EA041819B1 - SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINES AND THEIR USE IN THE TREATMENT OF DISEASES - Google Patents

Description

The field of technology to which the invention belongs

The invention provides substituted pyrazolo[1,5-a]pyrimidines, including specific compounds, pharmaceutical compositions containing such compounds, and a method of treating a disease selected from the group consisting of Gaucher's disease, Parkinson's disease, and Lewy body disease in a patient.

State of the art

Gaucher disease is an inherited disease caused by a deficiency of the lysosomal enzyme glucocerebrosidase. Gaucher disease has been reported to have an incidence of approximately 1 in 20,000 live births per general population and is a typical lysosomal storage disease. Current treatments for patients suffering from this disease include enzyme replacement therapy, which is usually expensive, analgesics to relieve bone pain, and medical procedures such as blood and platelet transfusions, splenectomy, and joint replacement in patients suffering from bone erosion. However, new treatment options are needed that are more effective in a wider range of patients and/or reduce side effects.

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

In this regard, there is a need for new therapeutic agents for the treatment of Gaucher's disease, Parkinson's disease and related medical disorders. The present invention addresses this problem and provides other related benefits.

The essence of the invention

The present invention provides substituted pyrazolo[1,5-a]pyrimidines, including specific compounds, pharmaceutical compositions containing such compounds, and a method of treating a disease selected from the group consisting of Gaucher's disease, Parkinson's disease, and Lewy body disease in a patient. In the following, various aspects and embodiments of the invention are described in more detail.

Accordingly, one aspect of the invention provides a pharmaceutical composition having the ability to activate glucocerebrosidase (Gcase) containing a compound of formula I

(I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein:

R ¹ is independently at each occurrence C _1-4 alkyl, C _1-4 haloalkyl, CM alkoxy, cyclopropyl, cyano, chlorine or fluorine;

R ² is hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, -(CM alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, chlorine, fluorine or -N(H) ( ^R3 );

R ³ is independently at each occurrence hydrogen or C _1-4 alkyl;

R ⁴ is independently at each occurrence hydrogen, C _1-4 alkyl or —C(O)R ³ ;

X ¹ is one of the following:

(a) a carbonyl-containing linker selected from C(O)N(H)-ψ and -C(O)N(H) (C1-6 alkylene)-ψ, where ψ is a bond to A ¹ , or (b ) an amine-containing link selected from -(C ₁ . ₄ alkylene)-N(H)-ψ and -(CM alkylene)-N(H)(C _1-4 alkylene)-ψ;

A ¹ is C ₃ _ ₁₀ cycloalkyl which is substituted 1 or 2 times with Y ¹ and 0, 1, 2 or 3 times with Y ² ;

Y ¹ is independently in each case one of the following:

2-8 membered heteroalkyl optionally substituted with 6-10 membered aryl or 3-10 membered heterocyclyl;

3-10 membered heterocyclyl, 6-10 membered aryl, -O-(3-6 membered heterocyclyl), -O-(6-10 membered aryl) or -O-(C ₂ _ ₆ alkynyl); or

C ₂ _ ₆ alkynyl, -C \u003d C-(Cm alkylene) -OR ⁴ , -C ^ C - (C1.6 alkylene) -N (R ³ ) 2, - (C ₂ _ ₄ alkynylene) - (5- 6 member

- 1 041819 heteroaryl) or C _2-6 alkenyl;

Y ² is independently at each occurrence, C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, C2-4 alkynyl, cyano, azido, -N( R ³ )2, -( _C1.6 alkylene)-(5-6 membered heterocyclyl), -(C1-6 alkylene)-CO ₂ R ³ or C _1-6 haloalkyl-substituted C _3-6 cycloalkyl and n is 1 , 2 or 3.

Another aspect of the invention provides a compound of formula IIa:

(Ila) or a pharmaceutically acceptable salt thereof, wherein

R ¹ and R ² are each independently at each occurrence hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, -( _C1.4 alkylene)-(2-6 membered heteroalkyl) , cyclopropyl, cyano, chlorine or fluorine;

R ³ is independently at each occurrence hydrogen or C _1-4 alkyl;

X ¹ is one of the following:

(a) a carbonyl-containing linker selected from C(O)N(H)-ψ and -C(O)N(H) (C _1-6 alkylene)-ψ, where ψ is a bond to A ¹ ; or (b) an amine-containing linker selected from -(Ci. ₄ alkylene)-N(H)-ψ and -(Ci. ₄ alkylene)-N(H)(Ci. ₄ alkylene)-ψ;

A ¹ is C ₃ . ₁₀ cycloalkyl which is substituted with (a) 1, 2 or 3 halogens and (b) 0, 1, 2 or 3 times with Y ² ;

Y ² is independently at each occurrence, C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, azido, -N(R ³ )2, -(C1-6 alkylene)-(5-6 membered heterocyclyl), -(C _1-6 alkylene)-CO ₂ R ³ or C _1-6 haloalkyl-substituted C _3-6 cycloalkyl and n is 1, 2 or 3.

Specific pyrazolo[1,5-a]pyrimidines are disclosed in the detailed description and examples of the invention.

Another aspect of the invention provides a pharmaceutical composition having the ability to activate glucocerebrosidase (Gcase) containing a compound of formula IIa or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Another aspect of the invention provides a compound of formula I

I(R ¹ )n+ L/^ ^r2 x ¹ -(a>

(I) or a pharmaceutically acceptable salt thereof, wherein

R ¹ is independently at each occurrence C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, cyclopropyl, cyano, chlorine or fluorine;

R ² is hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, -(C _1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, chlorine, fluoro or -N (H)(R ³ );

R ³ is independently at each occurrence hydrogen or C _1-4 alkyl;

X ¹ is one of the following:

(a) a carbonyl-containing linker selected from C(O)N(H)-ψ and -C(O)N(H) (C _1-6 alkylene)-ψ, where ψ is a bond to A ¹ , or ( b) an amine-containing linker selected from -(C _1-4 alkylene)-N(H)-ψ and -(C _1-4 alkylene)-N(H)(C _1-4 alkylene)-ψ;

A ¹ is C _3-10 cycloalkyl which is substituted 1 or 2 times with Y ¹ and 0, 1, 2 or 3 times with Y ² ;

Y ¹ is -O-(C _1-7 alkyl);

Y ² is independently at each occurrence, C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, C2-4 alkynyl, cyano, azido, -N( R ³ )2, -(C1-6 alkylene)-(5-6 membered heterocyclyl), -(C _1-6 alkylene)-CO ₂ R ³ or C _1-6 haloalkyl-substituted C _3-6 cycloalkyl and n is 1, 2 or 3.

Another aspect of the invention provides a method for treating a disease selected from the group consisting of Gaucher's disease, Parkinson's disease and Lewy body disease in a patient. The method includes administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or formula IIa or a pharmaceutical composition for the treatment of a disease selected from the group

- 2 041819 consisting of Gaucher's disease, Parkinson's disease and Lewy body disease.

Detailed description of the invention

The invention provides substituted pyrazolo[1,5-a]pyrimidines, pharmaceutical compositions containing such compounds, and a method for treating a disease selected from the group consisting of Gaucher's disease, Parkinson's disease and Lewy body disease in a patient. Unless otherwise indicated, conventional methods of organic chemistry, pharmacology, cell biology and biochemistry are used in the practice of the present invention. Such methods are set forth in publications such as Comprehensive Organic Synthesis (B.M. Trost & I. Fleming, eds., 1991-1992); Current protocols in molecular biology (F.M. Ausubel et al., eds., 1987, and updates from time to time); and Current protocols in immunology (J.E. Coligan et al., eds., 1991), the content of each of which is incorporated into the present invention by reference. Various aspects of the invention are set forth in the sections below; however, the aspects of the invention described in one particular section are not limited to any particular section.

I. Definitions

For a more complete understanding of the present invention, the following are definitions of a number of terms and expressions.

Used in the invention, the singular means one or more and includes the plural form, unless it is contrary to the context.

The term alkyl as used herein refers to a saturated linear or branched hydrocarbon such as a linear or branched group containing 1-12, 1-10 or 1-6 carbon atoms, referred to in the invention as C1- _C12 alkyl, _C1 - _C10 alkyl and C1- _C6 alkyl, respectively. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl and other alkyls.

