N-(chroman-4-yl-l -i))-4-methylpyrrolo[l,2-a]pyrimidine-8-carboxamide;

(^-2,4-Dimethyl-N-(l -phenylpropyl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; (R)-2,4- Dimethyl-N-(l-phenylethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; (<S)-2,4-Dimethyl-N-(l- phenylethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(l,2,3,4- tetrahydronaphthalen-l -yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; (i?)-2,4-Dimethyl-N- (l,2,3,4-tetrahydronaphthalen-l -yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(8- Oxabicyclo[3.2 ]octan-3-yl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(6-(2- Methoxyethoxy)chroman-4-yl)-2,4-dimethylpyrrolo[l ,2-a]pyrimidine-8-carboxamide; N-(5,8- Difluorochroman-4-yl)-2,4-dimethylpyrrolo[l ,2-a]pyrimidine-8-carboxamide; N-(5,6- Difluorochroman-4-yl)-2,4-dimethylpyrrolo[l ,2-a]pyrimidine-8-carboxamide; N-(5,6-Difluoro-

4- methylchroman-4-yl)-2,4-dimethylpyrrolo[l ,2-a]pyrimidine-8-carboxamide; N-(6,7- Difluoro-4-methylchroman-4-yl)-2,4-dimethylpyrrolo[l ,2-a]pyrimidine-8-carboxamide; 2,4- Dimethyl-N-(5-methyl-5,6,7,8-tetrahydroquinazolin-5-yl)pyrrolo[l,2-a]pyrimidine-8- carboxamide; 2,4-Dimethyl-N-(3-(pentyloxy)cyclopent l)pyrrolo[l ,2-a]pyrimidine-8- carboxamide; 2,4-Dimethyl-N-((15',35)-3-(pentyloxy)cyclopentyl)pyrrolo[l ,2-a]pyrimidine-8- carboxamide; 2,4-Dimethyl-N-((li?,35 -3-(pentyloxy)cyclopentyl)pyrrolo[l ,2-a]pyrimidine-8- carboxamide; 2,4-Dimethyl-N-((15',3i?)-3-(pent loxy)cyclopentyl)pyrrolo[l,2-a]pyrimidine-8- carboxamide; 2,4-Dimethyl-N-(4-methylchroman-4-yl)pyrrolo[l,2-a]pyrimidine-8- carboxamidei N-iil i^ i^^S^-S-ButoxybicycloCS^. lloctan-S-y ^^-dimethylpyrroloCl^- a]pyrimidine-8-carboxamide; N-(4-Ethynyl-2-(2-methoxyethoxy)phenyl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(3-oxaspiro[5.5]undecan-7- yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; ^((^^^^^^^-(S-ButoxybicyclofS^. lJoctan-S- yl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(4-(thiophen-2- yl)cyclohex-3-en-l-yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(4-(thiophen- 2-yl)cyclohexyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(((lS,4S)-4- (thiophen-2-yloxy)cyclohexyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N- (((li?,4i?)-4-(thiophen-2-yloxy)cyclohexyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4- Dimethyl-N-(3-(thiophen-2-yloxy)cyclohexyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4- Dimethyl-N-(5-(thiazol-4-yl)-2,3-dihydro-lH-inden-2-yl)pyrrolo[l,2-a]pyrimidine-8- carboxamide; 2,4-Dimethyl-N-(5,6,7,8-tetrahydroquinolin-8-yl)pyrrolo[l,2-a]pyrimidine-8- carboxamide; 2,4-Dimethyl-N-((li?,4i?)-4-(pent-4-yn-l -yloxy)cyclohexyl)pyrrolo[l ,2- a]pyrimidine-8-carboxamide; N-(5-Fluorochroman-4-yl)-2,4-dimethylpyrrolo[l,2- a]pyrimidine-8-carboxamide; N-(7-Fluorochroman-4-yl)-2,4-dimethylpyrrolo[l,2- a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-((li?, 4i?)-4-(2- propoxyethoxy)cyclohexyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-((li?,3i?)-3- Butoxycyclobutyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(4- (tetrahydrofuran-2-yl)cyclohexyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N- ((li?,4i?)-4-(pentyloxy)cyclohexyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N- ((l^,4^-4-(pent loxy)cyclohexyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N- ((li?,4i?)-4-(methyl(pentyl)carbamoyl)cyclohexyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(l-(2,2-Difluorobutyl)piperidin-4-yl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(l-(2,2-Difluorobutyl)pyrrolidin-3-yl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-((li?,4i?)-4-(pyridin-3-yloxy)cyclohexyl)pyrrolo[l,2-a]pyrimidine-8- carboxamide; 2,4-Dimethyl-N-(6-(oxazol-2-yl)chroman-4-yl)pyrrolo[l,2-a]pyrimidine-8- carboxamide; N-((li?,4i?)-4-(Hex-5-yn-l-yloxy)cyclohexyl)-2,4-dimethylpyrrolo[l,2- a]pyrimidine-8-carboxamide; N-(7-Cyano-l,2,3,4-tetrahydronaphthalen-l-yl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(Isochroman-4-yl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(Chroman-4-yl)-2,4-dimethylpyrrolo[l,2- a]pyrimidine-8-carboxamide; N-(4-Methoxy- 1 ,2,3,4-tetrahy dronaphthalen- 1 -yl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(4-Ethynyl-2-(hydroxymethyl)phenyl)- 2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(4-Chloro-3-(oxazol-5-yl)phenyl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(2,3-Dihydro-lH-inden-2-yl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; (5 -N-(2,3-Dihydro-lH-inden-l-yl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; (i?)-N-(2,3-Dihydro-lH-inden-l-yl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(2-Chloro-4-(oxazol-2-yl)phenyl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(2,3-Dihydro-lH-inden-4-yl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(3-((5-methyl-l ,3,4- oxadiazol-2-yl)oxy)-2,3-dihydro-lH-inden-5-yl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; N-(3-Hydroxy-2,3-dihydro-lH-inden-5-yl)-2,4-dimethylpyrrolo[l ,2-a]pyrimidine-8- carboxamide; N-(5-Chloro-6-(pyrimidin-2-yl)pyridin-3-yl)-2,4-dimethylpyrrolo[l ,2- a]pyrimidine-8-carboxamide; N-(8-Fluorochroman-4-yl)-2,4-dimethylpyrrolo[l ,2- a]pyrimidine-8-carboxamide; N-(6-Fluorochroman-4-yl)-2,4-dimethylpyrrolo[l ,2- a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5- yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(5,6,7,8-tetrahydroisoquinolin-8- yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(l,2,3,4-tetrahydronaphthalen-2- yl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; N-(Hexahydrobenzo[d] [l,3]dioxol-5-yl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(7-(methylsulfonyl)- l ,2,3,4-tetrahydronaphthalen-l-yl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide;

N-(4-(2-Ethoxyethoxy)-l ,2,3,4-tetrahydronaphthalen-l-yl)-2,4-dimethylpyrrolo[l ,2- a]pyrimidine-8-carboxamide; N-(4-Ethoxy-4-methylcyclohexyl)-2,4-dimethylpyrrolo[l ,2- a]pyrimidine-8-carboxamide; N-(2-(2-Methoxyphenyl)propan-2-yl)-2,4-dimethylpyrrolo[l ,2- a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(3-(pentyloxy)cyclohexyl)pyrrolo[l ,2- a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(l -(2,2,2-trifluoroethyl)pyrrolidin-3- yl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; N-(2-((li?,4i?)-4-Methoxycyclohexyl)propan-2- yl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(2-((15',45)-4- Methoxycyclohexyl)propan-2-yl)-2,4-dimethylpyrrolo[l ,2-a]pyrimidine-8-carboxamide; 2,4- Dimethyl-N-(((li?,3i?)-3-propoxycyclobutyl)methyl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(((li?,4i?)-4-propoxycyclohexyl)methyl)pyrrolo[l,2-a]pyrimidine-8- carboxamide; N-((li?,4i?)-4-((i?)-sec-Butoxy)cyclohexyl)-2,4-dimethylpyrrolo[l ,2- a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(5-(oxazol-2-yl)-2,3-dihydro-lH-inden-2- yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(3-((5-methylisoxazol-3- yl)oxy)cyclopentyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(4-(oxazol-2- yl)cyclohexyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(4-(oxazol-2- yl)cyclohex-3-en-l-yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 4-Methyl-N-(6- oxaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 4- Methyl-N-(5-methyl-5,6,7,8-tetrahydroquinazolin-5-yl)-2-(trifluoromethyl)pyrrolo[l,2- a]pyrimidine-8-carboxamide; 4-Methyl-N-(l,2,3,4-tetrahydronaphthalen-l-yl)-2- (trifluoromethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide;

4-Methyl-N-(4-(oxazol-4-yl)phenyl)-2-(trifluoromethyl)pyrrolo[l,2-a]pyrimidine-8- carboxamide; 2-Methyl-N-(l ,2,3,4-tetrahy dronaphthalen- 1 -yl)-4-(trifluoromethyl)pyrrolo[ 1 ,2- a]pyrimidine-8-carboxamide; 2-Methyl-N-(4-(oxazol-4-yl)phenyl)-2- (trifluoromethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; (5 -4-Methyl-N-(l,2,3,4- tetrahydronaphthalen-l-yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 4-Methyl-N-(4-(oxazol-2- yl)phenyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 4-Methyl-N-(4-methylchroman-4- yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(8-Fluoro-4-methylchroman-4-yl)-4- methylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 4-Methyl-N-(2-phenylpropan-2- yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 4-Methyl-N-((li?,4i?)-4- (pentyloxy)cyclohexyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; f??)-N-(l-(4- Fluorophenyl)ethyl)-4-methylpyrrolo[l ,2-a]pyrimidine-8-carboxamide; 4-Methyl-N-(l -methyl- l,2,3,4-tetrahydronaphthalen-l-yl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 4-Methyl-N- (l,2,3,4 etrahydronaphthalen-l-yl-l-i))pyrrolo[l,2-a]pyrimidine-8-carboxamide;

N-(6-Fluoro-4-methylchroman-4-yl)-4-methylpyrrolo[l,2-a]pyrimidine-8-carboxamide 2-Methyl-N-(4-(oxazol-2-yl)phenyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide;

2-Cyclopropyl-N-(6,7-difluoro-4-methylchroman-4-yl)-4-(methoxymethyl)pyrrolo[l,2- a]pyrimidine-8-carboxamide; N-(6,7-Difluoro-4-methylchroman-4-yl)-4-(methoxymethyl)-2- propylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-((li?,4i?)-4-butoxycyclohexyl)-2- cyclopropyl-4-(methoxymethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-((li?,4i?)-4- butoxycyclohexyl)-4-(methoxymethyl)-2-propylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 4- Cyclopropyl-N-(6,7-difluoro-4-methylchroman-4-yl)-2-(methoxymethyl)pyrrolo[l,2- a]pyrimidine-8-carboxamide; 6-Fluoro-2,4-dimethyl-N-(4-(oxazol-4-yl)phenyl)pyrrolo[l,2- a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(3-(pent-4-yn-l-yloxy)cyclopentyl)pyrrolo[l,2- a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(4-(pentyloxy)phenyl)pyrrolo[l,2-a]pyrimidine- 8-carboxamide; 2,4-Dimethyl-N-(4-(oxazol-2-yl)phenyl)pyrrolo[l,2-a]pyrimidine-8- carboxamide; N-(6-(thiophen-2-yl)pyridin-3-yl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; N-(4- (Furan-2-yl)phenyl)-2,4-dimethylpyrrolo[l ,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(4- (pyridin-4-yl)phenyl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(4-(l -methyl- lH-pyrazol-4-yl)phenyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(4-Chloro-3-((pyridin-3- yloxy)methyl)phenyl)-2,4-dimethylpyrrolo[l,2-a]pyrimdine-8-carboxamide; N- (Benzo[d] [l ,3]dioxol-5-yl)-2,4-dimethylpyrrolo[l ,2-a]pyrimidine-8-carboxamide; 2,4- Dimethyl-N-(4-(piperidin-l -yl)phenyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(6-(3- Methoxyprop-l -yn-l -yl)pyridin-3-yl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(6-(l -methyl-lH-pyrazol-4-yl)pyridin-3-yl)pyrrolo[l,2-a]pyrimidine-8- carboxamide; 2,4-Dimethyl-N-(2-methyl-4,5,6,7-tetrahydrobenzo[d]oxazol-6-yl)pyrrolo[l ,2- a]pyrimidine-8-carboxamide; N-(3-Methoxy-2,3-dihydro-lH-inden-l -yl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-((li?,4i?)-4-Cyclopropoxycyclohexyl)- 2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(2-phenylbutan-2- yl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; N-((li?,4i?)-4-Isobutoxycyclohexyl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-((li?,4i?)-4-tert-Butoxycyclohexyl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-((li?,4i?)-4- propoxycyclohexyl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; (5 -N-(l-(2-Fluorophenyl)ethyl)- 2,4-dimethylpyrrolo[l ,2-a]pyrimidine-8-carboxamide; (5 -N-(l-(4-Fluorophenyl)ethyl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(2-(2-Chlorophenyl)propan-2-yl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide;_N-(2-(2,3-dihydrobenzo[ )] [l,4]dioxin-6- yl)propan-2-yl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; (i?)-2,4-dimethyl-N-(l- (naphthalen-l -yl)ethyl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; (i?)-N-(l -(4- chlorophenyl)ethyl)-2,4-dimethylpyrrolo[l ,2-a]pyrimidine-8-carboxamide; (5)-2,4-dimethyl-N- (l-(naphthalen-l-yl)ethyl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; (5 -N-(l -(2- methoxyphenyl)ethyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; (5 -N-(l-(3- chlorophenyl)ethyl)-2,4-dimethylpyrrolo[l ,2-a]pyrimidine-8-carboxamide; (i?)-N-(l-(2- methoxyphenyl)ethyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; (5 -2,4-dimethyl- N-(l -(/?-tolyl)ethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; (i?)-2,4-dimethyl-N-(l- (naphthalen-2-yl)ethyl)pyrrolo[l ,2-a]pyrimidine-8-carboxamide; (i?)-N-(l -(3- methoxyphenyl)ethyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; (5 -N-(l -(3- methoxyphenyl)ethyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(2-(3- chlorophenyl)propan-2-yl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(l-(4- ethylphenyl)ethyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(l- (benzo[(i| [l,3]dioxol-5-yl)ethyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide;

(^-N-(l-(4-chlorophenyl)ethyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide;

2,4-dimethyl-N-(l-(naphthalen-l-yl)ethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide;

2,4-dimethyl-N-(2-(naphthalen- 1 -yl)propan-2-yl)pyrrolo[ 1 ,2-a]pyrimidine-8-carboxamide; 2,4-dimethyl-N-(l-(l-methyl-lH-indol-3-yl)ethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-dimethyl-N-(l-(pyridin-3-yl)propyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide;

N-( 1 -(3,4-dihy dro-2H-benzo [b] [ 1 ,4] dioxepin-6-y l)ethy l)-2,4-dimethy lpyrrolo [ 1 ,2- a]pyrimidine-8-carboxamide; 2,4-dimethyl-N-(l-(6-methylpyridin-2-yl)propyl)pyrrolo[l,2- a]pyrimidine-8-carboxamide; N-(l-(4-fluorophenyl)propyl)-2,4-dimethylpyrrolo[l,2- a]pyrimidine-8-carboxamide; N-(l-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)propyl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(l-(4-chlorophenyl)propyl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(l-(3-fluoro-4-methoxyphenyl)ethyl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(l-(2,3-dihydrobenzo[i] [l,4]dioxin-6- yl)propyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-dimethyl-N-(l-(4,5,6,7- tetrahydrobenzo[(i]thiazol-2-yl)ethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-dimethyl- N-(l-(5-phenyloxazol-2-yl)ethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-dimethyl-N-(3- methyl-l-phenylbutyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(l-(2-(lH-pyrazol-l- yl)phenyl)ethyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(l-(4-(lH-pyrazol-l- yl)phenyl)ethyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(l-(3-cyclohexyl- l,2,4-oxadiazol-5-yl)ethyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(l-([l,l'- biphenyl]-2-yl)ethyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-dimethyl-N- (l-(l-phenylcyclopentyl)ethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(l-(5-fluoro-2- methoxyphenyl)ethyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(l-(3-(lH- pyrazol-l-yl)phenyl)ethyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(l-([l,l'- biphenyl]-4-yl)ethyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(l-(2- ethoxyphenyl)ethyl)-2,4-dimethylpyrrolo[l ,2-a]pyrimidine-8-carboxamide; 2,4-dimethyl-N-(l - (2-methyl-2,3-dihydrobenzofuran-5-yl)ethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide;

N-(l-(2,3-dihydrobenzo[ )] [l,4]dioxin-2-yl)ethyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8- carboxamide; N-(l-(4-methoxyphenyl)propyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8- carboxamide; (i?)-N-(l-(benzo[<i][l,3]dioxol-5-yl)ethyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine- 8-carboxamide; 2,4-dimethyl-N-(l-(3-methyl-2,3-dihydrobenzofuran-2-yl)ethyl)pyrrolo[l,2- a]pyrimidine-8-carboxamide; N-(l-(4-ethoxyphenyl)ethyl)-2,4-dimethylpyrrolo[l,2- a]pyrimidine-8-carboxamide; (i?)-2,4-dimethyl-N-(l -(5,6,7, 8-tetrahy dronaphthalen-1 - yl)ethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; N-(2-(3-chlorophenyl)propan-2-yl)-2,4- dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide; 2,4-dimethyl-N-(l-(4- propionamidophenyl)ethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; (5 -2,4-dimethyl-N-(l- (5,6,7,8-tetrahydronaphthalen-l-yl)ethyl)pyrrolo[l,2-a]pyrimidine-8-carboxamide; and N-(l-(3-chlorophenyl)propyl)-2,4-dimethylpyrrolo[l,2-a]pyrimidine-8-carboxamide.

EXAMPLE 2 - BIOLOGICAL ACTIVITY DATA FOR EXEMPLARY SUBSTITUTED PYRROLO[1,2- A] P YRIMIDINE AND RELATED ORGANIC COMPOUNDS

[00415] The ability of exemplary compounds to activate glucocerebrosidase (Gcase) was measured. Experimental procedures and results are provided below.

Part I: Assay Procedure

[00416] A 484 aliquot of a 1.0 mg/mL solution of phosphatidylserine (PS) (Sigma P7769) in chloroform was evaporated under a stream of nitrogen for 1 hour. The lipid film was dissolved over 4 minutes of vigorous vortexing in 40 mL of 176 mM K₂HPO₄/5O mM citric acid (pH 4.7) containing 7.5 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.

[00417] Test compounds were diluted to the desired concentrations with dimethylsulfoxide (DMSO) from 10 mM stocks, and 0.41 μΐ, of the DMSO compound mixture was added to 100 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 μΐ. of substrate solution with 25 μΐ. of

compound/Gcase/saposin mixture. The reaction proceeded for 15 minutes at room temperature and was stopped by adding 150 μΐ. of 1M glycine, pH 12.5. The endpoint of the reaction was monitored by measuring fluorescence intensity (excitation: 365 nm; emission: 440 nm) on a SpectraMax i3 instrument (Molecular Devices). Test compounds were screened at 1.0 and 0.1 μΜ final concentration, and subsequent 8-point dose response curves were obtained using 3- fold dilutions from a maximum final concentration of 5 μΜ.

Part II: Results

[00418] Exemplary tested compounds are listed in Table 7 and grouped according to their observed Gcase activation value; the GCase activation value is that observed when the test compound was used at a concentration of 1.0 μΜ. Group 1 compounds had a Gcase activation greater value than 60%. Group 2 compounds had a Gcase activation value in the range of 30% up to 60%. Group 3 compounds had a Gcase activation value less than 30%.

TABLE 7.





ı42

Isomer I

Isomer II

Isomer I

Isomer II

(.roup 3 ( (impounds

Isomer II

Isomer I

Isomer II

EXAMPLE 3 - PREPARATION OF SUBSTITUTED PYRAzoLO[l,5-a]PYRiMiDiNE AND RELATED ORGANIC COMPOUNDS

[00419] The synthesis of exemplary substituted pyrazolo[l,5-a]pyrirnidine and related organic compounds is described below.

PART 1 - PREPARATION OF ETHYL 5,7-DiMETHYLPYRAzoLO[l,5-a]PYRiMiDiNE-3-

CARBOXYLATE (1)

[00420] A mixture of ethyl 3 -amino- lH-pyrazole-4-carboxy late (2.0 g, 12.9 mmol) and pentane-2,4-dione (1.46 mL, 14.0 mmol) in acetic acid (10 mL) was refluxed for 16 h. The reaction mixture was cooled to room temperature and neutralized with saturated NaHCC , then extracted with ethyl acetate (3 x 100 mL). The organic layer was dried over sodium sulfate and the solvent removed under vacuum to give the title compound 1 (2.2 g, 78%) as an off-white solid. ^lH NMR (400 MHz, DMSO-c¾) 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) . PREPARATION OF 5,7-DIMETHYLPYRAZOLO[l,5-a]PYRIMIDINE-3-CARBOXYLIC ACID

[00421] To a solution of compound 1 (2.2 g, 10.0 mmol) in MeOH (15 mL) was added NaOH (5.67 mL, 7.2 M solution) and the reaction mixture heated at 80 °C for 5 h. Then, the reaction mixture was cooled and neutralized by 2M HCl. The solid precipitated out of 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%). ^l NMR (400 MHz, DMSO-c¾) 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)⁺.