The term alkylene refers to the divalent radical of an alkyl group. An example of an alkylene group is CH2CH2-.

The term haloalkyl refers to an alkyl group that is substituted with at least one halogen. For example, -CH2F, -CHF2, -CF ₃ , -CH ₂ CF ₃ , -CF ₂ CF ₃ and other similar haloalkyls.

As used herein, _the term heteroalkyl refers to _an alkyl group _in which at least one carbon atom has been replaced by an O or S atom _. an O-C ₁ -C ₆ alkyl group or a C1-C6 alkylene-OH group. In specific embodiments, the heteroalkyl may be 2-8 membered heteroalkyl, which means that the heteroalkyl contains from 2 to 8 atoms selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. In yet other embodiments, heteroalkyl is a 2-6 membered, 4-8 membered, or 5-8 membered heteroalkyl group (which may contain, for example, 1 or 2 heteroatoms selected from the group of oxygen and nitrogen). In specific embodiments, heteroalkyl is an alkyl group in which 1-3 carbon atoms have been replaced by oxygen atoms. One type of heteroalkyl group is an alkoxy group.

As used herein, the term alkenyl refers to an unsaturated linear or branched hydrocarbon having at least one carbon-carbon double bond, such as a linear or branched group containing 2-12, 2-10 or 2-6 carbon atoms, referred to in the invention as C ₂ _C ₁₂ alkenyl, C ₂ -C ₁₀ alkenyl and C ₂ -C ₆ alkenyl, respectively. Examples of alkenyl groups include vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene)pentenyl, and other similar alkenyls.

As used herein, the term alkynyl refers to an unsaturated linear or branched hydrocarbon having at least one carbon-carbon triple bond, such as a linear or branched group containing 2-12, 2-10 or 2-6 carbon atoms, referred to in the invention as C ₂ -C ₁₂ alkynyl, C ₂ -C ₁₀ alkynyl and C ₂ -C ₆ alkynyl, respectively. Examples of alkynyl groups include ethynyl, prop-1-yn-1-yl, and but-1-yn-1-yl.

The term cycloalkyl refers to a monovalent saturated cyclic, bicyclic or bridged cyclic (e.g. adamantyl) hydrocarbon group containing 3-12, 3-8, 4-8 or 4-6 carbons, referred to in the invention, for example, _C4-8 cycloalkyl, obtained from cycloalkane. Examples of cycloalkyl groups include, but are not limited to, cyclohexanes, cyclopentanes, cyclobutanes, and cyclopropanes. Unless otherwise indicated, 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 may be fused with other cycloalkyl, aryl or heterocyclyl groups. In specific

- 3 041819 embodiments, the cycloalkyl group is not substituted, that is, it is unsubstituted.

The term cycloalkylene refers to a divalent radical of a cycloalkyl group. An example of a cycloalkylene group is

As used herein, the term cycloalkenyl refers to a monovalent unsaturated cyclic, bicyclic, or bridged cyclic (e.g., alamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons containing one carbon-carbon double bond, referred to as invention, for example, C ₄ - ₈ cycloalkenyl derived from cycloalkane. Examples of cycloalkenyl groups include, but are not limited to, cyclohexenes, cyclopentenes, and cyclobutenes. Unless otherwise indicated, 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 specific embodiments, the cycloalkenyl group is unsubstituted, that is, it is unsubstituted.

The term aryl is conventional and refers to a carbocyclic aromatic group. Representative aryl groups include phenyl, naphthyl, anthracenyl, and the like. The term aryl includes polycyclic ring systems having two or more carbocyclic rings in which two or more carbons are shared by two adjacent rings (the rings are fused rings) where at least one of the rings is aromatic and, for example, the other ring ( other rings) may be cycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls. Unless otherwise indicated, an aromatic ring may be substituted at one or more positions with, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, sulfhydryl, imino, amido, carboxylic acid, C(O)alkyl, CO ₂ alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl fragments, -CF3, -CN or other similar substituents. In specific embodiments, the aromatic ring is substituted at one or more ring positions with halo, alkyl, hydroxyl, or alkoxy. In other specific embodiments, the aromatic ring is unsubstituted, that is, it is unsubstituted. In specific embodiments, the aryl group is a 6-10 membered ring structure.

The term aralkyl refers to an alkyl group substituted with an aryl group.

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 non-aromatic. Representative examples of a bicyclic carbocyclyl that is partially unsaturated ΓΥλ ΥΥΊ ΓΎΥ include, for ^example

The terms ortho, meta and para are generally accepted and refer to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and orthodimethylbenzene are identical.

The terms heterocyclyl and heterocyclic group are conventional and refer to saturated, partially unsaturated or aromatic 3-10 membered ring structures, alternatively 3-7 membered rings whose ring structures include one to four heteroatoms such as nitrogen, oxygen and sulfur. The number of ring atoms in a heterocyclyl group may be indicated using the nomenclature C _x -C _x , where x is an integer indicating the number of ring atoms. For example, C ₃ -C ₇ heterocyclyl group refers to a saturated or partially unsaturated 3-7 membered ring structure containing one to four heteroatoms such as nitrogen, oxygen and sulfur. The designation C ₃ -C ₇ indicates that the heterocyclic ring contains a total of 3 to 7 ring atoms, including any heteroatoms that occupy the position of the ring atom. One example of C ₃ heterocyclyl is aziridinyl. The heterocycles may also be mono-, bi-, or other polycyclic ring systems, including a spirocyclic ring system, wherein at least one ring contains a ring heteroatom. The 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, pyrazolidinyl, pyrandinyl, pyrimidinyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyr- 4 041819 nyl, tetrahydroquinolyl, thiazolidinyl, thiolanyl, thiomorpholinyl, thiopyranyl, xanthenyl, lactones, lactams such as azetidinones and pyrrolidinones, sultams and the like, sultams heterocyclyl groups. Unless otherwise indicated, 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 specific embodiments, the implementation of the heterocyclyl group is not substituted, that is, it is unsubstituted.

The term bicyclic heterocyclyl refers to a heterocyclyl group that contains two rings that are fused to each other. Typical examples of bicyclic

heterocyclyl include, for example, ·

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

The term heterocycloalkyl is conventional and refers to a saturated heterocyclyl group as defined above. In specific embodiments, heterocycloalkyl is 3-10 membered ring structures, alternatively 3-7 membered rings, whose ring structures include one to four heteroatoms such as nitrogen, oxygen and sulfur.

The term heterocycloalkylene refers to a divalent radical of a heterocycloalkyl group. An example of a heterocycloalkylene group is

The heterocycloalkylene may contain, for example, 3-6 ring atoms (ie, a 3-6 membered heterocycloalkylene). In particular embodiments, the heterocycloalkylene is a 3-6 membered heterocycloalkyl containing 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur.

The term heteroaryl is generally accepted and refers to aromatic groups that include at least one ring heteroatom. In some instances, the heteroaryl group contains 1, 2, 3, or 4 ring heteroatoms. Typical examples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl and other similar groups. Unless otherwise indicated, a heteroaryl ring may be substituted at one or more ring positions with, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, sulfhydryl, imino, amido, carboxylic acid, -C(O)alkyl, -CO ₂ alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl fragments, -CF ₃ , -CN or the like deputies. The term heteroaryl also includes polycyclic ring systems having two or more rings in which two or more carbons are shared by two adjacent rings (the rings are fused rings), where at least one of the rings is, for example, heteroaromatic and the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls and/or aryls. In specific embodiments, the heteroaryl ring is substituted at one or more ring positions with halo, alkyl, hydroxy, or alkoxy. In other specific embodiments, the heteroaryl ring is unsubstituted, that is, it is unsubstituted. In specific embodiments, the heteroaryl group is a 5-10 membered ring structure, alternatively a 5-6 membered ring structure, whose ring structure includes 1, 2, 3, or 4 heteroatoms such as nitrogen, oxygen, and sulfur.

The term heteroaralkyl refers to an alkyl group substituted with a heteroaryl group.

The terms amine and amino are generally accepted and refer to both unsubstituted and substituted amines, for example a moiety represented by the general formula -N(R ⁵⁰ )(R ⁵¹ ), where

R ⁵⁰ and R ⁵¹ are each independently hydrogen, alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl, aralkyl or (CH2) _m -R ⁶¹ or

R ⁵⁰ and R ⁵¹ taken together with the N atom to which they are attached form a heterocycle having 4 to 8 atoms in the ring structure;

R ⁶¹ is aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle and

- 5 041819 m is zero or an integer in the range 1 to 8.

In specific embodiments, R ⁵⁰ and R ⁵¹ are each independently hydrogen, alkyl, alkenyl, or -(CH2) _m -R ⁶¹ .

The terms alkoxy or alkoxy are conventional and refer to an alkyl group as defined above having an oxygen radical attached to it. Representative alkoxy groups include methoxy, ethoxy, propyloxy, t-butoxy, and the like. An ether is two hydrocarbons covalently bonded with oxygen. Accordingly, such an alkyl substituent results in the formation of an alkyl ether that is or resembles an alkoxy, such as represented by one of -O-alkyl, -O-alkenyl, O-alkynyl, -O-(CH ₂ ) _m -R ₆₁ , where m and R61 are described above.

As used herein, the term carbamate refers to a radical of the formula R _g OC(O)N(R _h ), R _g OC(O)N(R _h )R _i or OC(O)NR _h Ri, where R _g , R _h and Ri are each independently alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro , sulfide, sulfonyl or sulfonamide. Examples of carbamates include aryl carbamates and heteroaryl carbamates, where, for example, at least one of Rg, R _h and Ri are independently aryl or heteroaryl such as phenyl and pyridinyl.

Used in the invention, the term carbonyl refers to the radical -C(O)-.

Used in the invention, the term carboxamido refers to the radical-C(O)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.

As used herein, the term carboxy refers to the COOH radical or its corresponding salts, eg -COONa and so on.

As used herein, the term amide or amido refers to a radical of the formula R _a C(O)N(R _b ), R _a C(O)N(R _b )R _c , -C(O)NR _b R _{c ,} or -C( O)NH2, where Ra, 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 carbon, nitrogen, R _b , Rc or Ra. The amide may also be cyclic, for example R _b and Rc Ra and R _b or Ra and R _c may be combined to form a 3-12 membered ring such as a 3-10 membered ring or a 5-6 membered ring.

As used herein, the term amidino refers to a radical of the formula 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.

As used herein, the term alkanoyl refers to the -O-CO-alkyl radical.

The term oxo is generally accepted and refers to the =O substituent. For example, oxo-substituted cyclopentane is cyclopentanone.

As used herein, the term sulfonamide or sulfonamido refers to a radical having the structure -N(R _r )-S(O) ₂ -R _s - or -S(O) ₂ -N(R _r )R _s where R _r and R _s may be, for example, hydrogen, alkyl, aryl, cycloalkyl and heterocyclyl. Examples of sulfonamides include alkylsulfonamides (eg, where R _s is alkyl), arylsulfonamides (eg, where R _s is aryl), cycloalkylsulfonamides (eg, where R _s is cycloalkyl) and heterocyclylsulfonamides (eg, where R s is heterocyclyl), and so on.

As used herein, the term sulfonyl refers to a radical having the structure R _u SO ₂ , where R _u can be alkyl, aryl, cycloalkyl and heterocyclyl, for example alkylsulfonyl. As used herein, the term alkylsulfonyl refers to an alkyl group attached to a sulfonyl group.

The symbol indicates the connection point.

The compounds of the invention may contain one or more chiral centers and/or double bonds and therefore exist as stereoisomers such as geometric isomers, enantiomers or diastereomers. As used herein, the term stereoisomers includes all geometric isomers, enantiomers or diastereomers. These compounds may be designated R or S, depending on the configuration of the substituents around the stereogenic carbon atom. The present invention covers various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be labeled with the symbol (+), but one of ordinary skill in the art will appreciate that the structure may implicitly contain a chiral center. It should be borne in mind that the graphic representations of chemical structures, such as general chemical structures, cover all stereoisomeric forms of these compounds, unless otherwise indicated.

The individual stereoisomers of the compounds of the present invention may be synthesized from commercially available starting materials which contain asymmetric centers or stereogenic centers or may be prepared in the form of racemic mixtures and then resolved by methods well known to those of ordinary skill in the art. Examples of these separation methods

- 6 041819 are:

(1) reacting a mixture of enantiomers with a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography and isolating the optically pure product from the auxiliary, (2) forming a salt using an optically active resolving agent, or (3) directly separating the mixture of optical enantiomers by chiral chromatographic columns.

Stereoisomeric mixtures may also be separated into their constituent components by well-known methods such as chiral phase gas chromatography, chiral high performance liquid chromatography, crystallization of a compound in the form of a chiral complex salt, or crystallization of a compound in a chiral solvent. In addition, enantiomers can be separated by supercritical fluid chromatography (SFC) methods described in the literature. Moreover, stereoisomers can be obtained from stereoisomerically pure intermediates, reagents and catalysts by well-known asymmetric synthesis methods.

The compounds of the present invention may also exist in the form of geometric isomers.

The symbol = denotes a bond, which can be, as described in the invention, single, double or triple. The present invention encompasses various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or the arrangement of substituents around a carbocyclic ring. Substituents around the carbon-carbon double bond are referred to as being in the Z or E configuration, where the terms Z and E are used in accordance with IUPAC rules. Unless otherwise indicated, double bond structures encompass both the E and Z isomers.

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

The invention also encompasses isotopically labeled compounds of the invention which are identical to the compounds described in the invention, except that one or more of their atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes ^of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine such as ² H, ³ H, 13 C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ 0 , ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl, respectively.

Specific isotopically labeled disclosed compounds (eg, compounds labeled with ³ H and ¹⁴ C) are used in studies of the distribution of the compound and/or substrate in tissues. Tritium (ie, ³ H) and carbon-14 (ie, ¹⁴ C) labeled compounds are particularly preferred because of their ease of preparation and detection. In addition, substitution with heavier isotopes such as deuterium (i.e., ² H) may confer certain therapeutic advantages due to higher metabolic stability (eg, increased in vivo half-life or reduced dose required), and therefore may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by the following methods, which are similar to those disclosed, for example, in the examples of the invention, by replacing a non-isotopically labeled reagent with an isotopically labeled reagent.

As used herein, the terms subject and patient refer to living beings that are treated with the methods of the present invention. Such living beings are preferably mammals (eg mice, monkeys, horses, ruminants, pigs, dogs, cats and the like) and more preferably humans.

As used herein, the term effective amount refers to an amount of a compound (eg, a compound of the present invention) that is sufficient to achieve beneficial or desired results. An effective amount may be administered in one or more administrations, applications, or doses and is not intended to be limited to a particular dosage form or route of administration. As used herein, the term "treatment" includes any effect, such as alleviation, reduction, modulation, amelioration, or elimination, that results in an amelioration of a condition, disease, disorder, and other similar disease states, or improvement in their symptoms.

Used in the invention, the term pharmaceutical composition refers to the combination of active drug with a carrier, inert or active, obtaining a composition, especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

- 7 041819

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

As used herein, the term pharmaceutically acceptable salt refers to any pharmaceutically acceptable salt (e.g., an acid or base addition salt) of a compound of the present invention which, when administered to a subject, is capable of providing a compound of the invention or an active metabolite or fragment thereof. Those skilled in the art will recognize that salts of the compounds of the present invention may be prepared from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, chloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic , benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid and other similar acids. Other acids such as oxalic acid, although not pharmaceutically acceptable per se, may be used in the preparation of salts useful as intermediates in the preparation of the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Examples of bases include, but are not limited to, alkali metal (eg sodium) hydroxides, alkaline earth metal (eg magnesium), ammonium hydroxides, and compounds of formula NW4+ where W is C _1-4 alkyl, and other similar bases.