PART 3 - PREPARATION OF 4-(ISOXAZOL-3- YL)ANILINE (3)

[00422] To a solution of 3-(4-nitrophenyl)isoxazole (500 mg, 2.63 mmol) in MeOH (30 mL) was added 10% Pd/C (70 mg, 10% wt) under nitrogen atmosphere at room temperature. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 14 h. Then, the reaction mixture was filtered, and the filtrate was concentrated under vacuum to afford the title compound 3 as a brown sticky oil (550 mg, 93%). ^XH NMR (400 MHz, DMSO- di) 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).

PART 4 - PREPARATION OF 4-(OXAZOL-4-YL)ANILINE (4)

[00423] To a solution of 4-(4-nitrophenyl)oxazole (500 mg, 2.60 mmol) in MeOH:THF (3:3 mL) was added 10% Pd/C (50 mg, 10% wt) under nitrogen atmosphere at room temperature. The reaction mixture was stirred under hydrogen atmosphere at room temperature for 16h. Then, the reaction mixture was filtered over a pad of celite, and the filtrate was concentrated under vacuum to afford crude compound. The crude compound was purified by FCC (eluent, 30% ethyl acetate in hexane) to afford the title compound 4 as light brown thick liquid (260 mg, 62%). ^XH NMR (400 MHz, DMSO-c¾) 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)⁺.

PART 5 - PREPARATION OF iV-(4-IODOPHENYL)-5,7-DiMETHYLPYRAzoLO[l,5-a]PYRiMiDiNE- 3-CARBOXAMIDE (5)

[00424] A solution of 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3-carboxylic acid 2 (1.5 g, 7.84 mmol) in DMF (7.5 mL) was charged with HATU (4.4 g, 11.7 mmol), DIPEA (4.2 mL, 23.5 mmol) and 4-iodoaniline (2.06 g, 9.4 mmol) at room temperature and stirred for 16 h. The reaction mixture was quenched with water (1 mL), the solid precipitated out was filtered and dried to obtain crude compound. The crude compound was purified by 100-200 mesh size silica gel column chromatography (eluent, 3-5% methanol in DCM) to afford the title compound 5 as a white solid (1.7 g, 56%). ^l NMR (400 MHz, CDC1₃) 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).

PART 6 - PREPARATION OF 5,7-DIMETHYL-A^-(4-(4,4,5,5-TETRAMETHYL- 1,3,2- DIOXABOROLAN-2-YL)PHENYL)PYRAZOLO[L,5-A]PYRIMIDINE-3-CARBOXAMIDE (6)

[00425] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxamide 5 (1 g, 2.5 mmol) in DMF (25 mL) was charged with bispinacolato diboron (1.3 g, 5.1 mmol), potassium acetate (736 mg, 7.5 mmol) and Pd(dppf)Cl₂ DCM adduct (204 mg, 0.25 mmol) under argon at room temperature. The reaction mixture was heated to 100°C for 2 h. The reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (3 X 30 mL) and concentrated under vacuum to obtain crude compound. The crude compound was purified by trituration in 10% ethanol: w-hexane to afford the title compound 6 as a brown solid (800 mg, 80%). ^XH NMR (400 MHz, CDC1₃) 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).

PART 7 - GENERAL PROCEDURE A (AMIDATION REACTION)

[00426] A mixture of 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3-carboxylic acid 2 (150 mg, 0.78 mmol), DIPEA (0.408 mL, 2.35 mmol) and HATU (300 mg, 0.78 mmol) was dissolved in DMF (4 mL) and stirred at room temperature (RT) for lh. Then, the corrersponding amine (0.78 mmol) was added to the reaction mixture and stirred at RT for 16 h. The reaction mixture was diluted with water and filtered off. The residue was further washed with water (3 x 20 mL) and recrystallized with ether to obtain a white solid compound.

PART 8 - GENERAL PROCEDURE B (AMIDATION REACTION)

[00427] To a stirred solution of amine (1.1 eq) in toluene (8 mL) was added Α1Μβ3 (2 M solution, 4 eq) at 0 °C and the mixture stirred at rt for 30 min. To this reaction mixture ethyl 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3-carboxylate 1 (1 eq) was added and the reaction mixture stirred at 110 °C for 18h or until starting material was consumed. The reaction was quenched with HC1 (1M, 0.5 mL) and extracted with ethyl acetate (3 X 10 mL) to obtained crude compound. The crude compound was purified by FCC (eluent, 2% MeOH in DCM) and further trituration with ether to afford the desired compound as a solid.

PART 9 - PREPARATION OF 5,7-DIMETHYL-A^-(5-ETHYNYLPYRIDIN-2-YL)PYRAZOLO[1,5- A]PYRIMIDINE-3-CARBOXAMIDE

[00428] Using general procedure B, the title compound was obtained as a white solid (20%). ^lH NMR (400 MHz, CDC1₃) 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%. PART 10 - PREPARATION OF 5,7-DIMETHYL-A^-(6-ETHYNYLPYRIDIN-3-YL)PYRAZOLO[1,5- A]PYRIMIDINE-3-CARBOXAMIDE

^{1 1} Using general procedure B, the title compound was obtained as a white solid (50%). ^lH NMR (400 MHz, DMSO-c¾) 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%.

PART 11 - PREPARATION OF A^-([1,1'-BIPHENYL]-4-YL)-5,7-DIMETHYLPYRAZOLO[1,5- A]PYRIMIDINE-3-CARBOXAMIDE

^{1 1} Using general procedure A, the title compound was obtained as a white solid (29 mg, 11%). ^XH NMR (400 MHz, CDC1₃) 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%.

PART 12 - PREPARATION OF A^-(4-(3-METHOXYPROP-1-YN-1-YL)PHENYL)-5,7- DIMETHYLPYRAZOLO[L,5-A]PYRIMIDINE-3-CARBOXAMIDE

[00431] Using general procedure A, the title compound was obtained as a white solid (39 mg, 15%). ^XH NMR (400 MHz, CDC1₃) 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 2.71 (s, 3 H). ES-MS m/z 335.15 (M+H)⁺. HPLC purity 95.1%.

PART 13 - PREPARATION OF 5,7-DIMETHYL-A^-(4-PHENOXYPHENYL)PYRAZOLO[1,5- A]PYRIMIDINE-3-CARBOXAMIDE

[00432] Using general procedure A, the title compound was obtained as an off-white solid (90 mg, 32%). ^XH NMR (400 MHz, CDC1₃) 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, 3 H). ES-MS m/z 359.20 (M+H)⁺. HPLC purity 98.3%.

PART 14 - PREPARATION OF 5,7-DiMETHYL-iV-(4-(lH-lMiDAzoL-l-

YL)PHENYL)PYRAZOLO[l,5-a]PY -3-CARBOXA

^{1 1} Using general procedure A, the title compound was obtained as an off-white solid (151 mg, 58%). ^XH NMR (400 MHz, CDC1₃) 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%.

PART 15 - PREPARATION OF 5,7-DIMETHYL-A^-(4-(THIAZOL-2-YL)PHENYL)PYRAZOLO[1,5- A]PYRIMIDINE-3-CARBOXAMIDE

[00434] Using general procedure A, the title compound was obtained as an off-white solid (90 mg, 33%). ^XH NMR (400 MHz, CDC1₃) 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, 3 H). ES-MS m/z 350.15 (M+H)⁺. HPLC purity 98.3%.

PART 16 - PREPARATION OF 5,7-DIMETHYL-A^-(4-ETHYNYL-2-METHOXYPHENYL)

P YRAZOLO [ L,5-A]P YRIMIDINE-3-CARBOXAMIDE

^{1 1} Using general procedure B, the title compound was obtained as a white solid (9%). ^XH NMR (400 MHz, CDC1₃) 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%.

PART 17 - PREPARATION OF 5,7-DIMETHYL-A^-(4-(ISOXAZOL-3-YL)PHENYL) PYRAZOLO[1,5- A]PYRIMIDINE-3-CARBOXAMIDE

[00436] Using general procedure B, the title compound was obtained as a white solid (27%). ^XH NMR (400 MHz, CDCI₃) 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 puirty 96.1%.

PART 18 - PREPARATION OF 5,7-DIMETHYL-A^-(4-(OXAZOL-4-YL)PHENYL)PYRAZOLO[1,5- A]PYRIMIDINE-3-CARBOXAMIDE

[00437] Using general procedure B, the title compound was obtained as a white solid (18%). ^XH NMR (400 MHz, CDC1₃) 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%.

PART 19 - PREPARATION OF 5,7-DIMETHYL-A^-(4-(OXAZOL-2-YL)PHENYL)PYRAZOLO[1,5- A]PYRIMIDINE-3-CARBOXAMIDE

[00438] Using general procedure B, the title compound was obtained as a white solid (10%). ^XH NMR (400 MHz, CDC1₃) 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%. PART 20 - PREPARATION OF A^-(4-ETHYNYLCYCLOHEXYL)-5,7-DIMETHYLPYRAZOLO[1,5- A]PYRIMIDINE-3-CARBOXAMIDE

[00439] A solution of 4-((tert-butoxycarbonyl)amino)cyclohexane-l-carboxylic acid (1 g, 4.11 mmol) and N,0-dimethyl hydroxyl amine hydrochloride (602 mg, 6.17 mmol) in DMF (10 mL) was charged with EDCI (955 mg, 6.16 mmol) and HOBt (277 mg, 2.05 mmol) and stirred at room temperature for 12 h. 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, 20-25% ethyl acetate in hexane) to afford fert-butyl (4-

(methoxy(methyl)carbamoyl) cyclohexyl)carbamate as a colorless liquid (133 mg, 68%). ^XH NMR (400 MHz, CDC1₃) 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)⁺.

[00440] A solution of fert-butyl (4-(methoxy(methyl)carbamoyl)cyclohexyl)carbamate (1.2 g, 4.19 mmol) in THF (30 mL) was charged at -70°C with lithium aluminum hydride (LAH) (1.75g, 4.60 mmol) portionwise. The reaction mixture was warmed to room temperature and stirred for 5h. 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 afford the crude compound which was purified by FCC (eluent, 15-20% ethyl acetate in hexane) to afford fert-butyl (4-formylcyclohexyl)carbamate (647 mg, 68%) as a yellow sticky oil which was used directly in the next step.

[00441] A solution of dimethyl (2-oxopropyl)phosphonate (219 mg, 1.32 mmol) in acetontrile (20 mL) was charged with 4-methylbenzenesulfonyl azide (260 mg, 1.32 mmol) and K₂CO₃ (485 mg, 3.52 mmol) and stirred at room temperature for 12h. To the resulting solution was added fert-butyl (4-formylcyclohexyl)carbamate (200 mg, 0.88 mmol) and stirred at room temperature for 12h. The reaction mixture was concentrated in vacuo, diluted with water (20 mL), extracted with ethyl acetate (3 X 15 mL), dried over Na₂SC>4 and concentrated in vacuo. The crude compound was purified by FCC (eluent, 15-20% ethyl acetate in hexane) to afford fert-butyl (4-ethynylcyclohexyl)carbamate as a colorless oil (133 mg, 68%).

[00442] A solution of fert-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 3h. The reaction mixture was comcentrated in vacuo and purified by trituration with w-pentane to afford 4-ethynylcyclohexan-l -amine as a yellow oil (120 mg, 87%).

[00443] A solution of 5,7-dimethylpyrazolo[l,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 min and charged with 4-ethynylcyclohexan-l -amine (92 mg, 0.75 mmol) and stirred for another 16 h at room temperature. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3 X 10 mL), dried over Na₂SC>4 and concentrated in vacuo. The crude compound which was purified by FCC (eluent, 2-4% methanol in DCM) to afford the title compound as a white solid (120 mg, 65%). ^XH NMR (400 MHz, CDC1₃) 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). ES-MS m/z 297.25 (M+H)⁺. HPLC purity 99.9%.

PART 21 - PREPARATION OF A^-(4-(ISOTHIAZOL-4-YL)PHENYL)-5,7- DIMETHYLPYRAZOLO[L,5-A]PYRIMIDINE-3-CARBOXAMIDE

[00444] A solution of 5,7-dimethyl-N-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)pyrazolo[l,5-a]pyrimidine-3-carboxarnide 6 (286 mg, 0.73 mmol) in DMF (5 mL) was charged 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 to 100°C for 16 h. The reaction mixture was quenched with water (5 mL), extracted with ethyl acetate (3 X 10 mL) and concentrated under vacuum to obtain crude compound. The crude compound was purified by FCC (eluent, 3-5% methanol in DCM) to afford the title compound as an off-white solid (50 mg, 23%). ^XH NMR (400 MHz, CDCI₃) 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%.

PART 22 - PREPARATION OF A^-(4-(ISOXAZOL-4-YL)PHENYL)-5,7-DIMETHYLPYRAZOLO[1,5- A]PYRIMIDINE-3-CARBOXAMIDE

[00445] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[l,5-a]pyrirnidine-3- carboxamide 5 (350 mg, 0.89 mmol), isoxazol-4-ylboronic acid (164 mg, 1.33 mmol), KF (155 mg, 2.67 mmol) in DMF was degassed with argon for 30 min. To the resulting solution was added Pd(dppf)Cl₂ (73 mg, 0.08 mmol) and the solution degassed for another 10 min in a sealed tube and heated to 50°C for 8h. The reaction mixture was cooled to room temperature, diluted with water and stirred for 15 min. The solid that precipitated out was filtered and dried to obtain crude compound which was purified by FCC (eluent, 2-4% methanol in DCM) to afford the title compound as a light grey solid (45 mg, 15%). ^XH NMR (400 MHz, CDC1₃) 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%.

PART 23 - PREPARATION OF A^-(3-CYCLOPROPYLISOXAZOL-5-YL)-5,7- DIMETHYLPYRAZOLO[L,5-A]PYRIMIDINE-3-CARBOXAMIDE

[00446] A solution of 5,7-dimethylpyrazolo[l,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 mmol). The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was concentrated in vacuo to afford 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3-carbonyl chloride as a brown solid (210 mg, 95%) which was used directly in the next step.

[00447] To a solution of 3-cyclopropylisoxazol-5-amine (136 mg, 1.09 mmol) and DIPEA (0.87 mL, 4.90 mmol) in THF (3 mL) at 0°C under argon atmosphere was added a solution of 5, 7-dimethylpyrazolo[l, 5-a]pyrimidine-3-carbonyl chloride 2 (210 mg, 0.95 mmol) in THF (2 mL). The reaction mixture was warmed to room temperature and stirred for 16 h. 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 sulphate 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 Ammonium formate in water + 0.1% ammonia, Mobile phase B - Acetonitrile + 0.1% ammonia; Gradient programme: 10% B to 50% B) to afford the title compound as an off-white solid (10 mg, 3%). ¾ NMR (400 MHz, DMSO-c¾) 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%.

PART 24 - PREPARATION OF 5,7-DIMETHYL-A^-(5-(1-(TRIFLUOROMETHYL)CYCLOPROPYL) ISOXAZOL-3-YL)PYRAZOLO[L,5-A]PYRIMIDINE-3-CARBOXAMIDE

[00448] A solution of 5-(l-(trifluoromethyl)cyclopropyl)isoxazol-3-amine (241 mg, 1.25 mmol) and DIPEA (0.91 mL, 5.20 mmol) in THF (3 mL) at 0°C under argon atmosphere was added to a solution of 5,7-dimethylpyrazolo[l,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 h. 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 sulphate and concentrated in vacuo to obtain crude product which was purified by FCC (eluent, 15-20% ethyl acetate in hexane) to afford the title compound as an off-white solid (180 mg, 47%). ^XH

NMR (400 MHz, CDC1₃) 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%.

PART 25 - PREPARATION OF iV-(4-(lH-PYRROL-2-YL)PHENYL)-5,7-DiMETHYLPYRAzoLO[l,5- a]PYRIMIDINE-3-CARBOXAMIDE

[00449] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxamide 5 (100 mg, 0.25 mmol) in DMF (2 mL) was charged with (l-(tert- butoxycarbonyl)-lH-pyrrol-2-yl)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 min and heated to 100°C for 30 h. Then, the reaction mixture was filtered through a pad of celite and washed with ethyl acetate (10 mL). The filtrate was washed with ice water (lOmL) and brine (10 mL) and concentrated in vacuo to obtain crude compound which was purified by FCC (eluent, 5-10% methanol in DCM) to afford the title compound as a white solid (50 mg, 59%). ¾ NMR (400 MHz, DMSO-c¾) 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%.

PART 26 - PREPARATION OF 5,7-DIMETHYL-A^-(6-(OXAZOL-4-YL)PYRIDIN-3- YL)P YRAZOLO [ 1 ,5-A] P YRIMIDINE-3-C ARBOXAMIDE

[00450] A solution of 5,7-dimethylpyrazolo[l,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-yl)pyridin-3-amine (45 mg, 0.27 mmol). The reaction mixture was warmed to room temperature and stirred for 16 h. 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 sulphate and concentrated in vacuo to obtain crude compound. The crude compound was purified by FCC (eluent, 1-3% methanol in DCM) to afford the title compound as a white solid (18 mg, 19%). ^l NMR (400 MHz, CDC1₃) 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%.

PART 27 - PREPARATION OF 5,7-DIMETHYL-A^-(6-(THIOPHEN-2-YL)PYRIDIN-3- YL)P YRAZOLO [ 1 ,5-A] P YRIMIDINE-3-C ARBOXAMIDE

[00451] A solution of 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3-carboxylic acid 1 (500 mg, 2.63 mmol), HATU (1.5 g, 3.94 mmol), DIPEA (1.2 mL, 7.89 mmol) in DMF (2 mL) was stirred at room temperature for 30 min and charged with 6-bromopyridin-3-amine (542 mg, 3.15 mmol) and stirred for another 16 h at room temperature. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 X 10 mL), dried over Na₂SC>4 and concentrated in vacuo. The crude compound was purified by FCC (eluent, 1-3% methanol in DCM) to afford N-(6-bromopyridin-3-yl)-5,7-dimethylpyrazolo[l,5-a]pyrirnidine-3- carboxamide as a yellow solid (510 mg, 56%). ^l NMR (400 MHz, CDC1₃) 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=8.8 Hz, 1H), 6.79 (s, 1H), 2.82 (s, 3H), 2.71 (s, 3H). ES-MS m/z 346.00(M+H)⁺.

[00452] A solution of N-(6-bromopyridin-3-yl)-5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxamide (150 mg, 0.43 mmol) in DMF (5 mL) was charged with 4,4,5,5-tetramethyl-2- (thiophen-2-yl)-l,3,2-dioxaborolane (136 mg, 0.65 mmol), K₂C0₃ (178 mg, 1.29 mmol), Pd(PPh₃)4 (49 mg, 0.042 mmol) and the reaction mixture was degassed with argon for 30 min and heated to 100°C for 30 h. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate (10 mL). The filtrate was washed with ice water (lOmL) and brine (10 mL) and concentrated under vacuum to obtain crude compound which was purified by trituration in methanol to afford the title compound as an off-white solid (30 mg, 20%). ^XH NMR (400 MHz, CDC1₃) δ 10.28 (br s, IH), 8.65 (s, IH), 8.62 (s, IH), 8.42 (d, J=8.5 Hz, IH), 7.61 (d, J=8.5 Hz, IH), 7.49 (d, J=2.2 Hz, IH), 7.29 (d, J=4.9 Hz, IH), 7.04 (t, J=4.3 Hz, IH), 6.72 (s, IH), 2.76 (s, 3H), 2.65 (s, 3H). ES-MS m/z 350.30 (M+H)⁺. HPLC purity 99.5%.

PART 28 - PREPARATION OF A^-([2,4'-BIPYRIDIN]-5-YL)-5,7-DIMETHYLPYRAZOLO[1,5- A]PYRIMIDINE-3-CARBOXAMIDE

[00453] A solution of N-(6-bromopyridin-3-yl)-5,7-dimethylpyrazolo[l,5-a]pyrirnidine-3- carboxamide (95 mg, 0.27 mmol) in DMF (5 mL) was charged with pyridin-4-ylboronic acid (40 mg, 0.32 mmol), K₂C0₃ (111 mg, 0.80 mmol), Pd(PPh₃)₄ (31 mg, 0.02 mmol) and the solution was degassed with argon for 30 min and heated to 100°C for 16 h. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate (10 mL). The filtrate was washed with ice cooled water (lOmL) and brine (10 mL) and concentrated in vacuo to obtain crude compound which was purified by trituration in methanol to afford the title compound as an off-white solid (30 mg, 32%). ^l NMR (400 MHz, CDC1₃) δ 10.41 (s, IH), 8.79 (d, J=2.69 Hz, IH), 8.61-8.68 (m, 3H), 8.56 (dd, J=2.47, 8.75 Hz, IH), 7.94 (d, J=6.28 Hz, 2H), 7.82 (d, J=8.53 Hz, IH), 6.76 (s, IH), 2.78 (s, 3H), 2.69 (s, 3H). ES-MS m/z 345.35 (M+H)⁺. HPLC purity 96.9%.

PART 29 - PREPARATION OF A^-(6-(FURAN-2-YL)PYRIDIN-3-YL)-5,7- DIMETHYLPYRAZOLO[L,5-A]PYRIMIDINE-3-CARBOXAMIDE

[00454] A solution of N-(6-bromopyridin-3-yl)-5,7-dimethylpyrazolo[l,5-a]pyrirnidine-3- carboxamide (150 mg, 0.43 mmol) in DMF (5 mL) was charged with furan-2-ylboronic acid (77 mg, 0.65 mmol), K₂C0₃ (178 mg, 1.29 mmol), Pd(PPh₃)₄ (49 mg, 0.042 mmol) and the mixture was degassed with argon for 30 min and heated to 100°C for 30 h. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate (10 mL). The filtrate was washed with ice water (lOmL) and brine (10 mL) and concentrated under vacuum to obtain crude compound which was purified by triturating in methanol to afford the title compound as brown solid (40 mg, 28%). ^lH NMR (400 MHz, CDC1₃) 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). ES-MS m/z 345.35 (M+H)⁺. HPLC purity 96.9%.