Examples of salts include, but are not limited to, acetates, adipates, alginates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentane propionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, flucoheptanoates, glycerophosphates, hemisulfates, heptanoates , hydrochlorides, hydrobromides, hydroiodides, 2hydroxyethanesulfonates, lactates, maleates, metpansulfonates, 2-naphthalenesulfonates, nicotinates, oxalates, palmoates, pectinates, persulfates, phenylpropionates, picrates, pivalates, propionates, succinates, tartrates, thiocyanates, tosylates, undecanoates and other similar salts . Other examples of salts include anions of the compounds of the present invention reacted with a suitable cation such as Na ⁺ , NH4 ⁺ and NW4+ (where W is a C _1-4 alkyl group) and other similar salts.

In the case of therapeutic use, the salts of the compounds of the present invention are expected to be pharmaceutically acceptable. However, salts of acids and bases that are not pharmaceutically acceptable can also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

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

In the description of the invention, in cases where compositions are described having, including or containing specific components, or when methods are described having, including or containing specific steps, it is assumed that in addition there are compositions of the present invention that mainly consist or consist of of these components, and that there are methods of the present invention that essentially consist or consist of the listed processing steps.

In General, the composition of the compositions are specified in percent by weight, unless otherwise indicated. Also, if no definition is given for a variable, then the previous definition is valid for that variable.

II. Substituted parazolo[1,5-a]pyrimidine compounds

One aspect of the invention provides substituted pyrazolo[1,5-a]pyrimidine compounds. It is contemplated that substituted pyrazolo[1,5-a]pyrimidines may be used in the methods and compositions described herein. In specific embodiments, the substituted pyrazolo[1,5a]πyrimidine compounds are a compound encompassed by Formula I:

- 8 041819 or a pharmaceutically acceptable salt thereof, where

R ¹ is independently at each occurrence C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, cyclopropyl, cyano, chlorine or fluorine;

R ² is hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, -(C _1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, chlorine, fluoro or -N (H)(R ³ );

R ³ is independently at each occurrence hydrogen or C _1-4 alkyl;

X ¹ is one of the following:

(a) a carbonyl-containing linker selected from C(O)N(H)-ψ and -C(O)N(H)(C _1-6 alkylene)-ψ, where ψ is a bond to A ¹ , or ( b) an amine-containing linker selected from -(C _1-4 alkylene)-N(H)-ψ and -(C _1-4 alkylene)-N(H)(C _1-4 alkylene)-ψ;

A ¹ is C ₃ - ₁₀ cycloalkyl which is substituted 1 or 2 times with Y ¹ and 0, 1, 2 or 3 times with Y ² ;

Y ¹ is -O-(C _1-7 alkyl);

Y ² is independently at each occurrence C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, C2-4 alkynyl, cyano, azido, -N(R ³ )2, -(C _1-6 alkylene)-(5-6 membered heterocyclyl), -(C _1-6 alkylene)-CO ₂ R ³ or C 1-6 haloalkyl-substituted C ₃ - ₆ cycloalkyl and n is 1 , 2 or 3.

The definitions of the variables in Formula I above cover a variety of chemical groups. The invention provides for embodiments in which, for example,

i) the variable definition is one single chemical group selected from those chemical groups listed above, ii) the definition is a set of two or more chemical groups selected from those chemical groups listed above, and iii) the compound is defined by the combination variables, in which the variables are defined in paragraph (i) or (ii), for example, one in which R ¹ represents C 1-4 alkyl or cyclopropyl,

X ¹ is -C(O)N(H)-ψ and

A ¹ is phenyl substituted with 4-8 membered heteroalkyl.

Accordingly, in particular embodiments, R ¹ is independently at each occurrence C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, cyclopropyl, cyano, chlorine, or fluoro. In specific embodiments, R ¹ is methyl. In specific embodiments, the R ¹ groups are located at positions 5 and 7 of the pyrazolo[1,5-a]-pyrimidinyl.

In specific embodiments, n is 2. In other specific embodiments, n is 1.

In specific embodiments, R ² is hydrogen. In specific embodiments, R ² is methyl or halogen. In specific embodiments, R ² is methyl or halomethyl. In specific embodiments, R ² is methyl or cyclopropyl.

In particular embodiments, R ³ and R ⁴ are each independently at each occurrence hydrogen, methyl, or ethyl. In specific embodiments, R ³ is hydrogen.

In specific embodiments, X ¹ is -C(O)N(H)-ψ.

In particular embodiments, whenever present, Y ² is independently C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, or hydroxyl. In specific embodiments, whenever present, Y ² is independently C1-3 alkyl.

In specific embodiments, A ¹ is C3-7 cycloalkyl substituted once with Y ¹ and 0-1 times with Y ² . In specific embodiments, A ¹ is _C5-10 cycloalkyl which is substituted 1 or 2 times with Y ¹ and 0, 1, 2 or 3 times with Y ² .

In specific embodiments, Y ¹ is -O-(C ₁ - ₇ alkyl).

The above description discloses a variety of embodiments relating to compounds of formula I. The invention specifically provides all combinations of embodiments. For example, the invention provides a compound of formula I wherein X ¹ is -C(O)N(H)-ψ, A ¹ is C3-10 cycloalkyl substituted 0, 1, 2 or 3 times with Y ² , and Y ¹ is -O-( _C1-7 alkyl).

In specific embodiments, the compound is a compound of formula I-A

^R1

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

- 9 041819

R ¹ is independently methyl, cyclopropyl or isopropyl;

R ² is hydrogen;

R ³ is independently at each occurrence hydrogen or C _1-4 alkyl;

A ¹ is C _3-10 cycloalkyl which is substituted 1 or 2 times with Y ¹ and 0, 1, 2 or 3 times with Y ² ;

Y ¹ is -O-(C _1-7 alkyl) and

Y ² is independently at each occurrence, C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, azido, -N(R ³ )2, -(C _1-6 alkylene)-(5-6 membered heterocyclyl), -(C _1-6 alkylene)-CO ₂ R ³ or C _1-6 haloalkyl-substituted C _3-6 cycloalkyl.

The definitions of the variables in Formula I-A above cover a variety of chemical groups. The invention provides for embodiments in which, for example,

i) the variable definition is one single chemical group selected from those chemical groups listed above, ii) the definition is a set of two or more chemical groups selected from those chemical groups listed above, and iii) the compound is defined by the combination variables, in which the variables are defined in paragraph (i) or (ii).

Accordingly, in specific embodiments, in any event, Y ² is independently C _1-3 alkyl, halogen, or C _1-3 haloalkyl.

In specific embodiments, A ¹ is C _3-10 cycloalkyl which is substituted 1 or 2 times with Y ¹ and 0, 1, 2 or 3 times with Y ² .

In specific embodiments, R ¹ is methyl. In specific embodiments, R ¹ is further selected from halogen and halomethyl, such that R ¹ may be methyl, halogen, or halomethyl.

The above description discloses a variety of embodiments relating to compounds of formula IA. The invention specifically provides all combinations of embodiments. For example, the invention provides a compound of formula IA wherein R ¹ is methyl and A ¹ is C3-10 cycloalkyl substituted (a) 0, 1, 2 or 3 times with Y ² and (b) C4-8 alkoxy.

The definitions of the variables in Formula I-A above cover a variety of chemical groups. The invention provides for embodiments in which, for example,

i) the variable definition is one single chemical group selected from those chemical groups listed above, ii) the definition is a set of two or more chemical groups selected from those chemical groups listed above, and iii) the compound is defined by the combination variables, in which the variables are defined in paragraph (i) or (ii), for example, such where R ¹ represents methyl and A ¹ represents C _3-10 cycloalkyl, substituted with C _4-8 alkoxy.

Accordingly, in specific embodiments, in any event, Y ² is independently C _1-3 alkyl, halogen, or C _1-3 haloalkyl.

In specific embodiments, R ¹ is methyl.

Another aspect of the invention provides a compound of formula IIa

(On) or a pharmaceutically acceptable salt thereof, wherein

R ¹ and R ² are each independently at each occurrence hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, -(C _1-4 alkylene)-(2-6 membered heteroalkyl ), cyclopropyl, cyano, chlorine or fluorine;

R ³ is independently at each occurrence hydrogen or C _1-4 alkyl;

X ¹ is one of the following:

(a) a carbonyl link selected from C(O)N(H)-ψ and -C(O)N(H)(C _1-6 alkylene)-ψ, where ψ is a bond to A ¹ ; or (b) an amine-containing link selected from -(C _1-4 alkylene)-N(H)-ψ and -(C _1-4 alkylene)-N(H)(C _1-4 alkylene)-ψ;

A ¹ is C _3-10 cycloalkyl which is substituted with (a) 1, 2 or 3 halogens and (b) 0, 1, 2 or 3 times with Y ² ;

Y ² is independently at each occurrence, C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, azido, -N(R ³ )2, -(C _1-6 alkylene)-(5-6 membered heterocyclyl), -(C _1-6 alkylene)-CO ₂ R ³ or C _1-6 haloalkyl-substituted C _3-6 cycloalkyl and n is 1, 2 or 3.

The definitions of the variables in Formula IIa above cover a variety of chemical

- 10 041819 groups. The invention provides for embodiments in which, for example,

i) the variable definition is one single chemical group selected from those chemical groups listed above, ii) the definition is a set of two or more chemical groups selected from those chemical groups listed above, and iii) the compound is defined by the combination variables, in which the variables are defined in paragraph (i) or (ii), for example, one in which R ¹ represents C1-4 alkyl or cyclopropyl, X ¹ represents -C(O)N(H)-ψ and A ¹ is C3-10 cycloalkyl substituted with 1, 2 or 3 halogens.

Accordingly, in particular embodiments, R ¹ is independently at each occurrence C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, cyclopropyl, cyano, chlorine, or fluoro. In specific embodiments, R ¹ is methyl.

In particular embodiments, n is 2.

In specific embodiments, the R ¹ groups are located at positions 5 and 7 of the pyrazolo[1,5a]pyrimidinyl.

In specific embodiments, X ¹ is -C (Ο)Ν(Η) -ψ.

In other specific embodiments, the compound is one of the compounds below, or a pharmaceutically acceptable salt thereof

Methods for preparing the compounds described in the invention are illustrated in the synthesis schemes below. These diagrams are provided for the purpose of illustrating the invention and should not be construed as limiting the scope or spirit of the invention in any way. The starting materials shown in the schemes can be purchased from manufacturers or can be synthesized in accordance with the methods described in the literature.

The synthetic method illustrated in Scheme 1 demonstrates an example of a procedure for the preparation of substituted pyrazolo[1,5-a]pyrimidine compounds. In the first stage, ethyl 5-amino-1H-pyrazole-4-carboxylate (Ri=H) A is subjected to a condensation reaction with pentane-2,4-dione (Ri-R ^iv =Me; Rii-H) in acetic acid at 80° C to give 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid ester B. Hydrolysis of ethyl ester B under basic conditions gives 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid C.

- 11 041819

Scheme 1 o o

The synthesis method illustrated in Scheme 2 demonstrates an example of a procedure for the preparation of substituted pyrazolo[1,5-a]pyrimidine compounds. In a first step, the carboxylic acid C can be coupled with various substituted aromatic or heteroaromatic amines such as HATU and/or HOBT using standard peptide coupling techniques in DMF in the presence of DIPEA. Alternatively, carboxylic acid ester B can be treated with AlMe ₃ to give a Weinreb amide intermediate, which reacts with an amine to give the substituted amide D. coupled with Weinreb amides to give an iodine- or bromo-substituted amide E. A bromine- or iodine-containing moiety can be used to couple with various functional groups using standard coupling techniques such as acetylenes using Sonogashira coupling, boric acids using a Suzuki coupling reaction, and amines using a Buchwald coupling to give a substituted amide D.

Scheme 2

It is assumed that the methods of synthesis in Scheme 2 can be applied to obtain a number of carboxamide compounds of substituted pyrazolo[1,5-a]pyrimidine, having various substituents in positions A ¹ and Y ¹ . In addition, if a functional group that is part of A ¹ and/or Y ¹ cannot be inert under the reaction conditions described in Scheme 2, then it is assumed that the functional group is first protected using standard chemical protecting group methods, and then, after the desired chemical transformation is completed, the protecting group is removed. Additional information on the use of protecting groups in organic synthesis can be found, for example, in the monograph by Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, ^2nd ed.; Wiley: New York, 1991. In other specific embodiments, the functional group in the substituent A ¹ and Y ¹ can be converted to another functional group using known standard functional group manipulation techniques. See, for example, Comprehensive Organic Synthesis (BM Trost & I. Fleming, eds., 1991-1992).

III. Therapeutic use

The invention provides a method for the treatment of diseases such as Gaucher's disease, Parkinson's disease and Lewy body disease using a substituted pyrazolo[1,5-a]pyrimidine, related compounds and pharmaceutical compositions described in the invention. Methods of treatment include the use of the substituted pyrazolo[1,5-a]pyrimidine or related compounds described herein as independent therapeutic agents and/or as a component of combination therapy with another therapeutic agent. Without wishing to be bound by any particular theory, however, it can be argued that the substituted pyrazolo[1,5-a]pyrimidines and related organic compounds described herein can activate glucocerebrosidase (Gcase).

Ways to treat diseases

One aspect of the invention provides a method of treating a disease selected from the group consisting of Gaucher's disease, Parkinson's disease and Lewy body disease. The method includes administering to the patient, if desired, a therapeutically effective amount of the substituted pyrazolo[1,5-a]pyrimidine described herein. The connection may be a compound of formula I, as described above in section II.

In specific embodiments, the implementation of the connection is a compound of formula IIa.

In specific embodiments, the disease is Gaucher's disease,

- 12 041819

Parkinson's or Lewy body disease. In other specific embodiments, the disease is Gaucher's disease. In specific embodiments, the disease is Parkinson's disease. In specific embodiments, the disease is Lewy body disease.

In specific embodiments, the disease is an anxiety disorder, such as panic disorder, social anxiety disorder, or generalized anxiety disorder.

The efficacy of compounds in the treatment of Gaucher's disease, Parkinson's disease and Lewy body disease can be assessed by testing compounds using assay methods that are commonly used to evaluate efficacy against these diseases and/or, for example, against glucocerebrosidase (Gcase) activation and which are described below in the examples of the invention.

In specific embodiments, the patient is a human.

In specific embodiments, the compound is one of the general or specific compounds described in Section II, such as a compound of formula I, a compound encompassed by one of the additional embodiments describing definitions for specific variables of formula I, a compound of formula I-A, or a compound encompassed by one of additional embodiments describing definitions for specific variables of Formula I-A. In other specific embodiments, the compound is a compound of formula IIa or a compound covered by one of the additional embodiments describing definitions for specific variables of formula IIa.

The above description discloses a variety of embodiments relating to methods of treating various diseases using specific substituted pyrazolo[1,5-a]pyrimidines or related organic compounds. The invention specifically provides all combinations of embodiments. For example, the invention provides methods for treating Gaucher's disease, Parkinson's disease, or Lewy body disease by administering a therapeutically effective amount of a compound of Formula I-A.

Medical use and drug preparation

Another aspect of the invention relates to the compounds described in the invention and compositions used in the treatment of the disease described in the invention.

IV. Pharmaceutical compositions

The invention provides pharmaceutical compositions comprising a substituted pyrazolo[1,5-a]pyrimidine compound of formula IIa as described herein.