PART 30 - PREPARATION OF 5,7-DiMETHYL-iV-(6-(i-METHYL-lH-PYRAzoL-4-YL)PYRiDiN-3- YL)P YRAZOLO [ 1 ,5-a] P YRIMIDINE-3-C ARBOXAMIDE

[00455] A solution of N-(6-bromopyridin-3-yl)-5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxamide (95 mg, 0.27 mmol) in DMF (5 mL) was charged with l-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-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 min and heated to 100°C for 30 h. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate (10 mL). The filtrate was washed with ice water (lOmL) and brine (10 mL) and concentrated under vacuum to obtain crude compound which was purified by triturating in methanol to afford the title compound as an off white solid (35 mg, 36%). i NMR (400 MHz, CDC1₃) 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%. PART 31 - PREPARATION OF 5,7-DIMETHYL-A^-(4-(THIAZOL-4-YL)PHENYL)PYRAZOLO[1,5- A]PYRIMIDINE-3-CARBOXAMIDE

[00456] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[l,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 solution of CH₃CO₂K (126 mg, 1.28 mmol) in water (0.5 mL) and the mixture was degassed with argon for 30 min. 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 h. Then, the reaction mixture was filtered through a pad of celite and washed with an excess of DCM. The combined filtrate was concentrated in vacuo to obtain crude compound which was purified by FCC (eluent, 1-2% methanol in DCM) to afford the title compound as a light brown solid (45 mg, 20%). ^XH NMR (400 MHz, CDC1₃) 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%.

PART 32- PREPARATION OF iV-(lH-BENZ0[d]iMiDAZ0L-2-YL)-5,7-DiMETHYLPYRAZ0L0[l,5- a]PYRIMIDINE-3-CARBOXAMIDE

^{1 1} A solution of 5,7-dimethylpyrazolo[l,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 lH-benzo[d]imidazol-2-amine (83 mg, 0.62 mmol). The reaction mixture was warmed to room temperature and stirred for 16 h. 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 sulphate and concentrated in vacuo to obtain crude compound. The crude compound was purified by FCC (eluent, 1-3% methanol in DCM) to afford the title compound as a white solid (20 mg, 13%). ^XH NMR (400 MHz, CDC1₃) 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%.

PART 33 - PREPARATION OF 5,7-DIMETHYL-A^-(4-(3-(PIPERIDIN-1-YL)PROP-1-YN-1- YL)PHENYL)PYRAZOLO[L,5-A]PYRIMIDINE-3-CARBOXAMIDE

[00458] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxamide 5 (200 mg, 0.51 mmol), prop-2-yn-l-ol (0.04 mL, 0.61 mmol), Cul (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 16h. Then, the reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (3 X 10 mL), dried over Na2SC>4 and concentrated in vacuo to provide crude compound, which was purified by FCC (eluent, 0-3% methanol in DCM) to afford N-(4-(3 -hydroxy prop- 1- yn-l-yl)phenyl)-5,7-dimethylpyrazolo[l,5-a]pyrimidine-3-carboxamide as an off-white solid (60 mg, 37%). ^XH NMR (400 MHz, CDC1₃) 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)⁺.

[00459] A solution of N-(4-(3-hydroxyprop-l-yn-l-yl)phenyl)-5,7-dimethylpyrazolo[l,5- a]pyrirnidine-3-carboxarnide (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 to 40°C for 16 h. The reacton mixture was quenched with water (10 mL), extracted with ethyl acetate (3 X 15 mL), dried over Na2SC>4 and concentrated in vacuo. The crude compound which was purified by FCC (eluent, 0-3% methanol in DCM) to afford as an off white solid (22 mg, 15%). ¾ NMR (400 MHz, CDC1₃) 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%. PART 34 - PREPARATION OF A^-(4-(3-(DIMETHYLAMINO)PROP-1-YN-1-YL)PHENYL)-5,7-

DIMETHYLPYRAZOLO[l,5-a]PYRIMIDINE-3-CARBOXAMIDE

[00460] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxamide 5 (100 mg, 0.25 mmol), 3-bromoprop-l-yne (91 mg, 0.76 mmol), Cul (5 mg, 0.02 mmol) and PdCl₂(PPh₃)₂ (10 mg, 0.01 mmol) in 2M solution of Ν,Ν dimethyl amine in THF (5 mL) was heated in a sealed tube at 60°C for 16h. 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 Na₂SC>4 and concentrated in vacuo to obtain crude compound which was purified by FCC (eluent, 0-3% methanol in DCM) to afford the title compound as a light brown solid (56 mg, 63%). ^XH NMR (400 MHz, DMSO-c¾) 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%.

PART 35 - PREPARATION OF 5,7-DIMETHYL-A^-(4-(3-MORPHOLINOPROP-1-YN-1- YL)PHENYL)PYRAZOLO[L,5-A]PYRIMIDINE-3-CARBOXAMIDE

[00461] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxamide 5 (300 mg, 0.76 mmol), 3-bromoprop-l-yne (0.21 mL, 2.29 mmol), Cul (29 mg, 0.15 mmol) and PdCl₂(PPh₃)₂ (54 mg, 0.07 mmol) in 2M solution of morpholine in THF (10 mL) was heated in a sealed tube at 60°C for 4h. 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 sulphate and concentrated in vacuo to obtain crude compound which was purified by FCC (eluent, 0-3% methanol in DCM) to afford the title compound as an off-white solid (60 mg, 20%). ^XH NMR (400 MHz, CDC1₃) 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%.

PART 36 - PREPARATION OF V-(4-(lH-lMiDAzoL-2-YL)PHENYL)-5,7- DIMETHYLPYRAZOLO[l,5-a]PYRIMIDINE-3-CARBOXAMIDE

[00462] A solution of 5,7-dimethyl-N-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)pyrazolo[l,5-a]pyrimidine-3-carboxarnide 6 (440 mg, 1.12 mmol) in DMF (5 mL) was charged with 2-bromo-lH-imidazole (150 mg, 1.02 mmol), potassium carbonate (422 mg, 3.06 mmol) and the mixture was degassed with argon for 15 min. To the resulting solution was added Pd(PPh₃)₄ (117 mg, 0.10 mmol) and the reaction mixture was degassed for another 10 min and heated at 100°C for 15h. 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 sulphate and concentrated in vacuo to obtain crude compound. The crude compound was purified by FCC (eluent, 1-3% methanol in DCM) to afford the title compound as a white solid (40 mg, 12%). ¾ NMR (400 MHz, DMSO-c¾) 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%.

PART 37 - PREPARATION OF 5,7-DIMETHYL-A^-(4-(PIPERIDIN-1-YL)PHENYL) PYRAZOLO[1,5- A]PYRIMIDINE-3-CARBOXAMIDE

[00463] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxamide 5 (200 mg, 0.51 mmol) in toluene (8 mL) was charged with piperidine (0 0.61 mmol), bis(dibenzylideneacetone)palladium(0) (2 mg, 0.002 mmol) and the mixture degassed with argon for 30 min. DavePhos (2 mg, 0.005 mmol) and KO^lBu (114 mg, 1.02 mmol) were added and the mixtire was heated to 90°C for 16h. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate (3 X 10 mL). The combined filtrate was washed with water, dried over sodium sulphate and concentrated in vacuo to obtain crude compound which was purified by FCC (eluent, 1-2% methanol in DCM) to afford the title compound as a white solid (160 mg, 47%). ^XH NMR (400 MHz, DMSO-c¾) 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%.

PART 38 - PREPARATION OF 5,7-DIMETHYL-A^-(4-(PIPERAZIN-1-YL)PHENYL) PYRAZOLO[1,5- A]PYRIMIDINE-3-CARBOXAMIDE

[00464] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxamide 5 (500 mg, 1.27 mmol) in toluene (5 mL) was charged with fert-butyl piperazine- 1-carboxylate (283 mg, 1.53 mmol), Pd(dba)2 (3.5 mg, 0.006 mmol) and degassed with argon for 30 min. To the resulting solution was added t-BuOK (286 mg, 2.55 mmol) and DavePhos (5 mg, 0.01 mmol) and the mixture heated to 90°C for 16h. The reaction mixture was filtered through a pad of celite 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 sulphate and concentrated in vacuo to provide a crude compound which was then purified by FCC (eluent, 1-3% methanol in DCM) and triturated with methanol to afford tert- butyl 4-(4-(5,7-dimethylpyrazolo[l,5-a]pyrinddine-3-carboxamido)phenyl) piperazine-1- carboxylate as an off-white solid (380 mg, 36%). ES-MS m/z 451.40 (M+H)⁺.

[00465] A solution of fert-butyl 4-(4-(5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxamido)phenyl)piperazine-l-carboxylate (280 mg, 0.62 mmol) in DCM (8 mL) was charged with TFA (1.5 mL) and stirred at room temperature for 12h. Then, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3 X 10 mL), dried over Na₂SC>4 and concentrated in vacuo to provide a crude compound which was then purified by FCC (eluent, 1-3% methanol in DCM) and triturated with methanol to afford the title compound as an off-white solid (58 mg, 16%). ^lH NMR (400 MHz, DMSO-c¾) 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%.

PART 39 - PREPARATION OF V-(4-(lH-PYRAzoL-3-YL)PHENYL)-5,7-

DIMETHYLPYRAZOLO[l,5-a]PYRIMIDINE-3-CARBOXAMIDE

[00466] A solution of 5,7-dimethyl-N-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)pyrazolo[l,5-a]pyrimidine-3-carboxarnide 6 (320 mg, 0.80 mmol) in propanol / water (4: 1 mL) was charged with 5-bromo-lH-pyrazole (100 mg, 0.60 mmol), Ce2CC>3 (585 mg, 1.80 mmol) and the mixture was degassed with argon for 15 min. To the resulting solution was added PdCl₂(dppf) (49 mg, 0.60 mmol), and the resulting solution degassed for another 10 min and then heated at 100°C for 16h. Next, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3 X 10 mL), dried over sodium sulphate and concentrated in vacuo to provide a crude compound that was then purified by FCC (eluent, 1-3% methanol in DCM) and triturated with methanol to afford the title compound as a brown solid (25 mg, 11%). Ti NMR (400 MHz, DMSO-c¾) 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%. PART 40 - PREPARATION OF 5,7-DIMETHYL-A^-(4-(PENTYLOXY)PHENYL)PYRAZOLO[1,5- a]PYRIMIDINE-3-CARBOXAMIDE

[00467] A solution of 5,7-dimethylpyrazolo[l,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 h. The reaction mixture was quenched with water (2 mL), extracted with ethyl acetate (3 X 10 mL), dried over Na₂SC>4 and concentrated in vacuo to provide a crude product that was then purified by FCC (eluent, 5% methanol in DCM) to afford N-(4-hydroxyphenyl)-5,7-dimethylpyrazolo[l,5-a]pyrinddine-3-carboxamide as an off-white solid (284 mg, 64%). Ti NMR (400 MHz, DMSO-c¾) 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)⁺.

[00468] A solution of N-(4-hydroxyphenyl)-5,7-dimethylpyrazolo[l,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 to 100°C for 16 h. 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 Na₂SC>4 and

concentrated in vacuo to provide a crude product that was then purified by preparatory HPLC (Column: YMC triart; Dimensions: (20 X 250mm X 5μ size); Method: Mobile phase A - 5mM Ammonium formate in water + 0.1% ammonia, Mobile phase B - Acetonitrile + 0.1% ammonia; Gradient programme: 10% B to 50% B) to afford the title compound as a white solid (50 mg, 29%). ¾ NMR (400 MHz, DMSO-c¾) 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%. PART 41 - PREPARATION OF 5,7-DIMETHYL-A^-(4-(PROP-2-YN-1- YLOXY)PHENYL)PYRAZOLO[L,5-A]PYRIMIDINE-3-CARBOXAMIDE

[00469] A solution of N-(4-hydroxyphenyl)-5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxamide (50 mg, 0.17 mmol) in DMF (2 niL) was charged with potassium carbonate (36 mg, 0.26 mmol) and 80% propargyl bromide (0.04 mL, 0.26 mmol) at room temperature ans the reaction mixture was heated to 100°C for 12 h. Then, the reaction mixture was diluted with water (2 mL), extracted with ethyl acetate (3 X 10 mL), dried over Na₂SC>4 and concentrated in vacuo to provide a crude compound that was then purified by PREP HPLC (Column: YMC triart; Dimensions: (20 X 250mm X 5μ size); Method: Mobile phase A - 5mM Ammonium formate in water + 0.1% ammonia, Mobile phase B - Acetonitrile + 0.1% ammonia; Gradient programme: 10% B to 50% B) to afford the title compound as a white solid (34 mg, 61%). Ti NMR (400 MHz, DMSO-c¾) δ 10.05 (s, IH), 8.61 (s, IH), 7.67 (d, J=8.8 Hz, 2H), 7.18 (s, IH), 7.01 (d, J=8.8 Hz, 2H), 4.79 (s, 2H), 3.56 (s, IH), 2.77 (s, 3H), 2.70 (s, 3H). ES-MS m/z 321.20 (M+H)⁺. HPLC purity 99.7%.

PART 42 - PREPARATION OF 4-(4-(5,7-DiMETHYLPYRAzoLO[l,5-a]PYRiMiDiNE-3- CARBOXAMIDO)PHENYL)BUTANOIC ACID

[00470] A solution of 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3-carboxylic acid 2 (200 mg, 1.04 mmol) in DMF (5 mL) was charged with EDC.HC1 (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 mins. To the resulting solution was added methyl 4-(4-aminophenyl)butanoate (240 mg, 1.25 mmol) and the mixture was stirred at room temperature for 16h. Then, the reaction mixture was quenched with ice-cooled water (50 mL) and stirred for another 30 mins. The solid was collected by filtration and washed with water followed by w-hexane and dried to afford 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)⁺.

[00471] A solution of the ester 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 3h. Then, the reaction mixture was concentrated in vacuo to dryness and the residue was diluted with water and acidified (pH = 1) with 2N HC1. The resulting solution was stirred at room temperature for 30 mins. The solid was filtered, washed with water followed by w-hexane and dried to afford the title compound as a white solid (160 mg, 43% for 2 steps). ^l NMR (400 MHz, DMSO-c¾) 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%.

PART 43 - PREPARATION OF A^-(4-(1-HYDROXYETHYL)PHENYL)-5,7- DIMETHYLPYRAZOLO[L,5-A]PYRIMIDINE-3-CARBOXAMIDE

[00472] A solution of 5,7-dimethylpyrazolo[l,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 mins at room temperature. To the resulting solution was added l-(4-aminophenyl)ethan-l-ol (86 mg, 0.63 mmol) and the mixture stirred an additional 16 h. Then, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (3 X 10 mL) and the combined organic extracts were dried over sodium sulphate and concentrated in vacuo to provide a crude compound that was then purified by PREP TLC to afford the title compound as an off-white solid (49 mg, 30%). ^XH NMR (400 MHz, DMSO-c¾) 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%. PART 44 - PREPARATION OF 3-(4-(5,7-DiMETHYLPYRAzoLO[l,5-a]PYRiMiDiNE-3-

CARBOXAMIDO)PHENYL)PROPANOIC ACID

[00473] A solution of 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3-carboxylic acid 2 (250 mg, 1.31 mmol) in DMF (5 mL) was charged with EDC.HC1 (304 mg, 1.96 mmol), HOBT (299 mg, 1.96 mmol), NEt (0.54 mL, 3.93 mmol) and stirred at room temperature for 30 mins. To the resulting solution was added methyl 3-(4-aminophenyl)propanoate (259 mg, 1.44 mmol) and the mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with ice-cooled water (50 mL) and stirred for another 30 mins. The precipitated solid was collected by filtration, washed with water followed by w-hexane and dried to afford methyl 3- (4-(5,7-dimethylpyrazolo[l,5-a]pyrinddine-3-carboxamido)phenyl)propanoate as a light brown solid (350 mg, 76%), which was used in the next step without further purification. ^XH NMR (400 MHz, CDC1₃) 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)⁺.

[00474] A solution of methyl 3-(4-(5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxamido)phenyl)propanoate in THF:H₂0 (10: 10 mL) was charged with a solution of LiOH (51 mg, 2.13 mmol) and stirred at room temperature for 3h. Then, the reaction mixture was concentrated in vacuo, diluted with water and stirred at room temperature for 30 mins. The precipitated solid was collected by filtration, washed with water followed by w-hexane and dried to afford the title compound as a white solid (170 mg, 71%). ^XH NMR (400 MHz, DMSO-c¾) 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%. PART 45 - PREPARATION OF A^-(4-AZIDOPHENYL)-5,7-DIMETHYLPYRAZOLO[1,5- a]PYRIMIDINE-3-CARBOXAMIDE

[00475] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxamide 5 (50 mg, 0.13 mmol), Cul (2 mg, 0.01 mmol), NaN₃ (17 mg, 0.26 mmol) and sodium ascorbate (2 mg, 0.01 mmol) in EtOH: H₂0 (2 mL) was degassed with argon for 15 min. NN-dimethyl ethylenediamine (0.002 mL, 0.02 mmol) was added and the mixture was heated to 100°C for 50 min in a microwave. The reaction mixture was diluted with water (2 mL), extracted with ethyl acetate (3 X 10 mL), dried over sodium sulphate and concentrated in vacuo to provide a crude compound that was then purified by SFC purification (Column: Silica 2-ethyl pyridine; Dimensions: 30 X 250mm, 5μ size; Method: Mobile phase A - CO2, Mobile phase B - 5mM Ammonium formate in MeOH; Gradient Programme: 10% co-solvent to 50% maximum) to afford the title compound as a brown solid (24 mg, 62%). ^XH NMR (400 MHz, CDCI₃) δ 10.08 (br s, IH), 8.62 (s, IH), 7.68 (d, J=8.0 Hz, 2H), 6.96 (d, J=8.1 Hz, 2H), 6.70 (s, IH), 2.75 (s, 3H), 2.65 (s, 3H). ES-MS m/z 308.05 (M+H)⁺. HPLC purity 95.9%.

PART 46 - PREPARATION OF 5,7-DIMETHYL-A^-(4-(THIOPHEN-2-YL)PHENYL)PYRAZOLO[1,5- A]PYRIMIDINE-3-CARBOXAMIDE

[00476] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[l,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-yl)-l,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 min and heated to 100°C for 30 h. Then, the reaction mixture was filtered through a pad of celite and washed with ethyl acetate (10 mL). The filtrate was washed with ice cooled water (lOmL) and brine (10 mL) and concentrated in vacuo to provide a crude compound that was then purified by FCC (eluent, 5-10% methanol in DCM) to afford the title compound as a brown solid (40 mg, 45%). ^XH NMR (400 MHz, CDC1₃) 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%.

PART 47 - PREPARATION OF 5,7-DiMETHYL-iV-(2-METHYL-lH-iNDOL-5-YL)PYRAzoLO[l,5- a]PYRIMIDINE-3-CARBOXAMIDE

[00477] To a stirred solution of 5,7-dimethylpyrazolo[l,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) in 1 mL of DMF was added 2-methyl-lH-indol-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 prep-HPLC (MeCN/10 mM NH₄HCO₃) to provide the title compound as a yellow solid (13.1 mg, 15.6%). ^XH 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%; t_R = 1.71 mm.

PART 48 - PREPARATION OF V-(lH-lNDAzoL-5-YL)-5,7-DiMETHYLPYRAzoLO[l,5- a]PYRIMIDINE-3-CARBOXAMIDE

[00478] To a stirred solution of 5,7-dimethylpyrazolo[l,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) was added 1H- indazol-5 -amine (42 mg, 0.314 mmol). 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), EtjO (2 niL) and dried to provide the title compound (20 mg, 25.0%) as a white solid. ^XH NMR (400 MHz, DMSO) <5 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%; t_R = 1.54 min.

PART 49 - PREPARATION OF V-(lH-lNDAzoL-6-YL)-5,7-DiMETHYLPYRAzoLO[l,5- a]PYRIMIDINE-3-CARBOXAMIDE

[00479] To a stirred solution of 5,7-dimethylpyrazolo[l,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) in 1 mL of DMF was added lH-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 H₂0, DCM and diethyl ether to provide the title compound (51 mg, 63.7%) as a brown solid. ^lH 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 %; t_R = 1.45 min.

PART 50 - PREPARATION OF iV-(2H-l,3-BENzoDioxoL-5-YL)-5,7-DiMETHYLPYRAzoLO[l,5- a]PYRIMIDINE-3-CARBOXAMIDE

[00480] To a stirred solution of 5,7-dimethylpyrazolo[l,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) in 1 mL of DMF was added 2H-l,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 prep-HPLC

(MeCN/NH₄HC0₃) to provide the title compound as a white solid (16.8 mg, 23%). ^l 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%; t_R = 1.72 min.

PART 51 - PREPARATION OF A^-(2-METHYL-1,3-BENZODIOXOL-6-YL)-5,7- DIMETHYLPYRAZOLO[L,5-A]PYRIMIDINE-3-CARBOXAMIDE

[00481] To a stirred solution of 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.262 mmol), 2-methyl-l,3-benzoxazol-6-amine (47 mg, 0.314 mmol) and HATU (149 mg, 0.393 mmol) in DMF (1 mL) was added DIPEA (0.1 mL, 0.524 mmol), and the reaction mixture was stirred at room temperature for 16 hours until the reaction was complete. The suspension was diluted with H₂0 (3 mL), and the precipitated solid was collected by filtration, washed with minimum DCM and Et^O, and dried in vacuo to provide the title compound (60 mg, 71%) as a white solid. ^l NMR (400 MHz, DMSO-c¾) 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%; t_R = 1.74 min.

PART 52- PREPARATION OF 5,7-DiMETHYL-iV-(2-METHYL-lH-l,3-BENzoDiAzoL-6-

YL)P YRAZOLO [ 1 ,5-a] P YRIMIDINE-3-C ARBOXAMIDE

[00482] To a stirred solution of 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.262 mmol), 2-methyl-lH-l,3-benzodiazol-6-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 room temperature for 16 hours until the reaction was complete. The suspension was diluted with H₂0 (3 mL), and the precipitated solid was collected by filtration, washed with minimum DCM and Et₂0, and purified by prep-HPLC (MeCN/10 mM NH₄HCO₃) to give the title compound (28 mg, 33%) as a white solid. ^XH NMR (400 MHz, DMSO-c¾) 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%; t_R = 1.46 min.

PART 53 - PREPARATION OF 5,7-DIMETHYL-A^-(1,2,3,4-TETRAHYDROISOQUINOLIN-6- YL)P YRAZOLO [ 1 ,5-A] P YRIMIDINE-3-C ARBOXAMIDE

[00483] To a mixture of 6-nitro-l,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 B0C₂O (168 mg, 0.772 mmol), and the reaction mixture was stirred at room temperature for 2 h 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 Mg₂S0₄ and concentrated to give crude tert-butyl 6-nitro-l,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%; t_R = 2.00 min.

[00484] To the suspension of tert-butyl 6-nitro-l,2,3,4-tetrahydroquinoline-2-carboxylate (220 mg, 0.772 mmol) and NH₄CI (330 mg, 6.176 mmol) in 6 mL of EtOH and 4 mL of H₂0 was added Fe powder (173 mg, 3.088 mmol) in portions. The reaction mixture was stirred at 70 °C for 2 h, cooled down to room temperature and then filtered through Celite. The filter cake was washed with ethanol. The orange solution was concentrated, and the residue was purified by prep-HPLC (MeCN/10 mM NH₄HCO₃) to give tert-butyl 6-amino- 1,2,3,4- tetrahydroquinoline-2-carboxylate as an oil (150 mg, 78% 2 steps). ^XH NMR (400 MHz, CDCI₃) 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).

[00485] To a stirred solution of 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3-carboxylic acid 2 (65 mg, 0.340 mmol), tert-butyl 6-amino-l,2,3,4-tetrahydroquinoline-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 prep-HPLC (MeCN/10 mM

NH₄HCO₃) to give 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%; t_R = 1.93 min. This boc protected derivative of the title compound was converted to the title compound using the procedure below.

[00486] TFA (0.5 mL) was added to the boc protected derivative of the title compound from the procedure above (64 mg, 0.152 mmol) at 0 °C. The mixture was stirred at room temperature for 2 hours, diluted with DCM, and basified to pH ~8 with saturated NaHCCb. The resulting mixture was separated, and the aqueous phase was extracted with DCM. The combined organic phases were dried over anhydrous Na₂SC>4, and concentrated in vacuo to provide a residue that was then purified by prep-HPLC (MeCN/10 mM NH₄HCO₃) to provide the title compound (24 mg, 51%) as a white solid. ^l NMR (400 MHz, DMSO-c¾) 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%; t_R = 1.51 min.

PART 54 - PREPARATION OF /V-(1,2-BENZOXAZOL-5-YL)-5,7-DIMETHYLPYRAZOLO[1,5- A]PYRIMIDINE-3-CARBOXAMIDE

[00487] To an ice cold stirred solution of SnCl₄ (1.828 g, 7.02 mmol) in 12M HC1 (0.5 mL) was added 5-nitro-l,2-benzoxazol (140 mg, 0.86 mmol) in one portion at 0 °C. 5 minutes later, a solution of SnCl₂.2H₂0 (792 mg, 3.51 mmol) in 12M HC1 (0.5 mL) was added dropwise at 0 °C, followed by the addition of another 1.0 mL of 12M HC1. Then the reaction mixture was stirred at room temperature for 3 hours, and extracted with Et^O. The aqueous layer was basified to pH ~8 with saturated NaHCC , and extracted with EtOAc. The organic phase was dried over anhydrous Na₂SC>4, filtered, concentrated and dried in vacuo to give 1 ,2-benzoxazol- 5-amine as a colorless solid (110 mg, 95%). ¾ NMR (400 MHz, CDC1₃) 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%; t_R = 1.32 min.

[00488] To a solution of 5,7-dimethylpyrazolo[l,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 2 hours until the reaction was complete. The suspension was diluted with H₂0 (3 mL), and the precipitated solid was collected by filtration, washed with minimum DCM and Et^O, and dried in vacuo to give the ester compound (105 mg, 65%) as a white solid. ES-MS m/z: 310.0 [M+H]⁺. LC-MS Purity (254 nm): 88%; = 1.61 min. The ester compound was used in the procedure below.

[00489] To a suspension of the ester compound from the procedure above (105 mg, 0.340 mmol) in DMF (0.5 mL) was added a solution of l,2-benoxazol-5-amine (46 mg, 0.340 mmol) in DMF (0.5 mL). The reaction mixture was stirred at room temperature for 2 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 NaHCCb to pH ~8. The aqueous layer was extracted with DCM, dried over anhydrous Na2SC filtered and

concentrated to provide a residue. The residue was purified by prep-HPLC (MeCN/H₂0) to provide the title compound (40 mg, 38%) as a white solid. ^XH NMR (400 MHz, CDC1₃) 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%; t_R = 9.36 min.

PART 55 - PREPARATION OF A/-[2-(FuRAN-2-YL)-lH-l,3-BENzoDiAzoL-5-YL]-5,7-

DIMETHYLPYRAZOLO[l,5-a]PYRIMIDINE-3-CARBOXAMIDE

[00490] A mixture of 4-nitrobenzene-l,2-diamine (1.53 g, 10 mmol), furan-2-carbaldehyde (1.22 g, 13.0 mmol), />-benzoquinone (1.19 g, 11 mmol) and 2-propanol (15 mL) in a sealed tube was refluxed for 2 hours. The reaction was diluted with water, filtrated and dried in vacuo to give 2-(furan-2-yl)-5-nitro-lH-l,3-benzodiazole as a yellow solid (1.2 g, 52%). LC-MS m/z: 234 (M+H) ⁺. LC-MS Purity (214 nm): >90%. [00491] A suspension of 2-(furan-2-yl)-5-nitro-lH-l,3-benzodiazole (1.2 g, 5.15 mmol) and 10% PdVC (120 mg) in EtOH (10 mL) was stirred at room temperature under H₂ for 2 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-yl)-lH-l,3- benzodiazol-5 -amine as a yellow solid (870 mg, 83%). ^lH NMR (400 MHz, DMSO-c¾) 5 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 %.

[00492] To a stirred solution of 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.262 mmol), 2-(furan-2-yl)-lH-l,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 room temperature for 16 hours until the reaction was complete. The suspension was diluted with H₂0 (3 mL), and the precipitated solid was collected by filtration, washed with minimum DCM and Et₂0, and dried in vacuo to give the title compound (73 mg, 75%) as a white solid. ^l NMR (400 MHz, DMSO-c¾) 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 = 3.6 Hz, 2.0 Hz, 1H), 2.77 (s, 3H), 2.73 (s, 3H). ES-MS m/z: 373.0 [M+H] ⁺. LC-MS Purity (254 nm): 96%; t_R = 1.62 min.

PART 56 - PREPARATION OF /V-(2-METHYL-1,3-BENZOTHIAZOL-6-YL)-5,7- DIMETHYLPYRAZOLO[L,5-A]PYRIMIDINE-3-CARBOXAMIDE

[00493] To a stirred solution of 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.262 mmol), 2-methyl-l,3-benzothiazol-6-amine (51 mg, 0.314 mmol) and HATU (149 mg, 0.393 mmol) in DMF (1 mL) was added DIPEA (0.1 mL, 0.524 mmol), and the reaction mixture was stirred at room temperature for 16 hours until the reaction was complete. The suspension was diluted with H₂0 (3 mL), and the precipitated solid was collected by filtration, washed with minimum DCM and Et₂0, and dried in vacuo to give the title compound as a white solid (53 mg, 60%). ^l NMR (400 MHz, DMSO-c¾) 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%; t_R = 1.75 min.

PART 57 - PREPARATION OF A^-(2-3-DIHYDRO-1H-INDEN-5-YL)-5,7- DIMETHYLPYRAZOLO[L,5-A]PYRIMIDINE-3-CARBOXAMIDE

[00494] To a stirred solution of 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.262 mmol), 2,3-dihydro-lH-inden-5-amine (42 mg, 0.314 mmol) and HATU (149 mg, 0.393 mmol) in DMF (1 mL) was added DIPEA (0.1 mL, 0.524 mmol), and the reaction mixture was stirred at room temperature for 16 hours until the reaction was complete. The reaction mixture was purified by reverse phase chromatography (MeCN/10 mM NH₄HCO₃) to give the title compound (37 mg, 46%) as a white solid. ^XH NMR (400 MHz, DMSO-c¾) 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%; t_R = 1.98 min.

PART 58- PREPARATION OF A^-{4-CHLORO-3-[(PYRIDIN-3-YLOXY)METHYL]PHENYL}-5,7- DIMETHYLPYRAZOLO[L,5-A]PYRIMIDINE-3-CARBOXAMIDE

[00495] 2-Chloro-5-nitrobenzaldeyhde (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 resultant reaction mixture was then stirred for one hour, acidified with 2N HC1 and left to stir overnight. The mixture was concentrated in vacuo, and the resulting solids were filtered then washed with water and dried in vacuo to give (2-chloro-5-nitrophenyl)methanol (9.3 g, 92%) as a white solid. ^XH NMR (400 MHz, OMSO-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%; t_R = 1.60 min.

[00496] To an ice cold solution of (2-chloro-5-nitrophenyl)methanol (1.82 g, 9.8 mmol) in DCM (60 mL) was added triphenylphosphine (2.62 g, 10 mmol), followed by CBr₄ (3.26 g, 9.8 mmol). The reaction mixture was stirred at room temnperature for 24 hours, and then diluted with DCM, washed with water and saturated brine solution. The organic layer was separated, dried (MgSC ), filtered, and concentrated in vacuo to provide a residue. The residue was purified by silica gel column (EA/PE: 1/10) to afford 2-(bromomethyl)-l-chloro-4- nitrobenzene (1.56 g, 64%). ¾ NMR (400 MHz, DMSO-c¾) 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%; t_R= 1.95 min.

[00497] To an ice cold suspension of NaH (60%, 110 mg, 2.75 mmol) in anhydrous DMF (1 mL) was added dropwise the solution of 3-hydroxypyridine (250 mg, 2.65 mmol) in DMF (2 mL. After the mixture was stirring at 0 °C for 15 minutes, a solution of 2-(bromomethyl)-l- chloro-4-nitrobenzene (610 mg, 2.45 mmol) 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 solution, dried over anhydrous (MgSC^), filtered, and concentrated in vacuo to provide a residue. The residue was purified by silica gel column (EA/PE: 1/1) to afford 3-[(2-chloro-5- nitrophenyl)methoxy]pyridine (350 mg, 54%) as a cream solid. ^l NMR (400 MHz, DMSO- <¾) 5 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%; t_R = 1.80 min.

[00498] To a suspension of 3-[(2-chloro-5-nitrophenyl)methoxy]pyridine (320 mg, 1.212 mmol) and NH₄CI (513 mg, 9.696 mmol) in 9 mL of EtOH and 6 mL of H₂O was added Fe powder (272 mg, 4.85 mmol) in portions. The reaction mixture was stirred at 80 °C for 3 hours, cooled down to room temperature and then filtered through Celite. The filter cake was washed with ethanol. The orange solution was concentrated in vacuo, and the residue was dissolved in DCM, washed with saturated NaHCC . The organic phase was dried over anhydrous Na₂SC>4, filtered and concentrated in vacuo. The residue was purified by silica gel column (EA/PE: 3/1) to afford 4-chloro-3-[(pyridin-3-yloxy)methyl)]aniline (167 mg, 59%) as a white solid. ^XH NMR (400 MHz, OMSO-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).

[00499] To a stirred solution of 5,7-dimethylpyrazolo[l,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) was added DIPEA (0.1 mL, 0.524 mmol), and the reaction mixture was stirred at room temperature for 16 hours, 45 °C for 2 hours and 60 °C for 2 hours until the reaction was complete. The suspension was diluted with H2O (3 mL), and the precipitated solid was collected by filtration, washed with minimum DCM and Et^O, and dried in vacuo to provide the title compound (57 mg, 53%) as a pale white solid. ^XH NMR (400 MHz, DMSO-c¾) 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%; t_R = 1.89 min.

PART 59 - PREPARATION OF 5,7-DIMETHYL-A^-{4-METHYL-3-(1,3-OXAZOL-2- YL)PHENYL]PYRAZOLO[L,5-A]PYRIMIDINE-3-CARBOXAMIDE

[00500] A suspension of 3-bromo-4-methylaniline (184 mg, 1.0 mmol), 2-(tributylstannyl)- 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 on microwave synthesizer to provide a crude product. The crude product was purified by prep-HPLC

(MeCN/10 mM NH₄HCO₃) to give 4-methyl-3-(l,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%; t_R= 1.31 min.

[00501] A mixture of 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3-carboxylic acid 2 (50 mg,

0.26 mmol), 4-methyl-3-(l,3-oxazol-2-yl)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), Et^O (2 mL) and dried in vacuo to give the title compound (62 mg, 68.0%) as a white solid. ^XH 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%; t_R = 1.91 min.

PART 60 - PREPARATION OF 5,7-DiMETHYL-iV-(4-(l-METHYL-lH-PYRAzoL-4-

YL)PHENYL)PYRAZOLO[l,5-a]PYRIMIDINE-3-CARBOXAMIDE

[00502] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxamide 5 (100 mg, 0.25 mmol) in DMF (2 mL) was charged with l-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-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 min and heated to 100°C for 30 h. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate (10 mL). The filtrate was washed with ice cooled water (lOmL) and brine (10 mL) and concentrated in vacuo to provide a crude compound. The crude compound was purified by FCC (eluent, 5-10% methanol in DCM) to afford the title compound as an off- white solid (35 mg, 39%). ¾ NMR (400 MHz, CDC1₃) 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%.

PART 61 - PREPARATION OF A^-(4-(FURAN-2-YL)PHENYL)-5,7-DIMETHYLPYRAZOLO[1,5- a]PYRIMIDINE-3-CARBOXAMIDE

[00503] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxamide 5 (100 mg, 0.25 mmol) in DMF (2 mL) was charged with furan-2-ylboronic acid (34 mg, 0.31 mmol), K₂C0₃ (105 mg, 0.76 mmol), Pd(PPh₃)₄ (29 mg, 0.025 mmol) and the reaction mixture was degassed with argon for 30 min and heated to 100°C for 30 h. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate (10 mL). The filtrate was washed with ice water (lOmL) and brine (10 mL) and concentrated in vacuo to obtain crude compound which was purified by FCC (eluent, 5-10% methanol in DCM) to afford the title compound as a yellow solid (30 mg, 35%). ^l NMR (400 MHz, CDC1₃) 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%.

PART 62 - PREPARATION OF 5,7-DIMETHYL-A^-(4-(P YRIDIN-4- YL)PHENYL)P YRAZOLO [1,5- A]PYRIMIDINE-3-CARBOXAMIDE

[00504] A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxamide 5 (100 mg, 0.25 mmol) in DMF (2 mL) was charged with pyridin-4-ylboronic acid (37 mg, 0.31 mmol), K₂C0₃ (105 mg, 0.76 mmol), Pd(PPh₃)₄ (29 mg, 0.025 mmol) and the reaction mixture was degassed with argon for 30 min and heated to 100°C for 30 h. Then, the reaction mixture was filtered through a pad of celite and washed with ethyl acetate (10 mL). The filtrate was washed with ice cooled water (lOmL) and brine (10 mL) and concentrated in vacuo to obtain crude compound which was purified by FCC (eluent, 5-10% methanol in DCM) to afford the title compound as a white solid (40 mg, 46%). ^XH NMR (400 MHz, CDC1₃) δ 10.26 (s, IH), 8.64 (s, IH), 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, IH), 2.77 (s, 3H), 2.68 (s, 3H). ES-MS m/z 344.15 (M+H)⁺. HPLC purity 92.4%.

PART 63 - PREPARATION OF ADDITIONAL PYRAzoLO[l,5-a]PYRiMiDiNE-3-CARBOXAMiDES

[00505] Additional pyrazolo[l,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 the preparation of 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[l,5- a]pyrimidine-3-carboxarnide compounds prepared according to the general procedures are provided in Part IV below.

Part I - General Procedures

[00506] To a stirred solution of carboxylic acid compound (1.0 equivalent), HATU (1.5 equivalents), and DIPEA (3.75 equivalents) in DCM or DMF (~4 mL/0.2 mmol) was added amine compound (1.25 - 2.0 equivalents). The reaction mixture was stirred at room

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

Compound

[00507] To a solution of carboxylic ester (1.0 equivalent) in EtOH (5.0 mL/1.0 mmol) and water (0-3.0 mL/1.0 mmol) was added NaOH (2.0-5.0 equivalents) and the mixture was heated at 80 °C for 2 hours and then concentrated. To the concentrate, 6N HC1 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 give the carboxylic acid compound. General Procedure C: Preparation of Amide from a Carboxylic Acid Compound and Amine Compound

[00508] 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 the addition of amine compound (5.0 equivalents) and triethylamine (2.0 equivalents). The reaction mixture was stirred at RT for 2 hours and then diluted with DCM (10 mL/0.5 mmol). The organic solution was washed sequentially with H₂0 (10 mL/0.5 mmol) and brine (10 mL/0.5 mmol), then dried over anhydrous Na₂SC>4, and next filtered. The filtrate was concentrated in vacuo, and the resulting residue was purified by preparatory HPLC or silica gel chromatography to give the amide compound.

Part II - Preparation of Specific Amine Compounds

[00509] Exemplary procedures for preparing specific amine compounds used in the preparation of certain pyrazolo[l,5-a]pyrimidine-3-carboxarnide compounds are provided below.

l-(4,4-Difluorocvclohexyl)ethan-l-amine

[00510] To a solution of 4,4-difluorocyclohexane-l-carboxylic acid (1.64 g, 10 mmol) and DIPEA (2.58 g, 20 mmol) in DMF (10 mL) at 0 °C was added HATU (5.7 g, 15 mmol) and the reaction mixture was stirred at 0 °C for 30 min, followed by the addition of Ν,Ο- dimethylhydroxylamine hydrochloride (970 mg, 10 mmol). The reaction mixture was allowed to warm to RT and stirred overnight, then quenched with saturated NaHCC solution, and separated. The aqueous phase was extracted with EtOAc (100 mL x3), and the combined organic phases were dried over Na₂SC>4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (PE/EtOAc; 4: 1) to afford 4,4-difluoro-N- methoxy-N-methylcyclohexane-l-carboxamide (880 mg, 42 %) as a colorless oil. LC-MS m/z: 208.0 [M+H]⁺. LCMS: t_R = 1.58 min. [00511] To a solution of 4,4-difluoro-N-methoxy-N-methylcyclohexane-l-carboxamide (880 mg, 4.25 mmol) in THF (12 mL) was added a solution of MeLi in 1,2-diethoxy ethane (3 mol/L, 2 mL) dropwise at 0 °C. After the addition was complete, the reaction mixture was allowed to warm to RT and stirred overnight, then quenched with saturated NH₄C1 solution and separated. The aqueous phase was extracted with EtOAc (120 mL x 3), and the combined organic phases were dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (PE/EA = 4: 1) to afford l-(4,4-difluorocyclohexyl)ethan-l-one (400mg, 43 %) as a light yellow oil. ^XH NMR (500 MHz, CDC1₃) 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).

[00512] A mixture of l-(4,4-difluorocyclohexyl)ethan-l-one ( (200 mg, 1.23 mmol), NH₄OAc (1.9 g, 24.6 mmol) and NaBH₃CN (388 mg, 6.15 mmol) in i-PrOH (15 mL) was stirred at RT for 4 h and then at 90 °C for 2 h. Then, the reaction mixture was poured into water (15 mL), extracted with CH2CI2 (30 ml, x3) and dried over Na2SC>4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (EtOAc/MeOH; 10: 1) to afford l-(4,4-difluorocyclohexyl)ethan-l -amine as a colorless oil. LC-MS m/z: 164.1 [M+H]⁺. LCMS: t_R = 1.13 min.

2-(4-Chlorophenyl)propan-2- amine

[00513] MgBrMe (3M in THF, 5 mL, 15 mmol) was added dropwise at RT to a solution of l-(4-chlorophenyl)ethan-l-one (1.54 g, 10 mol) in Et₂0 (60 mL). After the addition was complete the reaction mixture was stirred at RT for 12 hours and then quenched by the careful addition of saturated NH₄C1 solution (30 mL). The resulting mixture was stirred for 1 hour and then extracted with EtOAc (100 mL χ 3). The combined organic layers were dried over Na₂SC>4, filtered, concentrated in vacuo, and purified by silica gel chromatography (PE/EtOAc;

5: 1) to give 2-(4-chlorophenyl)propan-2-ol (1.365 g, 80%) as a colorless oil. ^XH NMR (400 MHz, CDCI₃) 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). [00514] A mixture of 2-(4-chlorophenyl)propan-2-ol (1.36 g, 8 mmol), TMSN₃ (2.4 g, 16 mmol) and BF₃ Et20 (16 mL) in CH2CI2 (20 mL) was stirred at RT for 2 h and quenched with saturated NaHC0₃ solution. The resulting mixture was separated, and the aqueous phase was extracted with CH2CI2 (30 mL χ 3). The combined organic phases were dried over Na2SC>4 and filtered. The filtrate was concentrated in vacuo to afford the target compound l-(2- azidopropan-2-yl)-4-chlorobenzene as 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 %; t_R= 1.44 min.