In another aspect, the invention provides pharmaceutical compositions containing a compound of formula I

L) or a pharmaceutically acceptable salt thereof, where

R ¹ is independently at each occurrence C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, cyclopropyl, cyano, chlorine or fluorine;

R ² is hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, -(C _1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, chlorine, fluoro or -N (H)(R ³ );

R ³ is independently at each occurrence hydrogen or C _1-4 alkyl;

R ⁴ is independently at each occurrence hydrogen, C _1-4 alkyl or —C(O)R ³ ;

X ¹ is one of the following:

(a) a carbonyl-containing linker selected from C(O)N(H)-ψ and -C(O)N(H) (C1-6 alkylene)-ψ, where ψ is a bond to A ¹ , or (b ) an amine-containing link selected from -(C ₁ - ₄ alkylene)-N(H)-ψ and -(C ₁ - ₄ alkylene)-N(H)(C _1-4 alkylene)-ψ;

A ¹ is C _3-10 cycloalkyl which is substituted 1 or 2 times with Y ¹ and 0, 1, 2 or 3 times with Y ² ;

Y ¹ is independently in each case one of the following:

2-8 membered heteroalkyl optionally substituted with 6-10 membered aryl or 3-10 membered heterocyclyl;

3-10 membered heterocyclyl, 6-10 membered aryl, -O-(3-6 membered heterocyclyl), -O-(6-10 membered aryl) or -O-(C _{2 -6} alkynyl) or

C ₂ - ₆ alkynyl, -C \u003d C-(C ₁ _ ₆ alkylene) -OR ⁴ , -C ^ C-(C1_6 alkylene) -N (K ³ ) 2, - (C ₂ . ₄ alkynylene) - (5 -6-membered heteroaryl) or C ₂ - ₆ alkenyl;

Y ² is independently in each occurrence C ₁ - ₆ alkyl, C 3-6 cycloalkyl, halogen, C ₁ - ₆ halo

- 13 041819 genalkyl, C _1-6 hydroxyalkyl, hydroxyl, C _1-6 alkoxy, C _2-4 alkynyl, cyano, azido, -N(R ³ )2, -(C1-6 alkylene) -(5-6- membered heterocyclyl), -(C1-6 alkylene)-CO2R ³ or C1-6 haloalkyl-substituted C _3-6 cycloalkyl and n is 1, 2 or 3.

In specific embodiments, the implementation of the pharmaceutical composition contains a compound of formula I, where R ¹ represents methyl. In specific embodiments, the pharmaceutical composition contains a compound of formula I, where n is 2. In other specific embodiments, the pharmaceutical composition contains a compound of formula I, where the R ¹ groups are located at the 5 and 7 positions of pyrazolo[1,5-a]pyrimidinyl. In specific embodiments, the implementation of the pharmaceutical composition contains a compound of formula I, where R ² represents hydrogen. In other specific embodiments, the implementation of the pharmaceutical composition contains a compound of formula I, where R ³ and R ⁴ each represents independently in each case, hydrogen, methyl or ethyl. In specific embodiments, the implementation of the pharmaceutical composition contains a compound of formula I, where X ¹ represents -C(O)N(H)-ψ. In other specific embodiments, the implementation of the pharmaceutical composition contains a compound of formula I, where in any case Y ² represents independently C 1-6 alkyl, C 3-6 cycloalkyl, halogen, C 1-6 haloalkyl or hydroxyl. In specific embodiments, the implementation of the pharmaceutical composition contains a compound of formula I, where in any case, Y ² represents independently C 1-3 alkyl. In other specific embodiments, the implementation of the pharmaceutical composition contains a compound of formula I, where Y ¹ represents a 2-8-membered heteroalkyl.

In specific embodiments, the implementation of the pharmaceutical composition contains a compound of formula I, where Y ¹ represents -O-(C ₁ - ₇ alkyl). In more specific embodiments, the implementation of the pharmaceutical composition contains a compound of formula I, where Y ¹ represents -O-butyl, -Opentyl or -O-hexyl.

In specific embodiments, the pharmaceutical composition comprises a compound of Formula I, wherein A ¹ is C _5-10 cycloalkyl which is substituted 1 or 2 times with Y ¹ and 0, 1, 2 or 3 times with Y ² . In more specific embodiments, the implementation of the pharmaceutical composition contains a compound of formula I, where A ¹ represents C3-7 cycloalkyl, substituted once with Y ¹ and 0-1 times with Y ² .

In specific embodiments, the pharmaceutical compositions preferably comprise a therapeutically effective amount of one or more of the substituted pyrazolo[1,5-a]pyrimidines described above, admixed together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. As described in more detail below, the pharmaceutical compositions of the present invention may be formulated specifically for administration in solid or liquid form, including in a form intended for the following routes of administration:

(1) oral administration, eg liquid preparations (aqueous or non-aqueous solutions or suspensions), tablets (eg tablets intended for buccal, sublingual and/or systemic administration), boluses, powders, granules, pastes for application to the tongue;

(2) parenteral administration, eg by subcutaneous, intramuscular, intravenous or epidural injection, eg a sterile solution or suspension or sustained release formulation;

(3) topical application, for example in the form of a controlled release cream, ointment or patch or spray applied to the skin;

(4) intravaginal or intrarectal administration, for example in the form of a suppository, cream or foam;

(5) sublingual administration;

(6) ocular introduction;

(7) transdermal administration; or (8) nasal administration.

As used herein, the phrase "therapeutically effective amount" means that the amount of a compound, material, or composition comprising a compound of the present invention is effective to achieve some desired therapeutic effect in at least a subset of cells in an animal at an acceptable risk-to-benefit ratio applied for any therapeutic treatment.

The phrase pharmaceutically acceptable is used in the invention to refer to those compounds, materials, compositions and/or dosage forms which, following careful medical evaluation, are approved for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, or other problem or complication, in accordance with an acceptable ratio of risk to expected benefit.

Wetting agents, emulsifiers, and lubricants such as sodium lauryl sulfate and magnesium stearate may also be present in the compositions, as well as colorants, disintegrants, coating agents, sweeteners, flavoring agents, and flavoring agents, preservatives, and antioxidants.

- 14 041819

Examples of pharmaceutically acceptable antioxidants include:

(1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and other similar water-soluble antioxidants;

(2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and other similar oil-soluble antioxidants; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and other similar chelating agents.

The dosage forms of the present invention include those dosage forms suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. Conveniently, the dosage forms may be in a single dose dosage form and may be prepared by any of the methods well known in the pharmaceutical art. The amount of active ingredient that may be combined with the carrier material to form a single dose dosage form may vary depending on the patient being treated, the particular route of administration.

The amount of active ingredient which can be combined with the carrier material to form a single dose dosage form will generally be that amount of the compound which produces a therapeutic effect. Typically, on a one hundred percent basis, this value will be from about 0.1% to about 99% active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.

In a specific embodiment, the dosage form of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, such as bile acids, and polymeric carriers, such as polyesters and polyanhydrides, and a compound of the present invention. In specific embodiments, the dosage form mentioned above carries an orally bioavailable compound of the present invention.

Methods for preparing these dosage forms or compositions include the step of mixing the compound of the present invention with the carrier and, optionally, with one or more accessory ingredients. Typically, dosage forms are prepared by uniformly and intimately mixing a compound of the present invention with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

Dosage forms of the invention for oral administration may be capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and gum arabic or gum tragacanth), powders, granules, or a solution or suspension in an aqueous or non-aqueous liquids, or liquid emulsion of oil-in-water or water-in-oil type, or elixir or syrup, or lozenges (using an inert base such as gelatin and glycerin or sucrose and gum arabic) and/or mouthwash and other similar forms, each containing a predetermined amount of a compound of the present invention as an active ingredient. The compound of the present invention may also be administered as a bolus, electuary or paste.

In solid oral dosage forms of the invention (capsules, tablets, pills, dragees, powders, granules, lozenges and the like), the active ingredient is admixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and /or with any of the following substances:

(1) fillers or dry diluents such as starches, lactose, sucrose, glucose, mannitol and/or silicic acid;

(2) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or gum arabic;

(3) humectants such as glycerin;

(4) disintegrants such as agar-agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates, and sodium carbonate;

(5) dissolution retarders such as paraffin;

(6) absorption accelerators such as quaternary ammonium compounds and surfactants such as poloxamer and sodium lauryl sulfate;

(7) wetting agents such as, for example, cetyl alcohol, glycerol monostearate, and nonionic surfactants;

(8) absorbents such as kaolin 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;

- 15 041819 (10) coloring agents and (11) controlled release agents such as crospovidone or ethylcellulose.

In the case of capsules, tablets and pills, the pharmaceutical compositions may also include buffering agents. Solid compositions of a similar type can also be used as fillers in soft and hard shell gelatin capsules using excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

Tablets may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using a binder (eg, gelatin or hydroxypropyl cellulose), a lubricant, an inert diluent, a preservative, a disintegrant (eg, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant, or a dispersing agent. Molded tablets can be made by molding a mixture of a powdered compound wetted with an inert liquid diluent in a suitable machine.