[00515] 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 2 h 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 CH2CI2, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the resulting residue was purified by reversed-phase

chromatography (0.05%TFA/MeCN) to give the desired product 2-(4-chlorophenyl)propan-2- amine (200 mg, 57% over two steps) as a pale oil. LC-MS m/z: 153.0 [M - NH₂]⁺. LCMS: Purity (214 nm): 98%; t_R= 1.71 min.

Part III - Preparation of Specific Carboxylic Acid Compounds

[00516] Exemplary procedures for preparing specific carboxylic acid compounds used in the preparation of certain substituted pyrazolo[l,5-a]pyrimidine compounds are provided below.

7-Chloro-5-methylpyrazolo [ 1 ,5-«l pyrimidine-3-carb oxylic acid

[00517] To a solution of ethyl 3-amino-lH-pyrazole-4-carboxylate (10 g, 64.5 mmol) in HOAc (50 mL) was added 4-methyleneoxetan-2-one (27 g, 322.5 mmol). The mixture was stirred at 110 °C for 2 h, cooled and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (PE/EA; 10:3) to afford ethyl 7-hydroxy-5- methylpyrazolo[l,5-a]pyrimidine-3-carboxylate (8.0 g, 57%) and ethyl 5-hydroxy-7- methylpyrazolo[l,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%, t_R= 1.26 min; 5-hydroxy product: LC-MS m/z: 221.0 [M+H]⁺, Purity (214 nm): >92%, t_R= 1.46 min.

[00518] A solution of ethyl 7-hydroxy-5-methylpyrazolo[l,5-a]pyrimidine-3-carboxylate (4.4 g, 20 mmol) in POCI₃ (30 mL) was stirred at 95 °C for 1 h and concentrated in vacuo. The residue was dissolved in EtOAc (20 mL) and basified with sat. NaHCCb 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 Na₂SC and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE/EA; 1 : 1) to give ethyl 7-chloro-5-methylpyrazolo[l,5-a]pyrimidine-3- carboxylate (1.0 g, 21%) as a white solid. LC-MS m/z: 239.0 [M+H]⁺, Purity (254 nm): >82%, = 1.55 min.

[00519] To a solution of ethyl 7-chloro-5-methylpyrazolo[l,5-a]pyrimidine-3-carboxylate (1.0 g, 4.18 mmol) in toluene (10 mL) was added (Bu3Sn)₂0 (5.0 g, 8.36 mmol). 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 sat. NaHC0₃ solution (10 mL) to pH~8-9. The aqueous phase was separated and acidified with 6N HC1 (10 mL) to pH~5. The solution was extracted with EtOAc (10 mL x 3). The organic phases were dried over anhydrous Na₂S0₄, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE/EA; 1 : 1) to give 7-chloro-5-methylpyrazolo[l,5-a]pyrimidine-3- carboxylic acid (230 mg, 26%) as a white solid. LC-MS m/z: 211.0 [M+H]⁺, Purity (214 nm): >97%, t_R= 1.23min.

5-Chloro-7-methylpyrazolo[l,5-alpyrimidine-3-carboxylic acid

[00520] A solution of ethyl 5-hydroxy-7-methylpyrazolo[l,5-a]pyrimidine-3-carboxylate (2.8 g, 12.6 mmol) in POCI₃ (30 mL) was stirred at 70 °C for 2 h and concentrated in vacuo. The resulting residue was dissolved in EtOAc (20 mL) and basified with sat. NaHC03 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 Na₂SC>4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE/EA; 1 : 1) to give ethyl 5-chloro-7-methylpyrazolo[l,5- a]pyrimidine-3-carboxylate (2.7 g, 90%) as a white solid. LC-MS m/z: 239.0 [M+H]⁺, Purity (214 nm) : >99%, t_R= 1.74 min.

[00521] To a solution of ethyl 5-chloro-7-methylpyrazolo[l,5-a]pyrimidine-3-carboxylate (1.0 g, 4.18 mmol) in toluene (10 mL) was added (Bu₃Sn)₂0 (5.0 g, 8.36 mmol). 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 sat. NaHCCb solution (10 mL) to pH~8-9. The aqueous phase was separated and acidified with 6N HC1 (10 mL) to pH~5. The solution was extracted with EtOAc (10 mL x 3). The organic phases were dried over anhydrous Na₂S0₄, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE/EA; 1 : 1) to give 5-chloro-7-methylpyrazolo[l,5-a]pyrimidine-3- carboxylic acid (330 mg, 37%) as a white solid. LC-MS m/z: 211.0 [M+H]⁺, Purity (214 nm): >97%, t_R= 1.28 min.

Part IV - Pyrazolo[l,5-a]pyrimidine-3-carboxamide Compounds Prepared Following General Procedures

[00522] The following compounds were prepared based on the general procedures described in Part I above.

5,7-Dimethyl-A/-(l,2,3.,4-tetrahvdronaphthalen-l-yl)pyrazolo[l,5-alpyrimidine-3- carboxamide

[00523] Following general procedure A, 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxylic acid (40 mg, 0.21 mmol) and 1,2,3,4-tetrahydronaphthalen-l-amine afforded the title compound (37 mg, 55%) as a yellow solid. ^l NMR (500 MHz, CDC1₃): δ 8.68 (s, 1H),8.42 (d, J= 8.5 Hz, 1H), 7.47 (d, J= 7.0 Hz, 1H), 7.18-7.13 (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 %; t_R= 8.26 min. 5,7-Dimethyl-A/-((li?,4i?)-4-(pentyloxy)cvclohexyl)pyrazolo[l,5-alpyrimidine-3- carboxamide

[00524] Following general procedure A, 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxylic acid (24 mg, 0.125 mmol) and (li?,4i?)-4-(pentyloxy)cyclohexan-l-amine afforded the title compound (29 mg, 64%) as a white solid. ^XH NMR (400 MHz, MeOO-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 %; t_R = 9.262 min.

(.S^-A/-(l-(2-Fluorophenyl)ethyl)-5 -dimethylpyrazolo[l,5-alpyrimidine-3-carboxamide

[00525] Following general procedure A, 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxylic acid (40 mg, 0.21 mmol) and (,S)-l -(2-fluorophenyl)ethan-l -amine afforded the title compound (34.3 mg, 49%) as a white solid. ^XH NMR (400 MHz, MeOD-c¾) 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%; t_R = 9.85 min. .S^-A/-(l-(2-Methoxyphenyl)ethyl)-5 -dimethylpyrazolo[l,5-alpyrimidine-3-carboxamide

[00526] Following general procedure A, 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxylic acid (25 mg, 0.13 mmol) and (5 -l-(2-methoxyphenyl)ethan-l-amine afforded the title compound (21.6 mg, 51%) as a yellow solid. ^l NMR (500 MHz, CDC1₃): 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 %; t_R= 9.82 min.

(i?)-A/-(l-(2-Methoxyphenyl)ethyl)-5 -dimethylpyrazolo[l,5-alpyrimidine-3-carboxamide

[00527] Following general procedure A, 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxylic acid (30 mg, 0.15 mmol) and (i?)-l-(2-methoxyphenyl)ethan-l -amine afforded the title compound (19.7 mg, 40%) as a pink solid. ^l NMR (500 MHz, DMSO-i¾): 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%; t_R = 9.82 min. .S^-A/-(l-(3-Chlorophenyl)ethyl)-5 -dimethylpyrazolo[l,5-alpyrimidine-3-carboxamide

[00528] Following general procedure A, 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxylic acid (40 mg, 0.21 mmol) and (5 -l-(3-chlorophenyl)ethan-l-amine afforded the title compound (26.1 mg, 38%) as a white solid. ^l NMR (400 MHz, MeOO-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 %; t_R = 10.24 min.

(i?)-A/-(l-(4-Chlorophenyl)ethyl)-5 -dimethylpyrazolo[l,5-alpyrimidine-3-carboxamide

[00529] Following general procedure A, 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxylic acid (38 mg, 0.20 mmol) and (i?)-l-(4-chlorophenyl)ethan-l -amine afforded the title compound (18 mg, 26%) as a white solid. ^l NMR (500 MHz, DMSO-i¾): 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 %; t_R = 10.32 min.

(i?)-jV-(l-(4-Fluorophenyl)ethyl)-5 -dimethylpyrazolo[l,5-alpyrimidine-3-carboxamide

[00530] Following general procedure A, 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxylic acid (30 mg, 0.16 mmol) and (i?)-l-(4-fluorophenyl)ethan-l -amine afforded the title compound (26.7 mg, 53%) as a white solid. ^l NMR (500 MHz, CDC1₃): 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%; t_R = 9.82 min.

A/-(l-(4,4-Difluorocvclohexyl)ethyl)-5,7-dimethylpyrazolo[l,5-alpyrimidine-3- carboxamide

[00531] Following general procedure A, 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxylic acid (20 mg, 0.1 mmol) and l-(4,4-difluorocyclohexyl)ethan-l-amine afforded the title compound (10 mg, 30%) as a white solid. ^l NMR (500 MHz, CDC1₃) 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%; t_R = 7.95 min.

A/-(2-(4-Chlorophenyl)propan-2-yl)-5,7-dimethylpyrazolo[l,5-alpyrimidine-3- carboxamide

[00532] Following general procedure A, 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxylic acid (40 mg, 0.21 mmol) and 2-(4-chlorophenyl)propan-2-amine afforded the title compound (23.5 mg, 33%) as a white solid. ^l NMR (500 MHz, DMSO-i¾): 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%; t_R= 8.99 min.

7-Chloro-A/-(2-(4-chlorophenyl)propan-2-yl)-5-methylpyrazolo[l,5-alpyrimidine-3- carboxamide

[00533] Following general procedure C, 7-chloro-5-methylpyrazolo[l,5-a]pyrimidine-3- carboxylic acid (100 mg, 0.47 mmol) and 2-(4-chlorophenyl)propan-2-amine afforded the title compound (40 mg, 23%) as a white solid. ^l NMR (500 MHz, OMSO-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%; t_R= 9.02 min.

5-Chloro-A/-(2-(4-chlorophenyl)propan-2-yl)-7-methylpyrazolo[l,5-alpyrimidine-3- carboxamide

Following general procedure C, 5-chloro-7-methylpyrazolo[l,5-a]pyrimidine-3-carboxylic acid (100 mg, 0.47 mmol) and 2-(4-chlorophenyl)propan-2-amine afforded the title compound (60 mg, 35%) as a white solid. ^XH NMR (500 MHz, DMSO-i¾) 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%; t_R = 9.44 min.

A/-(2-(2,4-Difluorophenyl)propan-2-yl)-5,7-dimethylpyrazolo[l,5-alpyrimidine-3- carboxamide

[00534] Following general procedure A, 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxylic acid (19 mg, 0.1 mmol) and 2-(2,4-difluorophenyl)propan-2-amine afforded the title compound (20 mg, 58) as a white solid. ^l NMR (500 MHz, CDC1₃) 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%; t_R = 8.62 min.

A/-( -((li?,4i?)-4-Methoxycvclohexyl)propan-2-yl)-5,7-dimethylpyrazolo[l,5-alpyrimidine- 3-carboxamide and jV-( -((l 4,SV4-Methoxycvclohexyl)propan-2-yl)-5.,7- dimethylpyrazolo[l,5-«lpyrimidine-3-carboxamide

[00535] Following general procedure A, 5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxylic acid (50 mg, 0.26 mmol) and 2-(4-methoxycyclohexyl)propan-2-amine afforded N- (2-((li?,4i?)-4-methoxycyclohexyl)propan-2-yl)-5,7-dimethylpyrazolo[l ,5-a]pyrimidine-3- carboxamide (7.2 mg) and N-(2-((15',45)-4-methoxycyclohexyl)propan-2-yl)-5,7- dimethylpyrazolo[l,5-a]pyrimidine-3-carboxarnide (8.4 mg) as white solids.

[00536] N-(2-((li?.4i?)-4-Methoxycvclohexyl)propan-2-yl)-5.7-dimethylpyrazolori .5- alpyrimidine-3-carboxamide: ^XH NMR (500 MHz, MeOD-c¾) δ 8.46 (s, 1H), 8.43 (s, 1H), 7.02 (s, 1H), 3.37 (s, 3H), 3.22-3.17 (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%; t_R= 8.08 min.

[00537] N-(2-((1^.4y)-4-Methoxycvclohexynpropan-2-ylV5.7-dimethylpyrazolori.5- alpyrimidine-3-carboxamide: ^XH NMR (500 MHz, DMSO-c¾) 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%; t_R = 8.46 min.

PART 64 - PREPARATION OF ADDITIONAL PYRAzoLO[l,5-a]PYRiMiDiNE-3-CARBOXAMiDES

[00538] The following additional pyrazolo[l,5-a]pyrirnidine-3-carboxarnide compounds were prepared based procedures described above:

EXAMPLE 4 - BIOLOGICAL ACTIVITY DATA FOR EXEMPLARY SUBSTITUTED PYRAZOLO[1,5- A] P YRIMIDINE AND RELATED ORGANIC COMPOUNDS

[00539] The ability of exemplary compounds to activate glucocerebrosidase (Gcase) was measured. Experimental procedures and results are provided below.

Part I: Assay Procedure

[00540] A 484 aliquot of a 1.0 mg/mL solution of phosphatidylserine (PS) (Sigma P7769) in chloroform was evaporated under a stream of nitrogen for 1 hour. The lipid film was dissolved over 4 minutes of vigorous vortexing in 40 mL of 176 mM K₂HPO₄/5O mM citric acid (pH 4.7) containing 7.5 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.

[00541] Test compounds were diluted to the desired concentrations with dimethylsulfoxide (DMSO) from 10 mM stocks, and 0.41 μΐ, of the DMSO compound mixture was added to 100 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 of substrate solution with 25 of

compound/Gcase/saposin mixture. The reaction proceeded for 15 minutes at room temperature and was stopped by adding 150 of 1M glycine, pH 12.5. The endpoint of the reaction was monitored by measuring fluorescence intensity (excitation: 365 nm; emission: 440 nm) on a SpectraMax i3 instrument (Molecular Devices). Test compounds were screened at 1.0 and 0.1 μΜ final concentration, and subsequent 8-point dose response curves were obtained using 3- fold dilutions from a maximum final concentration of 5 μΜ.

Part II: Results

[00542] Gcase activation values for tested compounds are provided in Table 8 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 μΜ, the symbol "+" indicates less than 30% Gcase activation; the symbol "++" indicates Gcase activation in the range of 30% up 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 μΜ, the symbol "*" indicates less than 10% Gcase activation; the symbol "**" indicates Gcase activation in the range of 10% up to 20%; and the symbol "***"indicates greater than 20% Gcase activation.

TABLE 8.

EXAMPLE 5 - PREPARATION OF SUBSTITUTED lMiDAzo[l,5-a]PYRiMiDiNE AND RELATED ORGANIC COMPOUNDS

[00543] The synthesis of exemplary substituted imidazo[l,5-a]pyrimidine and related organic compounds is described below.

PART 1 - PREPARATION OF 2,4-DIMETHYLIMIDAZO [!,5-a]PYRiMiDiNE-8-CARBOXAMiDE (1)

[00544] A solution of pentane-2,4-dione (1.5 g, 11.8 mmol) in MeOH (10 mL) was charged with acetic acid (10 mL) and 4-amino-lH-imidazole-5-carboxarnide (1.8 g, 17.8 mmol) at room temperature. The resulting solution was heated to 80°C for 5 h. The reaction mixture was concentrated in vacuo to dryness to obtain crude residue which was triturated with diethyl ether to afford compound 1 as a yellow solid (2 g, 88%). ^l NMR (400 MHz, DMSO-c¾) δ 8.37 (s, 2H), 7.21(s, 1H), 6.81 (s, 1H), 2.63 (s, 3H), 2.50 (s, 3H). ES-MS m/z 191.00 (M+H)⁺.

PART 2 - PREPARATION OF ETHYL 2,4-DiMETHYLiMiDAzo[l,5-a]PYRiMiDiNE-8-

CARBOXYLATE (2)

[00545] A solution of 2,4-dimethylimidazo[l,5-a]pyrimidine-8-carboxarnide 1 ( 7 g, 36.8 mmol) in POCI₃ (140 mL) was heated to reflux at 80°C for 3 h. The reaction mixture was concentrated in vacuo to obtain a crude residue which was diluted with water (50 mL), basified with saturated NaHCCb solution and extracted with dichloromethane (DCM) (3 x 50 mL). The combined organic layer was dried over sodium sulfate and the solvent removed under vacuum to give a yellow solid which was dissolved in ethanol (100 mL) and added to cone. H2SO4 (10 mL) and heated to 80°C for 16 h. Then, the solvent was removed under vacuum to remove ethanol, diluted with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was dried over sodium sulfate and the solvent removed under vacuum to obtain crude compound. The crude compound was purified by FCC (eluent, 3-5% methanol in DCM) to afford compound 2 as a yellow solid ( 7 g, 52%). ^l NMR (400 MHz, CDC1₃) δ 7.97 (s, 1H), 6.56 (s, 1H), 4.50 (q, J=6.80 Hz, 2H), 2.67 (s, 3H), 2.66 (s, 3H), 1.47 (t, J=7.60 Hz, 3H).

PART 3 - PREPARATION OF 2,4-DiMETHYLiMiDAzo[l,5-a]PYRiMiDiNE-8-CARBOXYLic ACID (3)

^{1 1} A solution of ethyl 2,4-dimethylimidazo[l,5-a]pyrirnidine-8-carboxylate 2 (150 mg, 0.68 mmol) in THF:H₂0 (10:2 mL) was charged with LiOH (33 mg, 1.36 mmol) at room temperature. The reaction mixture was heated to reflux at 50°C for 16 h. Then, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The separated aqueous layer was acidified (pH=5) with acetic acid and extracted with 10% methanol in DCM (3 x 10 mL). The combined organic layer was dried over sodium sulfate and the solvent removed under vacuum to afford compound 3 as an off-white solid (60 mg, 45%). ^XH NMR (400 MHz, DMSO): δ 8.22 (s, 1H), 6.70 (s, 1H), 2.61 (s, 3H), 2.48 (s, 3H). ES-MS m/z 192.00 [M+H]⁺.

PART 4 - PREPARATION OF iV-(4-IODOPHENYL)-2,4-DiMETHYLiMiDAzo[l,5-a]PYRiMiDiNE-8-

CARBOXAMIDE (4)

[00547] A solution of 4-iodoaniline (299 mg, 1.14 mmol) in toluene (4 mL) at 0°C was charged with a 2M solution of trimethyl aluminum in toluene (2.2 mL, 5.6 mmol) and stirred at 0°C for 30 min. To the resulting solution was added a solution of ethyl 2,4- dimethylimidazo[l,5-a]pyrirnidine-8-carboxylate 2 (250 mg, 1.14 mmol) in toluene (1 mL) and stirred for 10 min. The reaction mixture was heated to 120°C for 16 h. Then, the reaction mixture was quenched with IN HC1 and extracted with ethyl acetate (2 x 10 mL) to obtain crude compound. The crude compound was purified by FCC (eluent, 2-4% methanol in DCM) to afford product 4 as an off-white solid (260 mg, 58%). ^l NMR (400 MHz, CDC1₃) δ 9.84 (br s, 1H), 8.00 (s, 1H), 7.63-7.67 (m, 2H), 7.57-7.61 (m, 2H), 6.56 (s, 1H), 2.68 (s, 3H), 2.66 (s, 3H). ES-MS m/z 393.00 (M+H)⁺.

PART 5 - PREPARATION OF A^-(4-ETHYNYLPHENYL)-2,4-DIMETHYLIMIDAZO[1,5- A]PYRIMIDINE-8-CARBOXAMIDE

[00548] A solution of 2,4-dimethylimidazo[l,5-a]pyrirnidine-8-carboxylic acid 3 (57 mg, 0.29 mmol) in DMF (0.5 mL) was charged with HATU (165 mg, 0.43 mmol), DIPEA (0.15 mL, 0.87 mmol) and 4-ethynylaniline (42 mg, 0.35 mmol) at room temperature and stirred for 48 h. Then, the reaction mixture was quenched with water (1 mL), the solid precipitated out was filtered and dried to obtain crude compound. The crude compound was purified by washing with methanol to afford the title compound as an off-white solid (40 mg, 46%). ^XH NMR (400 MHz, DMSO-c¾) δ 10.34 (s, 1H), 8.47 (s, 1H), 7.84 (d, J=8.53 Hz, 2H), 7.46 (d, J=8.53 Hz, 2H), 6.90 (s, 1H), 4.08 (s, 1H), 2.70 (s, 3H), 2.60 (s, 3H). ES-MS m/z 291.10 (M+H)⁺. HPLC purity 99.6%.

PART 6 - PREPARATION OF A^-(4-(3-METHOXYPROP-1-YN-1-YL)PHENYL)-2,4- DIMETHYLIMIDAZO[L,5-A]PYRIMIDINE-8-CARBOXAMIDE

[00549] A solution of N-(4-iodophenyl)-2,4-dimethylinddazo[l,5-a]pyrimidine-8- carboxamide 4 (100 mg, 0.25 mmol) in DMF (1 mL) was purged with argon for 15 min. To the resulting solution was added 3-methoxyprop-l-yne (47 mg, 0.68 mmol), copper iodide (1 mg, 0.05 mmol), triphenyl phosphine (13 mg, 0.05 mmol), triethylamine (0.1 mL, 0.075 mmol) and catalyst PdCl₂(PPh₃)₂ (3.5 mg, 0.05 mmol) and purged with argon for another 30 min. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 10 mL) to obtain crude compound. The crude compound was purified by supercritical fluid chromatograph (SFC) (Column: Silica 2- ethyl pyridine; Dimensions: 30 X 250mm, 5μ size; Method: Mobile phase A - CO2, Mobile phase B - 5mM Ammonium formate in MeOH; Gradient Programme: 10% co-solvent to 50% maximum) to afford the title compound as a yellow solid (40 mg, 47%). ^XH NMR (400 MHz, CDCI₃) δ 9.94 (s, 1H), 8.00 (s, 1H), 7.76 (d, J=8.57 Hz, 2H), 7.45 (d, J=9.00 Hz, 2H), 6.55 (d, J=0.86 Hz, 1H), 4.33 (s, 2H), 3.46 (s, 3H), 2.68 (s, 3H), 2.66 (s, 3H). ES-MS m/z

335.20(M+H)⁺. HPLC purity 97.7%.