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 coated and coated, such as enteric coatings and other coatings well known in drug formulation technology. They can also be formulated to provide slow or controlled release of the active ingredient, using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They can be formulated to provide rapid release, for example by lyophilization. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by administering sterilizing agents in the form of sterile solid compositions which may be dissolved in sterile water or some other sterile injectable medium immediately prior to use. These compositions may also optionally contain opacifying agents and may be a composition that releases the active ingredient(s) only or predominantly in a certain part of the gastrointestinal tract, optionally in a delayed manner. Examples of encapsulating formulations that may be used include polymeric materials and waxes. The active ingredient may also be in microencapsulated form, if desired, together with one or more of the excipients described above.

Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in pharmaceuticals, 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 (particularly cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerin, tetrahydrofuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof.

In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, coloring agents, flavoring agents and preservatives.

Suspensions may contain, in addition to active compounds, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitol esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and gum tragacanth, and mixtures thereof.

Dosage forms of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented in the form of a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable non-irritating excipients or carriers, including, for example, cocoa butter, polyethylene glycol, a wax or 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.

Dosage forms of the present invention which are used for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or aerosol forms containing such carriers as are considered acceptable in the pharmaceutical industry.

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

- 16 041819 may be required.

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

Powders and sprays may contain, in addition to the active compound of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

Transdermal patches have the added benefit of providing a controlled delivery of a compound of the present invention into the body. Such dosage forms can be prepared by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers may also be used to increase percutaneous absorption of the compound. The rate of such entry can be controlled either by using a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

Ophthalmic dosage forms, eye ointments, powders, solutions and the like are also considered to be within the scope of the present invention.

Pharmaceutical compositions of the present invention for parenteral administration include one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders, which can be reconstituted into sterile solutions or dispersions for injection immediately prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes that render the composition isotonic with the blood of the intended recipient, or suspending agents or thickeners.

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

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. Prevention of the action of microorganisms on these compounds can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and other similar agents. It may also be desirable to include isotonic substances such as sugars, sodium chloride and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be achieved by administering absorption delaying agents such as aluminum monostearate and gelatin.

In some cases, in order to prolong the action of a drug, it is desirable to slow the absorption of the drug at the site of subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material having low water solubility. The rate of drug absorption depends on its rate of dissolution, which, in turn, may depend on the size of the crystals and the crystalline form. Alternatively, delayed absorption of a parenterally administered dosage form is accomplished by dissolving or suspending the drug in an oil medium.

Injectable depot forms are prepared by forming microcapsular matrices of the compounds of the invention in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Depot injectables are also prepared by incorporating the drug into liposomes or microemulsions that are compatible with body tissues.

When the compounds of the present invention are administered to humans and animals in the form of drugs, these compounds can be administered in pure form or in the form of a pharmaceutical composition containing, for example, from 0.1 to 99% (more preferably from 10 to 30%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

The medicaments of the present invention may be administered orally, parenterally, topically or rectally. Of course, they are administered in forms suitable for each route of administration. For example, they are administered in the form of tablets or capsules, by injection, inhalation, eye lotion, ointment, suppository and the like, by injection, infusion or inhalation, topically in the form of a lotion or ointment, and rectally in the form of suppositories. Oral administration is preferred.

As used herein, the phrases parenteral and parenterally administered refer to modes of administration other than enteral and topical administration, which are usually by injection and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal , subcutaneous, intradermal, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injections and infusions.

As used herein, the phrases systemic, systemically administered, peripherally administered, and peripherally administered refer to the administration of a compound, drug, or other material, excluding direct administration to the central nervous system, such that the drug enters the patient's system and, as a result, is metabolized and other similar processes, as occurs, for example, with subcutaneous administration.

These compounds can be administered to humans and other animals for the purpose of treatment by any suitable route, including orally, nasally, for example by spraying, rectally, intravaginally, parenterally, intramuscularly and topically, in the form of powders, ointments or drops, including buccally and sublingually.

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

Actual dosage levels of active ingredients in the pharmaceutical compositions of the present invention may be varied in order to obtain an amount of active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition and route of administration without toxic effects on the patient.

The selected dose level will depend on a variety of factors, including the activity of the particular compound of the present invention or its ester, salt or amide used, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound used, the rate and extent of absorption, the duration of treatment. , other drugs, compounds and/or materials used in combination with the specific compound used, age, sex, weight, condition, general health of the patient being treated, past illnesses, and other similar factors well known in medicine .

A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian may first use doses of the compounds of the invention used in a pharmaceutical composition that are lower than those required to achieve the desired therapeutic effect, and then gradually increase the dose until the desired effect is achieved.

Generally, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose that is effective to achieve a therapeutic effect. Such an effective dose will usually depend on the factors described above. Preferably, the compounds are administered from about 0.01 to about 200 mg/kg, more preferably from about 0.1 to about 100 mg/kg, even more preferably from about 0.5 to about 50 mg/kg. When the compounds described in the invention are administered together with another agent (for example, as sensitizing agents), the effective amount may be less than when the agent is used alone.

If necessary, 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 as a single dose dosage form. The preferred dosage is one administration per day.

Examples

The invention described in general terms can be more easily understood by reading the following examples, which are included in the invention only for the purpose of illustrating certain aspects and embodiments of the present invention, and they do not limit the invention in any way.

Example 1 Preparation of ethyl 5,7-dimethylpyrazolo[1,5-a]-pyrimidine-3-carboxylate (1)

O

A mixture of ethyl 3-amino-1H-pyrazole-4-carboxylate (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 a saturated aqueous solution

NaHCO ₃ then was extracted with ethyl acetate (3x100 ml). The organic layer was dried over sodium sulfate and the solvent removed in vacuo to give the title compound 1 (2.2 g, 78%) as an off-white solid.

'll NMR (400 MHz, DMSO-d ₆ ) δ 8.53 (s, 1H), 7.11 (s, 1H), 4.27 (q, J=7.07 Hz, 2H), 2.71 (s, 3H), 2.57 (s, 3H), 1.30 (t, J=7.07 Hz, 3H). ES-MS m/z 220.10 (M+H)+.

Example 2 Preparation of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2)

XX

Hong o

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 was heated at 80°C for 5 h. Then the reaction the mixture was cooled and neutralized with 2M HCl solution. A solid precipitated from the solution, which 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%).

¹ H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 6.84 (s, 1H), 2.65 (s, 3H), 2.53 (s, 3H). ES-MS m/z 192.00 (M+H) ⁺ .

Example 3 Preparation of 4-(isoxazol-3-yl)aniline (3) ^Ο2Ν ^ΧΧ

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 at room temperature. The reaction mixture was stirred under hydrogen atmosphere at room temperature for 14 hours. The reaction mixture was then filtered and the filtrate was concentrated in vacuo to give the title compound 3 as a brown viscous oil (550 mg, 93%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.83 (d, J=1.35 Hz, 1H), 7.54 (d, J=8.53 Hz, 2H), 6.92 (d , J=1.35 Hz, 1H), 6.63 (d, J=8.53 Hz, 2H), 5.53 (s, 2H).

Example 4 Preparation of 4-(oxazol-4-yl)aniline (4)

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 at room temperature . The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. The reaction mixture was then filtered through a pad of celite and the filtrate was concentrated in vacuo to give the crude compound. The crude compound was purified by FCC (eluent, 30% ethyl acetate in hexane) to give the title compound 4 as a light brown viscous liquid (260 mg, 62%).

1H NMR (400 MHz, DMSO-d6) δ 8.27-8.34 (m, 2H), 7.40-7.46 (m, 2H), 6.56-6.62 (m, 2H), 5.23 (s, 2H). ES-MS m/z 160.95 (M+H) ⁺ .

Example 5 Preparation of N-(4-iodophenyl)-5,7-dimethylpyrazolo-[1,5-a]pyrimidine-3-carboxamide (5)

To a solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (1.5 g, 7.84 mmol) in DMF (7.5 ml) was added 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 hours. The reaction mixture was quenched with water (1 ml), the precipitated solid was filtered and dried to give the crude compound. The crude compound was purified by 100-200 mesh silica gel column chromatography (eluent, 3-5% methanol in DCM) to give the title compound 5 as a white solid (1.7 g, 56%).