PART 7 - ADDITIONAL iMiDAzo[l,5-a]PYRiMiDiNE-8-CARBOXAMiDE COMPOUNDS

[00550] Using the general procedures described in Part I below, additional imidazo[l,5- a]pyrirnidine-8-carboxarnide compounds were prepared. These addition imidazo[l,5- a]pyrirnidine-8-carboxarnide compounds prepared are listed in Part II below.

Part I - General Procedures

[00551] To a stirred solution of carboxylic acid compound (1.0 equivalent), HATU (1.5 equivalents), and DIPEA (3.75 equivalents) in DCM or DMF (~4 mL/0.2 mmol) was added amine compound (1.25 - 2.0 equivalents). The reaction mixture was stirred at room temperature for 4-16 hours, and then washed with saturated aqueous NaHCCb solution (5 mL/0.2 mmol), aqueous citric acid solution (5 mL/0.2 mmol) and brine (5 mL/0.2 mmol). The combined extracts were dried over anhydrous Na₂SC>4, filtered and concentrated in vacuo. The resulting crude material was purified by silica gel column chromatography or preparatory HPLC to give the amide compound.

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

[00552] To a solution of carboxylic ester (1.0 equivalent) in EtOH (5.0 mL/1.0 mmol) and water (0-3.0 mL/1.0 mmol) was added NaOH (2.0-5.0 equivalents) and the mixture was heated at 80 °C for 2 hours and then concentrated. To the concentrate, 6N HC1 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 give the carboxylic acid compound.

[00553] 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 the addition of amine compound (5.0 equivalents) and triethylamine (2.0 equivalents). The reaction mixture was stirred at RT for 2 hours and then diluted with DCM (10 mL/0.5 mmol). The organic solution was washed sequentially with ¾() (10 mL/0.5 mmol) and brine (10 mL/0.5 mmol), then dried over anhydrous Na₂SC>4, and next filtered. The filtrate was concentrated in vacuo, and the resulting residue was purified by preparatory HPLC or silica gel chromatography to give the amide compound.

Part II - Compounds Prepared Following General Procedures

[00554] The following compounds were prepared based on the general procedures described in Part I above.

4-isoPropyl-2-methyl-A/-((li?,4i?)-4-(pentyloxy)cvclohexyl)imidazo[l,5-alpyrimidine-8- carboxamide

[00555] Following general procedure A, 4-isopropyl-2-methylinridazolo[l,5-a]pyrinridine-8- carboxylic acid (40 mg, 0.18 mmol) and (li?,4i?)-4-(pentyloxy)cyclohexan-l -amine afforded the title compound (14 mg, 21%) as a yellow solid. ^l NMR (500 MHz, CDC1₃): δ 8.02 (s, 1H), 7.82 (d, J= 10.0 Hz, 1H), 6.48 (s, 1H), 4.11-4.07 (m, 1H), 3.45 (t, J= 8.5 Hz, 2H), 3.32- 3.25 (m, 2H), 2.61 (s, 3H), 2.20-2.17 (m, 2H), 2.07-2.04 (m, 2H), 1.61-1.51 (m, 2H), 1.49-1.37 (m, 7H), 1.34-1.26 (m, 7H), 0.91 (d, J= 8.5 Hz, 3H). LC-MS m/z: 387.2 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_R= 9.19 min. A/-(2 -Dihvdro-lH-inden-4-yl)-4-isopropyl-2-methylimidazo[l,5-alpyrimidine-8- carboxamide

[00556] Following general procedure C, 4-isopropyl-2-methylimidazolo[l,5-a]pyrimidine-8- carboxylic acid (40 mg, 0.18 mmol) and 2,3-dihydro-lH-inden-4-amine afforded the title compound (23 mg, 38%) as a yellow solid. ^l NMR (500 MHz, CDC1₃): δ 9.97 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.10 (s, 1H), 7.21 (t, J = 7.0 Hz, 1H), 6.99 (d, J= 7.5 Hz, 1H), 6.54 (s, 1H), 3.35-3.29 (m, 1H), 3.07 (t, J = 7.0 Hz, 2H), 2.99 (t, J = 7.0 Hz, 2H), 2.67 (s, 3H), 2.20-2.14 (m, 2H), 1.48 (d, J= 6.5Hz, 6H). LC-MS m/z: 335.2 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_R = 8.81 min.

4-Cvclopropyl-2-(methoxymethyl)-A/-(2-(3-propoxyphenyl)propan-2-yl)imidazo[l,5- alpyrimidine-8-carboxamide

[00557] Following general procedure B, ethyl 4-cyclopropyl-2- (methoxymethyl)imidazo[l,5-a]pyrimidine-8-carboxylate (774 mg, 2.81 mmol) afforded 4- cyclopropyl-2-(methoxymethyl)irnidazo[l,5-a]pyrimidine-8-carboxylic acid (225 mg, 33%) as a white solid. LC-MS m/z: 248.1 [M+H]⁺.

[00558] Following general procedure A, 4-cyclopropyl-2-(methoxymethyl)imidazo[l,5- a]pyrimidine-8-carboxylic acid (20 mg, 0.08 mmol) and 2-(3-propoxyphenyl)propan-2-amine afforded the title compound (11.7 mg, 36%) as a yellow oil. ^XH NMR (500 MHz, CDC1₃): δ 8.72 (s, 1H), 8.59 (s, 1H), 7.24 (t, J= 8.0 Hz, 1H), 7.08-7.05 (m, 2H), 6.80 (d, J= 2.0 Hz, 1H), 6.78 (s, 1H), 4.57 (s, 2H), 3.91 (t, J= 6.0 Hz, 2H), 3.49 (s, 3H), 2.45-2.42 (m, 1H), 1.86 (s, 6H), 1.79-1.75 (m, 2H), 1.37-1.34 (m, 2H), 1.11-1.09 (m, 2H), 1.02 (t, J= 7.5 Hz, 3H). LC- MS m/z: 423.3 [M+H]⁺. HPLC Purity (214 nm): >99%; t_R = 10.51 min.

PART 8 - ADDITIONAL COMPOUNDS

[00559] The following additional compounds were prepared based on procedures described above and in the detailed description:

2,4-Dimethyl-N-(4-(oxazol-4-yl)phenyl)imidazo[l,5-a]pyrirnidine-8-carboxamide; 2,4- Dimethyl-N-(4-(oxazol-2-yl)phenyl)imidazo[l,5-a]pyrirnidine-8-carboxamide; N-(6- Ethynylpyridin-3-yl)-2,4-dimethylimidazo[l,5-a]pyrirnidine-8-carboxamide; 2,4-Dimethyl-N- (5-methyl-lH-imidazol-2-yl)imidazo[l,5-a]pyrirnidine-8-carboxamide; 2,4-Dimethyl-N-(2- methyl-lH-indol-5-yl)imidazo[l,5-a]pyrirnidine-8-carboxamide; N-(lH-Indazol-5-yl)-2,4- dimethylimidazo[l,5-a]pyrirnidine-8-carboxarnide; 2,4-Dimethyl-N-(4-methyl-2-oxo-2H- chromen-7-yl)imidazo[l,5-a]pyrimidine-8-carboxarnide; 2,4-Dimethyl-N-(2-oxo-2,3-dihydro- lH-indol-5-yl)imidazo[l,5-a]pyrimidine-3-carboxarnide; N-(lH-Indazol-6-yl)-2,4- dimethylimidazo[l,5-a]pyrirnidine-8-carboxarnide; N-(2H-l,3-Benzodioxol-5-yl)-2,4- dimethylimidazo[l,5-a]pyrirnidine-8-carboxarnide; N-(2-Hydroxy-4-methylquinolin-6-yl)-2,4- dimethylimidazo[l,5-a]pyrirnidine-8-carboxarnide; N-[3-Methoxy-4-(l,3-oxazol-5-yl)phenyl]- 2,4-dimethylimidazo[l,5-a]pyrirnidine-8-carboxarnide; 2,4-Dimethyl-N-(l,2,3,4- tetrahydroisoquinoline-6-yl)imidazo[l,5-a]pyrirnidine-8-carboxamide; 2,4-Dimethyl-N-(2- methyl-4-oxo-4H-chromen-7-yl)imidazo[l,5-a]pyrirnidine-8-carboxamide; N-(l,2-Benzoxazol- 5-yl)-2,4-dimethylimidazo[l,5-a]pyrirnidine-8-carboxamide; N-[2-(Furan-2-yl)-lH-l,3- benzodiazol-5-yl]-2,4-dimethylimidazo[l,5-a]pyrimidine-3-carboxamide; 2,4-Dimethyl-N-(2- methyl-l,3-benzothiazol-6-yl)imidazo[l,5-a]pyrirnidine-8-carboxamide; N-(2-3-Dihydro-lH- inden-5-yl)-2,4-dimethylimidazolo[l,5-a]pyrirnidine-8-carboxamide; 2,4-Dimethyl-N-[4-oxo- l,4-dihydroquinolin-6-yl)phenyl]irmdazo[l,5-a]pyrimidine-8-carboxamide; N-(4- Hydroxyquinolin-6-yl)2,4-dimethylimidazo[l,5-a]pyrirnidine-8-carboxamide; 2,4-Dimethyl-N- [4-methyl-3-(l,3-oxazol-2-yl)phenyl]imidazo[l,5-a]pyrimidine-8-carboxamide; N-[4-Chloro-3- (l,3-oxazol-5-yl)phenyl]-2,4-dimethylimidazo[l,5-a]pyrimidine-8-carboxamide; N-(2-methyl-

1.3- benzodioxol-6-yl)-2,4-dimethylimidazo[l,5-a]pyrimidine-8-carboxamide; 2,4-dimethyl-N- [2-(pyridin-4-yl) -l,3-benzoxazol-5-yl]imidazo[l,5-a]pyrirnidine-8-carboxarnide; N-{4-chloro- 3 -[(py ridin-3 -y loxy )methy 1] pheny 1 } -2,4-dimethy limidazo [ 1 ,5 -a] py rimidine-8-carboxamide;

2.4- dimethyl-N-[4-(pentyloxy)phenyl]imidazo[l,5-a]pyrirnidine-8-carboxamide; 2,4-dimethyl- N-(6-(thiophen-2-yl)pyridin-3-yl)imidazo[l,5-a]pyrimidine-8-carboxamide; N-(4-(furan-2- yl)phenyl)-5 -dimethylimidazo[l,5-a]pyrimidine-8-carboxamide; N-(6-(furan-2-yl)pyridin-3- yl)-2,4-dimethylimidazo [l,5-a]pyrimidine-8-carboxamide; N-(6-(furan-2-yl)pyridin-3-yl)-2,4- dimethylimidazo [l,5-a]pyrimidine-8-carboxamide; 2,4-Bis(Difluoromethyl)-N-(l, 2,3,4- tetrahydronaphthalen-l-yl)imidazo[l,5-a]pyrimidine-8-carboxamide; 2-Cyclopropyl-N-(5,8- difluoro-4-methylchroman-4-yl)-4-(methoxymethyl)imidazo[l,5-a]pyrimidine-8-carboxamide 4-Methyl-N-(l-methyl-l,2,3,4 etrahydronaphthalen-l-yl)-2-(trifluoromethyl)imidazo[l,5- a]pyrimidine-8-carboxamide; (S)-4-isoPropyl-2-methyl-N-(l,2,3,4-tetrahydronaphthalen-l- yl)imidazo[l,5-a]pyrimidine-8-carboxamide; 2,4-Dimethyl-N-(l-methyl-l,2,3,4- tetrahydronaphthalen-l-yl)imidazo[l,5-a]pyrimidine-8-carboxamide; N-(8-Fluoro-4- methylchroman-4-yl)-4-isopropyl-2-methylimidazo[l,5-a]pyrimidine-8-carboxamide; 2,4- Dimethyl-N-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl-5-d)imidazo[l,5-a]pyrimidine-8- carboxamide; N-(2-(4-Ethynylphenyl)propan-2-yl)-4-methyl-2-(trifluoromethyl)imidazo[l,5- a]pyrimidine-8-carboxamide; N-(2-(3-Ethynylphenyl)propan-2-yl)-4-methyl-2- (trifluoromethyl)imidazo[l,5-a]pyrimidine-8-carboxamide; N-(2-(3-Ethynylphenyl)propan-2- yl)-2,4-dimethylimidazo[l,5-a]pyrimidine-8-carboxamide; N-(2-(4-Ethynylphenyl)propan-2- yl)-2,4-dimethylimidazo[l,5-a]pyrimidine-8-carboxamide; N-(2-(4-Fluorophenyl)butan-2-yl)- 2,4-dimethylimidazo[l,5-a]pyrimidine-8-carboxamide; N-((lR,4R)-4-((4,4- Dimethylcyclohexyl)oxy)cyclohexyl)-2,4-dimethylimidazo[l,5-a]pyrimidine-8-carboxamide; N-((lS,3S)-3-(Hexyloxy)cyclopentyl)-2,4-dimethylimidazo[l,5-a]pyrimidine-8-carboxamide; N-(4-Ethynyl-2-fluorophenyl)-2,4-dimethylimidazo[l,5-a]pyrimidine-8-carboxamide; N-(4- Ethynyl-3-fluorophenyl)-2,4-dimethylimidazo[l,5-a]pyrimidine-8-carboxamide; 2- Cyclopropyl-4-(methoxymethyl)-N-(2-(3-propoxyphenyl)propan-2-yl)imidazo[l,5- a]pyrimidine-8-carboxamide; 2,4-bis(Methoxymethyl)-N-(2-(3-propoxyphenyl)propan-2- yl)imidazo[l,5-a]pyrimidine-8-carboxamide; 3-Methoxy-4-(methoxymethyl)-2-methyl-N-(2- (3-propoxyphenyl)propan-2-yl)imidazo[l,5-a]pyrimidine-8-carboxamide; N-(2-(3- Cyanophenyl)propan-2-yl)-4-cyclopropyl-2-(methoxymethyl)imidazo[l,5-a]pyrimidine-8- carboxamide; N-(2-(3-cyclopropoxyphenyl)propan-2-yl)-4-cyclopropyl-2- (methoxymethyl)imidazo[l ,5-a]pyrimidine-8-carboxamide; N-(2-(3- Cyclopropoxyphenyl)propan-2-yl)-2-cyclopropyl-4-(methoxymethyl)imidazo[l,5- a]pyrimidine-8-carboxamide; N-(2-(3-Cyclopropoxyphenyl)propan-2-yl)-4-isopropyl-2- (methoxymethyl)imidazo[l ,5-a]pyrimidine-8-carboxamide; N-(2-(3- Cyclopropoxyphenyl)propan-2-yl)-2-isopropyl-4-(methoxymethyl)imidazo[l,5-a]pyrimidine-8- carboxamide; 2-Cyclopropyl-N-(2-(3-ethoxymethyl)phenyl)propan-2-yl)-4- (methoxymethyl)imidazo[l ,5-a]pyrimidine-8-carboxamide; N-(2-(3-

(ethoxymethyl)phenyl)propan-2-yl)-4-isopropyl-2-(methoxymethyl)imidazo[l,5-a]pyrimidine- 8-carboxamide; N-(2-(3-(ethoxymethyl)phenyl)propan-2-yl)-2-isopropyl-4- (methoxymethyl)imidazo[l,5-a]pyrimidine-8-carboxamide; N-(2-((lR4R)-4- Methoxycyclohexyl)propan-2-yl)-2,4-dimethylimidazo[l,5-a]pyrimidine-8-carboxamide; N-(2- ((lR4S)-4-Methoxycyclohexyl)propan-2-yl)-2,4-dimethylimidazo[l,5-a]pyrimidine-8- carboxamide; N-(2,3-Dihydro-lH-inden-2-yl)-2,4-dimethylimidazo[l,5-a]pyrimidine-8- carboxamide; 2,4-Dimethyl-N-(4-(thiazol-4-yl)phenyl)imidazo[l,5-a]pyrimidine-8- carboxamide; N-(2,3-Dihydro-lH-inden-4-yl)-2,4-dimethylimidazo[l,5-a]pyrimidine-8- carboxamide; 2,4-Dimethyl-N-(l,2,3,4 etrahydronaphthalen-l-yl)imidazo[l,5-a]pyrimidine-8- carboxamide; (S)-N-(l-(2-fluorophenyl)ethyl)-2,4-dimethylimidazo[l,5-a]pyrimidine-8- carboxamide; (S)-N-(l-(2-Methoxyphenyl)ethyl)-2,4-dimethylimidazo[l,5-a]pyrimidine-8- carboxamide; (R)-N-(l -(2-Methoxyphenyl)ethyl)-2,4-dimethylimidazo[l ,5-a]pyrimidine-8- carboxamide; (S)-N-(l-(3-Chlorophenyl)ethyl)-2,4-dimethylimidazo[l,5-a]pyrimidine-8- carboxamide; N-(l-(4-Fluorophenyl)propyl)-2,4-dimethylimidazo[l,5-a]pyrimidine-8- carboxamide; N-(l-(5-Fluoro-2-methoxyphenyl)ethyl)-2,4-dimethylimidazo[l,5-a]pyrimidine- 8-carboxamide; N-(l-(3-Chlorophenyl)propyl)-2,4-dimethylimidazo[l,5-a]pyrimidine-8- carboxamide; N-(2-(3-Chlorophenyl)propan-2-yl)-2,4-dimethylimidazo[l,5-a]pyrimidine-8- carboxamide; (R)-N-(l-(4-Chlorophenyl)ethyl)-2,4-dimethylimidazo[l,5-a]pyrimidine-8- carboxamide; N-((lR,3R,5S,8R)-3-Butoxybicyclo[3.2.1]octan-8-yl)-2,4-dimethylimidazo[l,5- a]pyrimidine-8-carboxamide; N-((lR,3R,5S,8R)-8-Butoxybicyclo[3.2.1]octan-3-yl)-2,4- dimethylimidazo[l,5-a]pyrimidine-8-carboxamide; N-((lR,3R,5S,8S)-8- Bbutoxybicyclo[3.2 ]octan-3-yl)-2,4-dimethylimidazo[l,5-a]pyrimidine-8-carboxamide; 4- Cyclopropyl-N-(5,8-difluoro-4-methylchroman-4-yl)-2-(methoxymethyl)imidazo[l,5- a]pyrimidine-8-carboxamide; and 4-Cyclopropyl-N-(2-(3-(ethoxymethyl)phenyl)propan-2-yl)- 2-(methoxymethyl)imidazo[l,5-a]pyrimidine-8-carboxamide. PART 9 - PREPARATION OF ADDITIONAL iMiDAzo[l,5-a]PYRiMiDiNE-3-CARBOXAMiDES

[00560] Compounds below were also prepared based procedures described above:

EXAMPLE 6 - BIOLOGICAL ACTIVITY DATA FOR EXEMPLARY IMIDAZO [1,5-A]PYRIMIDINES AND RELATED ORGANIC COMPOUNDS

[00561] The ability of exemplary compounds to activate glucocerebrosidase (Gcase) was measured. Experimental procedures and results are provided below.

Part I: Assay Procedure [00562] A 484 aliquot of a 1.0 mg/mL solution of phosphatidylserine (PS) (Sigma

P7769) in chloroform was evaporated under a stream of nitrogen for 1 hour. The lipid film was dissolved over 4 minutes of vigorous vortexing in 40 mL of 176 mM K₂HPO₄/5O mM citric acid (pH 4.7) containing 7.5 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.

[00563] Test compounds were diluted to the desired concentrations with dimethylsulfoxide (DMSO) from 10 mM stocks, and 0.41 μΐ, of the DMSO compound mixture was added to 100 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 μΐ. of substrate solution with 25 μΐ. of

compound/Gcase/saposin mixture. The reaction proceeded for 15 minutes at room temperature and was stopped by adding 150 μΐ. of 1M glycine, pH 12.5. The endpoint of the reaction was monitored by measuring fluorescence intensity (excitation: 365 nm; emission: 440 nm) on a SpectraMax i3 instrument (Molecular Devices). Test compounds were screened at 1.0 and 0.1 μΜ final concentration, and subsequent 8-point dose response curves were obtained using 3- fold dilutions from a maximum final concentration of 5 μΜ. Part II: Results

[00564] Exemplary tested compounds are listed in Table 9 and grouped according to their observed Gcase activation value; the GCase activation value is that observed when the test compound was used at a concentration of 1.0 μΜ. Group 1 compounds had a Gcase activation greater value than 60%. Group 2 compounds had a Gcase activation value in the range of 30% up to 60%. Group 3 compounds had a Gcase activation value less than 30%.

TABLE 9.

Croup I Compounds

220

roup 3 Com pounds

INCORPORATION BY REFERENCE

[00565] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.

EQUIVALENTS

[00566] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

What is claimed is:

1. A method of treating endometriosis in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one Formulae A-1, B-1, B-IIa, B-III, or C-l to treat the endometriosis, wherein:

Formula A-I is represented by:

(A-I) or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R² each represent independently for each occurrence hydrogen, deuterium, CM alkyl, Ci^ haloalkyl, C deuteroalkyl, CM alkoxyl, -(CM alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, halogen, hydroxyl, or -N(R⁴)₂;

R³ represents independently for each occurrence hydrogen, C_1-6 alkyl, or C₃-6 cycloalkyl;

R⁴ represents independently for each occurrence hydrogen, C alkyl, cyclopropyl, or -C(0)R³;

R⁵ represents independently for each occurrence CM alkyl or C₃-6 cycloalkyl;

X¹ is one of the following:

(a) a carbonyl-containing linker selected from -C(0)N(H)(C i_-6 and -C(0)-(3-6 membered heterocycloalkylene containing at least one ring -N(H)- where ψ is a bond to A¹; or

(b) an amine-containing linker selected from -(CM and -(CM alkylene)-N(H)-(Ci-4

A¹ is a cyclic group selected from:

· C₃-10 cycloalkyl, phenyl, naphthyl, or 5-6 membered heteroaryl, each of which is substituted by 1 or 2 occurrences of Y¹ and 0, 1, 2, or 3 occurrences of Y ; · a 5-14 membered partially unsaturated carbocyclyl, or a 3-16 membered

heterocyclyl, each of which is substituted by 0, 1, or 2 occurrences of Y¹ and 0, 1, 2, or 3 occurrences ofY²; and · phenyl substituted with 0, 1, 2, or 3 occurrences of Y²;

Y¹ represents, independently for each occurrence, one of the following:

· 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl, a 3- 10 membered heterocyclyl, or C3-6 halocycloalkyl;

· 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -O-C3-7 cycloalkyl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -O- (C_2-6 alkynyl);

· C₂-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(C_W alkylene)-N(R )₂, -(C_2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl; or

· Ci-6 haloalkyl, Ci_-6 alkyl, halogen, cyano, -C0₂R³, -C(0)R⁵, -S(0)₂R⁵, -C(0)N(R⁵)₂, -C(0)N(R )₂, -N(R )C(0)R⁵, or -0-(Ci_-8 haloalkyl); Y² represents, independently for each occurrence, deuterium, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, Ci-₆ hydroxyalkyl, hydroxyl, Ci-₆ alkoxyl, cyano, azido, -N(R )₂, -(Ci-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C0₂R³, or Ci-6 haloalkyl-substituted C3-6 cycloalkyl;

m is 1 or 2;

n is 1, 2, or 3; and

provided that at least one occurrence of R¹ or R² is other than hydrogen when (i) A¹ is an unsubstituted heterocyclyl, (ii) A¹ is an unsubstituted phenyl or a phenyl substituted only by halogen, or (iii) Y² is halogen; Formula B-I is represented by: or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R² each represent independently for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, -(C1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, chloro, fluoro, 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(0)R³; X¹ is one of the following:

(a) a carbonyl-containing linker selected from and -C(0)N(H)(Ci_-6 where ψ is a bond to A¹; or

(b) an amine-containing linker selected from -(CM and -(C

alkylene)-N(H)-(Ci-4

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-lH-inden-l -yl, or 2,3-dihydro-lH- inden-2-yl, each of which is substituted 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:

o 4-8 membered heteroalkyl;

o 2-6 membered heteroalkyl substituted by a 5-10 membered heteroaryl; o -C≡C-(Ci-₆ alkylene)-OR⁴ or -(C2-4 alkynylene)-(5-6 membered heterocyclyl);

o -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), -0-(C2-6 alkynyl), or azido; or

o 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;

Y¹ represents, independently for each occurrence, one of the following:

· 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl;

· 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered

heterocyclyl), -0(6-10 membered aryl), or -0-(C2-₆ alkynyl); or

· C₂-6 alkynyl, -C≡C-(d_-6 alkylene)-OR⁴, -C≡C-(C_W alkylene)-N(R )₂, -(C_2-4 alkynylene)-(5-6 membered heteroaryl), or C2-₆ alkenyl; 89 Y² represents, independently for each occurrence, C_1-6 alkyl, C3-₆ cycloalkyl, halogen,

90 Ci-₆ haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, C2-4 alkynyl, cyano, azido, -N(R )₂,

91 -(Ci-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R³, or C_1-6

92 haloalkyl-substituted C3-₆ cycloalkyl; and

93 n is i, 2, or 3;

94 Formula B-IIa is represented by:

96 (B-IIa)

97

98 or a pharmaceutically acceptable salt thereof, wherein:

99 R¹ and R² each represent independently for each occurrence hydrogen, C1-4 alkyl, C_1-4

100 haloalkyl, C_1-4 alkoxyl, -(C_1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl,

101 cyano, chloro, or fluoro;

102 R³ represents independently for each occurrence hydrogen or C_1-4 alkyl;

103 R⁴ represents independently for each occurrence hydrogen, C_1-4 alkyl, or -C(0)R³;

104 X¹ is one of the following:

105 (a) a carbonyl-containing linker selected from -C(0)N(H)-v|/ and -C(0)N(H)(Ci_-6

106 where ψ is a bond to A¹; or

107 (b) an amine-containing linker selected from -(C_1-4 alkylene)-N(H)-v|/ and -(C_1-4

108 alkylene)-N(H)-(Ci-4

109 A¹ is one of the following:

110 · C3-1₀ cycloalkyl that is substituted by (a) 1, 2, or 3 halogen and (b) 0, 1, 2, or 3

111 occurrences of Y² ;

112 · phenyl substituted by (a) halogen or C_1-6 alkoxyl and (b) 0, 1, 2, or 3 occurrences

113 ofY²; or

114 · phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y² and (b) one of the

115 following:

116 o phenyl substituted by 0, 1, 2, or 3 occurrences of Y²;

117 o 4-pyridinyl substituted by 0, 1, 2, or 3 occurrences of Y²;

118 o -C≡C-(Ci-₆ alkylene)-(5-6 membered heterocyclyl); 119 o a bicyclic carbocyclyl that is partially unsaturated and substituted by

120 (a) a 3-10 membered heterocyclyl, and (b) 0, 1, 2, or 3 occurrences

121 ofY²;

122 o piperazinyl substituted by 0, 1, or 2 occurrences of Y²; or

123 o both Ci-₆ alkoxyl and C2-4 alkynyl;

124 Y² represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen,

125 Ci-₆ haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, azido, -N(R )₂, -(C_1-6 alkylene)-

126 (5-6 membered heterocyclyl), -(C_1-6 alkylene)-C02R³, or C_1-6 haloalkyl-substituted C3-6

127 cycloalkyl; and

128 n is i, 2, or 3;

129 Formula B-III is represented by:

131

132

133 or a pharmaceutically acceptable salt thereof, wherein:

134 R¹ and R² each represent independently for each occurrence hydrogen, C1-4 alkyl, C_1-4

135 haloalkyl, C_1-4 alkoxyl, -(C_1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl,

136 cyano, chloro, or fluoro;

137 R³ represents independently for each occurrence hydrogen or C_1-4 alkyl;

138 R⁴ represents independently for each occurrence hydrogen, C_1-4 alkyl, or -C(0)R³;

139 X¹ is one of the following:

140 (a) a carbonyl-containing linker selected from -C(0)N(H)-v|/ and -C(0)N(H)(Ci_-6

141 where ψ is a bond to A¹; or

142 (b) an amine-containing linker selected from -(C_1-4 alkylene)-N(H)-v|/ and -(C_1-4

143 alkylene)-N(H)-(Ci-4

144 A¹ is a cyclic group selected from:

145 · phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y² and (b) one of the

146 following:

147 o a 5 -membered heteroaryl substituted by 0, 1, 2, or 3 occurrences of Y²;

148 o -(Ci_-6 alkylene)-C0₂R³; or 149 o Ci-e hydroxyalkyl;

150 · 5-6 membered heteroaryl substituted by 1 or 2 occurrences of Y¹ and 0, 1, 2, or

151 3 occurrences of Y²

152 Y¹ represents, independently for each occurrence, one of the following:

153 · 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a

154 3-10 membered heterocyclyl;

155 · 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -0-(3-6

156 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl); or

157 · C₂-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(C_W alkylene)-N(R )₂, -(C_2-4

158 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl;

159 Y² represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen,

160 Ci-6 haloalkyl, Ci-6 hydroxyalkyl, hydroxyl, Ci-6 alkoxyl, cyano, azido, -N(R )₂, -(Ci-6 alkylene)-

161 (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R³, or Ci-6 haloalkyl-substituted C3-6

162 cycloalkyl; and

163 n is 1, 2, or 3; and

164 Formula C-I is represented by:

167

168 or a pharmaceutically acceptable salt thereof, wherein:

169 R¹ represents independently for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, Ci-

170 4 alkoxyl, -(C₁-4 alky lene)-(C ₁-4 alkoxyl), cyclopropyl, cyano, chloro, or fiuoro;

171 R² is hydrogen, C₁-4 alkyl, C ₁-4 haloalkyl, C₁-4 alkoxyl, cyclopropyl, cyano, chloro, or

172 fluoro;

173 R³ represents independently for each occurrence hydrogen or C₁-4 alkyl;

174 R⁴ represents independently for each occurrence hydrogen, C₁-4 alkyl, or -C(0)R³;

175 X¹ is one of the following: 176 (a) a carbonyl-containing linker selected from -C(0)N(H)(C i_-6

177 and -C(0)-(3-6 membered heterocycloalkylene containing at least

178 one ring -N(H)- where ψ is a bond to A¹; or

179 (b) an amine-containing linker selected from -(C1-4 and -(C1-4

180 alkylene)-N(H)-(Ci-4

181 A¹ is a cyclic group selected from:

182 · C3-1₀ cycloalkyl, phenyl, or 5-6 membered heteroaryl, each of which is

183 substituted by 1 or 2 occurrences of Y¹ and 0, 1 , 2, or 3 occurrences of Y²; and

184 · a bicyclic carbocyclyl that is partially unsaturated or a mono-cyclic or bicyclic

185 heterocyclyl, each of which is substituted by 0, 1, or 2 occurrences of Y¹ and 0,

186 1, 2, or 3 occurrences of Y²;

187 Y¹ represents, independently for each occurrence, one of the following:

188 · 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a

189 3-10 membered heterocyclyl;

190 · 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -O-C3-7

191 cycloalkyl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -O-

192 (C_2-6 alkynyl);

193 · C₂-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(C_W alkylene)-N(R )₂, -(C_2-4

194 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl; or

195 · halogen or cyano;

196 Y² represents, independently for each occurrence, deuterium, Ci-6 alkyl, C3-6 cycloalkyl,

197 halogen, Ci-₆ haloalkyl, Ci-₆ hydroxyalkyl, hydroxyl, Ci-₆ alkoxyl, cyano, azido, -N(R )₂, -(Ci-6

198 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R³, or Ci-6 haloalkyl-substituted

199 C3-6 cycloalkyl; and

200 n is i, 2, or 3.

1 2. A method of treating Parkinson's disease in a patient, comprising administering to a patient

2 in need thereof a therapeutically effective amount of (i) a compound of any one Formulae

3 A-l, B-l, B-IIa, B-III, or C-l and (ii) a second therapeutic agent selected from the group

4 consisting of a glucosylceramide synthase inhibitor, an acid ceramidase inhibitor, and an

5 acid sphingomyelinase activator, in order to treat the Parkinson's disease, wherein: Formula A-I is represented by:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R² each represent independently for each occurrence hydrogen, deuterium, CM alkyl, Ci^ haloalkyl, C deuteroalkyl, CM alkoxyl, -(CM alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, halogen, hydroxyl, or -N(R⁴)2;

R³ represents independently for each occurrence hydrogen, C_1-6 alkyl, or C₃-6

cycloalkyl;

X¹ is one of the following:

(a) a carbonyl-containing linker selected from -C(0)N(H)(C_1-6 and -C(0)-(3-6 membered heterocycloalkylene containing at least one ring -N(H)- group)-v|/; where ψ is a bond to A¹; or

(b) an amine-containing linker selected from -(CM and -(CM alkylene)-N(H)-(Ci-4

A¹ is a cyclic group selected from:

heterocyclyl, each of which is substituted by 0, 1, or 2 occurrences of Y¹ and 0, 1, 2, or 3 occurrences ofY²; and

· phenyl substituted with 0, 1, 2, or 3 occurrences ofY²;

Y¹ represents, independently for each occurrence, one of the following:

· 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl, a 3- 10 membered heterocyclyl, or C₃-6 halocycloalkyl; · 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -O-C3-7 cycloalkyl, -0-(3-6 membered heterocyclyl), -O-(6-10 membered aryl), or -O- (C_2-6 alkynyl);

· C₂-6 alkynyl, -C≡C-(C_W alkylene)-OR⁴, -C≡C-(C_W alkylene)-N(R )₂, -(C_2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl; or

· Ci-6 haloalkyl, Ci_-6 alkyl, halogen, cyano, -C0₂R³, -C(0)R⁵, -S(0)₂R⁵, -C(0)N(R⁵)₂, -C(0)N(R )₂, -N(R )C(0)R⁵, or -0-(Ci_-8 haloalkyl); Y² represents, independently for each occurrence, deuterium, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, hydroxyl, Ci-6 alkoxyl, cyano, azido, -N(R )₂, -(Ci-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C0₂R³, or Ci-6 haloalkyl-substituted C3-6 cycloalkyl;

m is 1 or 2;

n is 1, 2, or 3; and

provided that at least one occurrence of R¹ or R² is other than hydrogen when (i) A¹ is an unsubstituted heterocyclyl, (ii) A¹ is an unsubstituted phenyl or a phenyl substituted only by halogen, or (iii) Y² is halogen;

Formula B-I is represented by : or a pharmaceutically acceptable salt thereof, wherein:

R³ represents independently for each occurrence hydrogen or C1-4 alkyl;

(a) a carbonyl-containing linker selected from and -C(0)N(H)(Ci_-6 where ψ is a bond to A¹; or (b) an amine-containing linker selected from -(CM and -(C alkylene)-N(H)-(Ci-4

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;

following:

o 4-8 membered heteroalkyl;

o 2-6 membered heteroalkyl substituted by a 5-10 membered heteroaryl; o -C≡C-(Ci-₆ alkylene)-OR⁴ or -(C₂-4 alkynylene)-(5-6 membered

heterocyclyl);

o C₂-4 alkynyl; and

Y¹ represents, independently for each occurrence, one of the following:

· 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C₂-₆ alkynyl); or · C2-6 alkynyl, -C≡C-(C_W alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C₂-₆ alkenyl;

Y² represents, independently for each occurrence, C_1-6 alkyl, C₃-₆ cycloalkyl, halogen, Ci-₆ haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, C₂-4 alkynyl, cyano, azido, -N(R )₂, -(Ci-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R³, or C_1-6

haloalkyl-substituted C₃-₆ cycloalkyl; and 95 n is i, 2, or 3;

96 Formula B-IIa is represented by:

99

100 or a pharmaceutically acceptable salt thereof, wherein:

101 R¹ and R² each represent independently for each occurrence hydrogen, C_1-4 alkyl, C_1-4

102 haloalkyl, C_1-4 alkoxyl, -(C_1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl,

103 cyano, chloro, or fluoro;

104 R³ represents independently for each occurrence hydrogen or C_1-4 alkyl;

105 R⁴ represents independently for each occurrence hydrogen, C_1-4 alkyl, or -C(0)R³;

106 X¹ is one of the following:

107 (a) a carbonyl-containing linker selected from and -C(0)N(H)(C_1-6

108 where ψ is a bond to A¹; or

109 (b) an amine-containing linker selected from -(C_1-4 alkylene)-N(H)-v|/ and -(C_1-4

110 alkylene)-N(H)-(Ci-4

111 A¹ is one of the following:

112 · C3-1₀ cycloalkyl that is substituted by (a) 1, 2, or 3 halogen and (b) 0, 1, 2, or 3

113 occurrences of Y² ;

114 · phenyl substituted by (a) halogen or C_1-6 alkoxyl and (b) 0, 1, 2, or 3 occurrences

115 ofY²; or

116 · phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y² and (b) one of the

117 following:

118 o phenyl substituted by 0, 1, 2, or 3 occurrences of Y²;

119 o 4-pyridinyl substituted by 0, 1, 2, or 3 occurrences of Y²;

120 o -C≡C-(Ci-6 alkylene)-(5-6 membered heterocyclyl);

121 o a bicyclic carbocyclyl that is partially unsaturated and substituted by

122 (a) a 3-10 membered heterocyclyl, and (b) 0, 1, 2, or 3 occurrences

123 ofY²;

124 o piperazinyl substituted by 0, 1, or 2 occurrences of Y²; or 125 o both Ci-₆ alkoxyl and C2-4 alkynyl;

126 Y² represents, independently for each occurrence, C_1-6 alkyl, C3-₆ cycloalkyl, halogen,

127 Ci-₆ haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, azido, -N(R )₂, -(C_1-6 alkylene)-

128 (5-6 membered heterocyclyl), -(C_1-6 alkylene)-C02R³, or C_1-6 haloalkyl-substituted C3-6

129 cycloalkyl; and

130 n is i, 2, or 3;

131 Formula B-III is represented by:

133 (B-III)

134

135 or a pharmaceutically acceptable salt thereof, wherein:

136 R¹ and R² each represent independently for each occurrence hydrogen, C1-4 alkyl, C_1-4

137 haloalkyl, C_1-4 alkoxyl, -(C_1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl,

138 cyano, chloro, or fluoro;

139 R³ represents independently for each occurrence hydrogen or C_1-4 alkyl;

140 R⁴ represents independently for each occurrence hydrogen, C_1-4 alkyl, or -C(0)R³;

141 X¹ is one of the following:

142 (a) a carbonyl-containing linker selected from -C(0)N(H)-v|/ and -C(0)N(H)(C_1-6

143 where ψ is a bond to A¹; or

144 (b) an amine-containing linker selected from -(C_1-4 alkylene)-N(H)-v|/ and -(C_1-4

145 alkylene)-N(H)-(Ci-4

146 A¹ is a cyclic group selected from:

147 · phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y² and (b) one of the

148 following:

149 o a 5 -membered heteroaryl substituted by 0, 1, 2, or 3 occurrences of Y²;

150 o -(Ci_-6 alkylene)-C0₂R³; or

151 o Ci-₆ hydroxyalkyl;

152 · 5-6 membered heteroaryl substituted by 1 or 2 occurrences of Y¹ and 0, 1, 2, or

153 3 occurrences of Y² 154 Y¹ represents, independently for each occurrence, one of the following:

155 · 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a

156 3-10 membered heterocyclyl;

157 · 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -0-(3-6

158 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl); or

159 · C₂-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(C_W alkylene)-N(R )₂, -(C_2-4

160 alkynylene)-(5-6 membered heteroaryl), or C2-₆ alkenyl;

161 Y² represents, independently for each occurrence, C_1-6 alkyl, C3-6 cycloalkyl, halogen,

162 Ci-6 haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, azido, -N(R )₂, -(C_1-6 alkylene)-

163 (5-6 membered heterocyclyl), -(C_1-6 alkylene)-C0₂R³, or C_1-6 haloalkyl-substituted C3-6

164 cycloalkyl; and

165 n is 1, 2, or 3; and

166 Formula C-I is represented by:

168

169

170 or a pharmaceutically acceptable salt thereof, wherein:

171 R¹ represents independently for each occurrence hydrogen, C_1-4 alkyl, C_1-4 haloalkyl, Ci_

172 4 alkoxyl, -(C_1-4 alkylene)-(C_1-4 alkoxyl), cyclopropyl, cyano, chloro, or fluoro;

173 R² is hydrogen, C_1-4 alkyl, C 1-4 haloalkyl, C_1-4 alkoxyl, cyclopropyl, cyano, chloro, or

174 fluoro;

175 R³ represents independently for each occurrence hydrogen or C_1-4 alkyl;

176 R⁴ represents independently for each occurrence hydrogen, C_1-4 alkyl, or -C(0)R³;

177 X¹ is one of the following:

178 (a) a carbonyl-containing linker selected from -C(0)N(H)(C i_-6

179 and -C(0)-(3-6 membered heterocycloalkylene containing at least

180 one ring -N(H)- where ψ is a bond to A¹; or

181 (b) an amine-containing linker selected from -(C_1-4 alkylene)-N(H)-v|/ and -(C_1-4

182 alkylene)-N(H)-(Ci-4 alkylene)-\|/; 183 A¹ is a cyclic group selected from:

184 · C3-10 cycloalkyl, phenyl, or 5-6 membered heteroaryl, each of which is

185 substituted by 1 or 2 occurrences of Y¹ and 0, 1, 2, or 3 occurrences of Y²; and

186 · a bicyclic carbocyclyl that is partially unsaturated or a mono-cyclic or bicyclic

187 heterocyclyl, each of which is substituted by 0, 1, or 2 occurrences of Y¹ and 0,

188 1, 2, or 3 occurrences ofY²;

189 Y¹ represents, independently for each occurrence, one of the following:

190 · 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a

191 3-10 membered heterocyclyl;

192 · 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -O-C3-7

193 cycloalkyl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -O-

194 (C_2-6 alkynyl);

195 · C2-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(Ci_-6 alkylene)-N(R )₂, -(C2-4

196 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl; or

197 · halogen or cyano;

198 Y² represents, independently for each occurrence, deuterium, Ci-6 alkyl, C3-6 cycloalkyl,

199 halogen, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, hydroxyl, Ci-6 alkoxyl, cyano, azido, -N(R )₂, -(Ci-6

200 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R³, or Ci-6 haloalkyl-substituted

201 C3-6 cycloalkyl; and

202 n is i, 2, or 3.

1 3. The method of claim 2, wherein the second therapeutic agent is a glucosylceramide

2 synthase inhibitor.

1 4. The method of claim 3, wherein the glucosylceramide synthase inhibitor comprises

2 ibiglustat.

1 5. The method of claim 2, wherein the second therapeutic agent is an acid ceramidase

2 inhibitor.

1 6. The method of claim 5, wherein the acid ceramidase inhibitor comprises carmofur.

1 7. The method of claim 2, wherein the second therapeutic agent is an acid sphingomyelinase

2 activator.

8. A method of treating a disorder selected from the group consisting of Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, major depression, and open angle glaucoma in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of (i) a compound of any one Formulae A-l, B-l, B-IIa, B-III, or C-l and (ii) an acid ceramidase inhibitor, in order to treat the disorder, wherein:

Formula A-I is represented by:

(A-I) or a pharmaceutically acceptable salt thereof, wherein:

X¹ is one of the following:

(c) a carbonyl-containing linker selected from -C(0)N(H)(Ci_-6 and -C(0)-(3-6 membered heterocycloalkylene containing at least one ring -N(H)- where ψ is a bond to A¹; or

(d) an amine-containing linker selected from -(CM and -(CM alkylene)-N(H)-(Ci-4

A¹ is a cyclic group selected from:

· C₃-10 cycloalkyl, phenyl, naphthyl, or 5-6 membered heteroaryl, each of which is substituted by 1 or 2 occurrences of Y¹ and 0, 1, 2, or 3 occurrences of Y ; · a 5-14 membered partially unsaturated carbocyclyl, or a 3-16 membered heterocyclyl, each of which is substituted by 0, 1, or 2 occurrences of Y¹ and 0, 1, 2, or 3 occurrences of Y²; and

· phenyl substituted with 0, 1, 2, or 3 occurrences of Y²;

Y¹ represents, independently for each occurrence, one of the following:

m is 1 or 2;

n is 1, 2, or 3; and

Formula B-I is represented by:

(B-I)

or a pharmaceutically acceptable salt thereof, wherein: R¹ and R² each represent independently for each occurrence hydrogen, C_1-4 alkyl, C_1-4 haloalkyl, C_1-4 alkoxyl, -(C_1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, chloro, fluoro, or -N(H)(R³);

R³ represents independently for each occurrence hydrogen or C_1-4 alkyl;

(a) a carbonyl-containing linker selected from -C(0)N(H)-v|/ and -C(0)N(H)(Ci_₆ where ψ is a bond to A¹; or

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-lH-inden-l-yl, or 2,3-dihydro-lH- inden-2-yl, each of which is substituted by 0, 1, or 2 occurrences ofY¹ and 0, 1, 2, or 3 occurrences ofY²;

· phenyl substituted by (a) 0, 1, 2, or 3 occurrences ofY² and (b) one of the

following:

o 4-8 membered heteroalkyl;

o 2-6 membered heteroalkyl substituted by a 5-10 membered heteroaryl; o -C≡C-(Ci-₆ alkylene)-OR⁴ or -(C_2-4 alkynylene)-(5-6 membered heterocyclyl);

o 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 ofY²;

Y¹ represents, independently for each occurrence, one of the following:

· 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl; 88 · 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered

89 heterocyclyl), -O-(6-10 membered aryl), or -0-(C_2-6 alkynyl); or

90 · C₂-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(C_W alkylene)-N(R )₂, -(C_2-4

91 alkynylene)-(5-6 membered heteroaryl), or C_2-6 alkenyl;

92 Y² represents, independently for each occurrence, C_1-6 alkyl, C3-6 cycloalkyl, halogen,

93 Ci-6 haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, C_2-4 alkynyl, cyano, azido, -N(R )₂,

94 -(Ci-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C0₂R³, or C_1-6

95 haloalkyl-substituted C3-6 cycloalkyl; and

96 n is i, 2, or 3;

97 Formula B-IIa is represented by:

99 (B-IIa)

100

101 or a pharmaceutically acceptable salt thereof, wherein:

102 R¹ and R² each represent independently for each occurrence hydrogen, C1-4 alkyl, C_1-4

103 haloalkyl, C_1-4 alkoxyl, -(C_1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl,

104 cyano, chloro, or fluoro;

105 R³ represents independently for each occurrence hydrogen or C_1-4 alkyl;

106 R⁴ represents independently for each occurrence hydrogen, C_1-4 alkyl, or -C(0)R³;

107 X¹ is one of the following:

108 (c) a carbonyl-containing linker selected from -C(0)N(H)-v|/ and -C(0)N(H)(Ci_-6

109 where ψ is a bond to A¹; or

110 (d) an amine-containing linker selected from -(C_1-4 and -(C_1-4

111 alkylene)-N(H)-(Ci-4

112 A¹ is one of the following:

113 · C3-10 cycloalkyl that is substituted by (a) 1, 2, or 3 halogen and (b) 0, 1, 2, or 3

114 occurrences of Y²;

115 · phenyl substituted by (a) halogen or C_1-6 alkoxyl and (b) 0, 1, 2, or 3 occurrences

116 ofY²; or · phenyl substituted by (a) 0, 1 , 2, or 3 occurrences of Y² and (b) one of the following:

o phenyl substituted by 0, 1, 2, or 3 occurrences of Y²;

o 4-pyridinyl substituted by 0, 1, 2, or 3 occurrences of Y²;

o -C≡C-(Ci-6 alkylene)-(5-6 membered heterocyclyl);

o a bicyclic carbocyclyl that is partially unsaturated and substituted by (a) a 3-10 membered heterocyclyl, and (b) 0, 1, 2, or 3 occurrences of Y²;

o piperazinyl substituted by 0, 1, or 2 occurrences of Y²; or o both Ci-6 alkoxyl and C₂-4 alkynyl;

Y² represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, hydroxyl, Ci-6 alkoxyl, cyano, azido, -N(R )₂, -(Ci-6 alkylene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R³, or Ci-6 haloalkyl-substituted C3-6 cycloalkyl; and

n is i, 2, or 3; Formula B-III is represented by:

(B-III) or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R² each represent independently for each occurrence hydrogen, C₁-4 alkyl, C₁-4 haloalkyl, C₁-4 alkoxyl, -(C₁-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, chloro, or fluoro;

R³ represents independently for each occurrence hydrogen or C₁-4 alkyl;

R⁴ represents independently for each occurrence hydrogen, C₁-4 alkyl, or -C(0)R³; X¹ is one of the following:

(c) a carbonyl-containing linker selected from and -C(0)N(H)(Ci_-6 where ψ is a bond to A¹; or

(d) an amine-containing linker selected from -(C₁-4 and -(C₁-4 alkylene)-N(H)-(Ci-4 alkylene)-\|/; 147 A¹ is a cyclic group selected from:

148 · phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y² and (b) one of the

149 following:

150 o a 5-membered heteroaryl substituted by 0, 1, 2, or 3 occurrences of Y²;

151 o -(Ci_-6 alkylene)-C0₂R³; or

152 o Ci-₆ hydroxyalkyl;

153 · 5-6 membered heteroaryl substituted by 1 or 2 occurrences of Y¹ and 0, 1, 2, or

154 3 occurrences of Y²

155 Y¹ represents, independently for each occurrence, one of the following:

156 · 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a

157 3-10 membered heterocyclyl;

158 · 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -0-(3-6

159 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl); or

160 · C₂-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(C_W alkylene)-N(R )₂, -(C_2-4

161 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl;

162 Y² represents, independently for each occurrence, C_1-6 alkyl, C3-₆ cycloalkyl, halogen,

163 Ci-₆ haloalkyl, C_1-6 hydroxyalkyl, hydroxyl, C_1-6 alkoxyl, cyano, azido, -N(R )₂, -(C_1-6 alkylene)-

164 (5-6 membered heterocyclyl), -(C_1-6 alkylene)-C02R³, or C_1-6 haloalkyl-substituted C3-6

165 cycloalkyl; and

166 n is 1, 2, or 3; and

167 Formula C-I is represented by:

169 (C-I)

170

171 or a pharmaceutically acceptable salt thereof, wherein:

172 R¹ represents independently for each occurrence hydrogen, C_1-4 alkyl, C_1-4 haloalkyl, Ci_

173 4 alkoxyl, -(C_1-4 alkylene)-(C_1-4 alkoxyl), cyclopropyl, cyano, chloro, or fluoro;

174 R² is hydrogen, C_1-4 alkyl, C 1-4 haloalkyl, C_1-4 alkoxyl, cyclopropyl, cyano, chloro, or

175 fluoro; 176 R³ represents independently for each occurrence hydrogen or C_1-4 alkyl;

177 R⁴ represents independently for each occurrence hydrogen, C_1-4 alkyl, or -C(0)R³;

178 X¹ is one of the following:

179 (c) a carbonyl-containing linker selected from -C(0)N(H)(C i_-6

180 and -C(0)-(3-6 membered heterocycloalkylene containing at least

181 one ring -N(H)- where ψ is a bond to A¹; or

182 (d) an amine-containing linker selected from -(C_1-4 and -(C_1-4

183 alkylene)-N(H)-(Ci-4

184 A¹ is a cyclic group selected from:

185 · C3-10 cycloalkyl, phenyl, or 5-6 membered heteroaryl, each of which is

186 substituted by 1 or 2 occurrences of Y¹ and 0, 1, 2, or 3 occurrences of Y²; and

187 · a bicyclic carbocyclyl that is partially unsaturated or a mono-cyclic or bicyclic

188 heterocyclyl, each of which is substituted by 0, 1, or 2 occurrences of Y¹ and 0,

189 1, 2, or 3 occurrences ofY²;

190 Y¹ represents, independently for each occurrence, one of the following:

191 · 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a

192 3-10 membered heterocyclyl;

193 · 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -O-C3-7

194 cycloalkyl, -0-(3-6 membered heterocyclyl), -O-(6-10 membered aryl), or -O-

195 (C_2-6 alkynyl);

196 · C₂-6 alkynyl, -C≡C-(Ci_-6 alkylene)-OR⁴, -C≡C-(C_W alkylene)-N(R )₂, -(C_2-4

197 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl; or

198 · halogen or cyano;

199 Y² represents, independently for each occurrence, deuterium, C_1-6 alkyl, C3-6 cycloalkyl,

200 halogen, Ci-₆ haloalkyl, Ci-₆ hydroxyalkyl, hydroxyl, Ci-₆ alkoxyl, cyano, azido, -N(R )₂, -(C_1-6

201 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C0₂R³, or C_1-6 haloalkyl-substituted

202 C3-6 cycloalkyl; and

203 n is i, 2, or 3.

1 9. The method of any one of claims 1-8, wherein the compound is a compound of Formula A-

2 I or a pharmaceutically acceptable salt thereof.

10. The method of claim 9, wherein R¹ represents independently for each occurrence C_1-4 alkyl, Ci-₄ haloalkyl, -(C_1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, halogen, or -N(R⁴)₂.

11. The method of claim 9, wherein R¹ is methyl.

12. The method of any one of claims 9-11, wherein n is 2.

13. The method of claim 12, wherein the R¹ groups are located at the 2 and 4 positions of the pyrrolo[l,2-a]pyrimidinyl.

14. The method of any one of claims 9-13, wherein R² is hydrogen.

15. The method of any one of claims 9-14, wherein R³ and R⁴ each represent independently for each occurrence hydrogen, methyl, or ethyl.

16. The method of any one of claims 9-15, wherein X¹ is

17. The method of any one of claims 9-15, wherein X¹ is -C(0)N(H)(C_1-6 alkylene)-v|/ or

-C(0)-(3-6 membered heterocycloalkylene containing at least one ring -N(H)-

18. The method of any one of claims 9-17, wherein A¹ is C5-10 cycloalkyl substituted once by Y¹ and 0-1 occurrences of Y².

19. The method of any one of claims 9-17, wherein A¹ is C3-7 cycloalkyl substituted once by Y¹ and 0-1 occurrences of Y².

20. The method of any one of claims 9-17, wherein A¹ is a bi cyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y¹ and 0, 1, or 2 occurrences of Y².

21. The method of any one of claims 9-17, wherein A¹ is phenyl substituted once by Y¹ and 0-1 occurrences of Y².

22. The method of any one of claims 9-17, wherein A¹ is a 5-6 membered heteroaryl substituted once by Y¹ and 0-1 occurrences of Y².

23. The method of any one of claims 9-17, wherein A¹ is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y² selected from the group consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, hydroxyl, and C_1-6 alkoxyl.

24. The method of any one of claims 9-17, wherein A¹ is

wherein m is 0, 1, or 2; and Y² represents independently for each occurrence Ci_6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, hydroxyl, or Ci-6 alkoxyl.

25. The method of any one of claims 9-22, wherein any occurrence of Y² is independently Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, or hydroxyl.

26. The method of any one of claims 9-22, wherein any occurrence of Y² is independently C1-3 alkyl.

27. The method of any one of claims 9-22, wherein Y² is Ci-₆ haloalkyl-substituted C3-6

cycloalkyl.

28. The method of any one of claims 9-22, wherein Y¹ is a 2-8 membered heteroalkyl

optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl.

29. The method of any one of claims 9-22, wherein Y¹ is -0-(Ci_7 alkyl).

30. The method of any one of claims 9-22, wherein Y¹ is -O-butyl, -O-pentyl, or -O-hexyl.

31. The method of any one of claims 9-22, wherein Y¹ is -(C1-3 alkylene)-0-(5-6 membered heteroaryl).

32. The method of any one of claims 9-22, wherein Y¹ is a 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-6 alkynyl).

33. The method of any one of claims 9-22, wherein Y¹ is a 3-10 membered heterocyclyl

selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl.

34. The method of any one of claims 9-22, wherein Y¹ is 5-membered heteroaryl.

35. The method of any one of claims 9-22, wherein Y¹ is furanyl, pyrrolyl, thiophenyl,

imidazoyl, pyrazolyl, oxazolyl, or thiazolyl.

36. The method of any one of claims 9-22, wherein Y¹ is C2-6 alkynyl, -C≡C-(Ci-6 alkylene)- OR⁴, -C≡C-(Ci-6 alkylene)-N(R )₂, -(C_2-4 alkynylene)-(5-6 membered heteroaryl), or C₂-₆ alkenyl.

37. The method of any one of claims 9-22, wherein Y¹ is C2-6 alkynyl.

38. The method of any one of claims 9-22, wherein Y¹ is -C≡CH.

39. The method of any one of claims 9-22, wherein Y¹ is -C≡C-(Ci_6 alkylene)-OR⁴.

40. The method of any one of claims 9-22, wherein Y¹ is -C≡C-CH₂-0-CH₃.

41. The method of any one of claims 1-8, wherein the compound is a compound of Formula B-I or a pharmaceutically acceptable salt thereof.

42. The method of claim 41, wherein R¹ represents independently for each occurrence C1-4 alkyl, Ci^ haloalkyl, Ci-₄ alkoxyl, cyclopropyl, cyano, chloro, or fiuoro.

43. The method of claim 41, wherein R¹ is methyl.

44. The method of any one of claims 41-43, wherein n is 2.

45. The method of claim 44, wherein the R¹ groups are located at the 5 and 7 positions of the pyrazolo[l,5-a]pyrimidinyl.

46. The method of any one of claims 41-45, wherein R² is hydrogen.

47. The method of any one of claims 41-46, wherein R³ and R⁴ each represent independently for each occurrence hydrogen, methyl, or ethyl.

48. The method of any one of claims 41-47, wherein X¹ is

49. The method of any one of claims 41-48, wherein any occurrence of Y² is independently Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, or hydroxyl.

50. The method of any one of claims 41-48, wherein any occurrence of Y² is independently C1-3 alkyl.

51. The method of any one of claims 41-50, wherein Y¹ is 2-8 membered heteroalkyl.

52. The method of any one of claims 41-50, wherein Y¹ is -0-(Ci_7 alkyl).

53. The method of any one of claims 41-50, wherein Y¹ is -O-butyl, -O-pentyl, or -O-hexyl.

54. The method of any one of claims 41-53, wherein A¹ is C5-1₀ cycloalkyl that is substituted by 1 or 2 occurrences of Y¹ and 0, 1, 2, or 3 occurrences of Y².

55. The method of any one of claims 41-53, wherein A¹ is C3-7 cycloalkyl substituted once by Y¹ and 0-1 occurrences of Y².

56. The method of any one of claims 41-53, wherein A¹ is 1,2,3,4-tetrahydronaphthalenyl substituted by 0, 1, 2, or 3 occurrences of Y².

57. The method of any one of claims 41-53, wherein A¹ is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y² and (b) one of the following:

o 4-8 membered heteroalkyl;

o 2-6 membered heteroalkyl substituted by a 5-10 membered heteroaryl;

o -C≡C-(Ci-₆ alkylene)-OR⁴ or -(C₂-₄ alkynylene)-(5-6 membered heteroaryl); or o -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), -0-(C2-e alkynyl), or azido.

58. The method of any one of claims 41-53, wherein A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) 4-8 membered heteroalkyl.

59. The method of any one of claims 41-53, wherein A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) -0-(C4_₇ alkyl).

60. The method of any one of claims 41-53, wherein A¹ is phenyl substituted by -O-butyl, -O- pentyl, or -O-hexyl.

61. The method of any one of claims 41-53, wherein A¹ is phenyl substituted by -O-pentyl or -O-hexyl at the />ara-position of the phenyl group.

62. The method of any one of claims 41-53, wherein A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) a 2-4 membered heteroalkyl substituted by a 5-6 membered heteroaryl.

63. The method of any one of claims 41-53, wherein A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) a 2-4 membered heteroalkyl substituted by pyridinyl.

64. The method of any one of claims 41-53, wherein A¹ is phenyl substituted by (a) 0 or 1 occurrences of Y² and (b) -C≡C-(C_W alkylene)-OR⁴.

65. The method of any one of claims 1-8, wherein the compound is a compound of Formula C-I or a pharmaceutically acceptable salt thereof.

66. The method of claim 65, wherein R¹ represents independently for each occurrence C1-4 alkyl, Ci^ haloalkyl, Ci-₄ alkoxyl, cyclopropyl, cyano, chloro, or fiuoro.

67. The method of claim 65, wherein R¹ is methyl.

68. The method of any one of claims 65-67, wherein n is 2.

69. The method of claim 68, wherein the R¹ groups are located at the 2 and 4 positions of the imidazo[l,5-a]pyrimidinyl.

70. The method of any one of claims 65-69, wherein R² is hydrogen.

71. The method of any one of claims 65-70, wherein R³ and R⁴ each represent independently for each occurrence hydrogen, methyl, or ethyl.

72. The method of any one of claims 65-71, wherein X¹ is

73. The method of any one of claims 65-71, wherein X¹ is or -C(0)-(3-6 membered heterocycloalkylene containing at least one ring -N(H)-

74. The method of any one of claims 65-73, wherein A¹ is C5-10 cycloalkyl substituted once by Y¹ and 0-1 occurrences of Y².

75. The method of any one of claims 65-73, wherein A¹ is C3-7 cycloalkyl substituted once by Y¹ and 0-1 occurrences of Y².

76. The method of any one of claims 65-73, wherein A¹ is a bicyclic carbocyclyl that is

partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y¹ and 0, 1, or 2 occurrences of Y².

77. The method of any one of claims 65-73, wherein A¹ is phenyl substituted once by Y¹ and 0- 1 occurrences of Y².

78. The method of any one of claims 65-73, wherein A¹ is a 5-6 membered heteroaryl

substituted once by Y¹ and 0-1 occurrences of Y .

79. The method of any one of claims 65-73, wherein A¹ is a bicyclic carbocyclyl that is

partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y² selected from the group consisting of C_1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-₆ haloalkyl, hydroxyl, and C_1-6 alkoxyl.

80. The method of any one of claims 65-73, wherein A¹ is

wherein m is 0, 1, or 2; and Y² represents independently for each occurrence C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, hydroxyl, or C_1-6 alkoxyl.

81. The method of any one of claims 65-78, wherein any occurrence of Y² is independently C_1-6 alkyl, C3-6 cycloalkyl, halogen, C_1-6 haloalkyl, or hydroxyl.

82. The method of any one of claims 65-78, wherein any occurrence of Y² is independently C_1-3 alkyl.

83. The method of any one of claims 65-78, 81, or 82, wherein Y¹ is a 2-8 membered

heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl.

84. The method of any one of claims 65-78, 81, or 82, wherein Y¹ is -0-(Ci_7 alkyl).

85. The method of any one of claims 65-78, 81, or 82, wherein Y¹ is -O-butyl, -O-pentyl, or -O- hexyl.

86. The method of any one of claims 65-78, 81, or 82, wherein Y¹ is -(C_1-3 alkylene)-0-(5-6 membered heteroaryl).

87. The method of any one of claims 65-78, 81, or 82, wherein Y¹ is a 3-10 membered

heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -0-(3-6 membered heterocyclyl), -0-(6- 10 membered aryl), or -0-(C2-e alkynyl).

88. The method of any one of claims 65-78, 81, or 82, wherein Y¹ is a 3-10 membered

heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl.

89. The method of any one of claims 65-78, 81, or 82, wherein Y¹ is 5-membered heteroaryl.

90. The method of any one of claims 65-78, 81, or 82, wherein Y¹ is furanyl, pyrrolyl,

thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.

91. The method of any one of claims 65-78, 81, or 82, wherein Y¹ is C2-₆ alkynyl, -C≡C-(Ci_6 alkylene)-OR⁴, -C≡C-(C_1-6 alkylene)-N(R )₂, -(C_2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl.

92. The method of any one of claims 65-78, 81, or 82, wherein Y¹ is C2-6 alkynyl.

93. The method of any one of claims 65-78, 81, or 82, wherein Y¹ is -C≡CH.

94. The method of any one of claims 65-78, 81, or 82, wherein Y¹ is -C≡C-(Ci_-6 alkylene)-OR⁴.

95. The method of any one of claims 65-78, 81, or 82, wherein Y¹ is -C≡C-CH₂-0-CH₃.

96. The method of any one of claims 1-95, wherein the compound is a compound in any one of Tables 1-9 herein or a pharmaceutically acceptable salt thereof

97. The method of any one of claims 1-96, wherein the patient is a human.