1H NMR (400 MHz, CDCl3) δ 10.14 (br. s, 1H), 8.67 (s, 1H), 7.65 (d, J=8.38 Hz, 2H), 7.54 (d , J=8.38 Hz, 2H), 6.77 (s, 1H), 2.82 (s, 3H), 2.71 (s, 3H).

Example 6 Preparation of 5,7-dimethyl-H-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide (6)

- 19 041819

Bispinacolatodibor (1.3 g , 5.1 mmol), potassium acetate (736 mg, 7.5 mmol) and Pd(dppf)Cl ₂ -DCM adduct (204 mg, 0.25 mmol) under argon at room temperature. The reaction mixture was heated to 100° C. for 2 hours. The reaction mixture was quenched with water (10 ml), extracted with ethyl acetate (3x30 ml) and concentrated in vacuo to give the crude compound. The crude compound was purified by trituration in 10% ethanol:n-hexane to give the title compound 6 as a brown solid (800 mg, 80%).

1H NMR (400 MHz, CDCl3) δ 10.20 (br. s, 1H), 8.69 (s, 1H), 7.84 (d, J=8.13 Hz, 2H), 7.76 (d , J=8.13 Hz, 2H), 6.76(s, 1H), 2.82(s, 3H), 2.73(s, 3H), 1.26(s, 12H).

Example 7 General Procedure A (Amidation Reaction)

A mixture of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (150 mg, 0.78 mmol), DIPEA (0.408 ml, 2.35 mmol) and HATU (300 mg, 0.78 mmol ) was dissolved in DMF (4 ml) and stirred at room temperature for 1 hour. The appropriate amine (0.78 mmol) was then added to the reaction mixture and stirred at room temperature for 16 hours. The reaction mixture was diluted with water and filtered. The residue was further washed with water (3x20 ml) and recrystallized in ether to give a white solid.

Example 8 General Procedure B (Amidation Reaction)

To a stirred solution of the amine (1.1 eq.) in toluene (8 ml) was added AlMe ₃ (2 M solution, 4 eq.) at 0° C. and the mixture was stirred at room temperature for 30 minutes. Ethyl 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylate 1 (1 eq.) was added to this reaction mixture, and the reaction mixture was stirred at 110°C for 18 h or until complete consumption of the starting material. The reaction was stopped with HCl (1M, 0.5 ml) and extracted with ethyl acetate (3x10 ml) to give the crude compound. The crude compound was purified by FCC (eluent, 2% MeOH in DCM) and then triturated with ether to give the desired compound as a solid.

Example 9 Preparation of 5,7-dimethyl-N-(5-ethynylpyridin-2-yl)-pyrazolo[1,5-a]pyrimidine-3-carboxamide

Using General Procedure B, the title compound was obtained as a white solid (20%).

1H NMR (400 MHz, CDCl3) δ 10.69 (br. s, 1H), 8.70 (s, 1H), 8.47 (d, J=1.82 Hz, 1H), 8.41 (d , J=8.63 Hz, 1H), 7.81 (dd, J=8.63, 1.82 Hz, 1H), 6.78 (s, 1H), 3.16 (s, 1H), 2 .82 (s, 3H), 2.76 (s, 3H).

ES-MS m/z 292.15 (M+H)+. HPLC purity 99.8%.

Example 10 Preparation of 5,7-dimethyl-N-(6-ethynylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Using General Procedure B, the title compound was obtained as a white solid (50%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.37 (s, 1H), 8.89 (d, J=2.13 Hz, 1H), 8.67 (s, 1H), 8.27 ( dd, J=8.31, 2.77 Hz, 1H), 7.59 (d, J=8.40 Hz, 1H), 7.22 (s, 1H), 4.26 (s, 1H), 2.77 (s, 3H), 2.72 (s, 3H).

ES-MS m/z 292.15 (M+H) ⁺ .

HPLC: 98.3%.

Example 11 Preparation of N-([1,1'-biphenyl]-4-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Using General Procedure A, the title compound was obtained as a white solid (29 mg, 11%).

1H NMR (400 MHz, CDCl ₃ ) δ 10.20 (s, 1H), 8.70 (s, 1H), 7.83 (d, J=8.76 Hz, 2H), 7.61 (d, J=8.34Hz, 4H), 7.44(t, J=7.71Hz, 2H), 7.30-7.35(m, 1H), 6.71-6.81(m, 1H), 2.81 (s, 3H), 2.72 (s, 3H).

ES-MS m/z 343.25 (M+H) ⁺ .

HPLC purity 98.4%.

- 20 041819

Example 12 Preparation of Rimidine-3-carboxamide

N-(4-(3-methoxyprop-1-yn-1-yl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pi-

Using General Procedure A, the title compound was obtained as a white solid (39 mg, 15%).

1H NMR (400 MHz, CDCl3) δ 10.22 (br. s, 1H), 8.68 (s, 1H), 7.72 (d, J=8.61 Hz, 2H), 7.46 (d , J=8.61 Hz, 2H), 6.71-6.82(m, 1H), 4.34(s, 2H), 3.47(s, 3H), 2.82(s, 3H) , 2.71 (s, 3H). ES-MS m/z 335.15 (M+H)+.

HPLC purity 95.1%.

Example 13 Preparation of 5,7-dimethyl-N-(4-phenoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Using General Procedure A, the title compound was obtained as an off-white solid (90 mg, 32%).

1H NMR (400 MHz, CDCl3) δ 10.10 (br. s, 1H), 8.69 (s, 1H), 7.72 (d, J=8.76 Hz, 2H), 7.30-7 .38 (m, 2H), 6.96-7.13 (m, 5H), 6.76 (s, 1H), 2.82 (s, 3H), 2.70 (s, 3H).

ES-MS m/z 359.20 (M+H) ⁺ .

HPLC purity 98.3%.

Example 14 Preparation of 5,7-dimethyl-N-(4-(1H-Imidazol-1-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3carboxamide

Using General Procedure A, the title compound was obtained as an off-white solid (151 mg, 58%).

1H NMR (400 MHz, CDCl3) δ 10.27 (s, 1H), 8.70 (s, 1H), 7.80 (d, J=8.40 Hz, 2H), 7.87 (s, 1H ), 7.39 (d, J=8.40 Hz, 2H), 7.27 (d, J=4.26 Hz, 2H), 6.79 (s, 1H), 2.85 (s, 3H ), 2.74 (s, 3H).

ES-MS m/z 333.15 (M+H) ⁺ . HPLC purity 99.9%.

Example 15 Preparation of 5,7-dimethyl-N-(4-(thiazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Using General Procedure A, the title compound was obtained as an off-white solid (90 mg, 33%).

1H NMR (400 MHz, CDCl ₃ ) δ 10.29 (br. s, 1H), 8.70 (s, 1H), 7.97 (d, J=8.61 Hz, 2H), 7.81- 7.89 (m, 3H), 7.29 (d, J=2.87 Hz, 1H), 6.78 (s, 1H), 2.84 (s, 3H), 2.74 (s, 3H ). ES-MS m/z 350.15 (M+H) ⁺ .

HPLC purity 98.3%.

Example 16 Preparation of 5,7-dimethyl-N-(4-ethynyl-2-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3carboxamide

Using General Procedure B, the title compound was obtained as a white solid (9%).

1H NMR (400 MHz, CDCl3) δ 10.73 (br. s, 1H), 8.69 (s, 1H), 8.64 (d, J=8.00 Hz, 1H), 7.19 (d , J=8.63 Hz, 1H), 7.04 (s, 1H), 6.77 (s, 1H), 4.00 (s, 3H), 3.05 (s, 1H), 2.82 (s, 3H), 2.73 (s, 3H). ES-MS m/z 321.10 (M+H) ⁺ .

HPLC purity 98.9%.

- 21 041819

Example 17 Preparation of 5,7-dimethyl-N-(4-(isoxazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Using General Procedure B, the title compound was obtained as a white solid (27%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.31 (br. s, 1 H), 8.71 (s, 1H), 8.45 (s, 1H), 7.75-7.99 (m , 4H), 6.79 (s, 1H), 6.67 (s, 1H), 2.83 (s, 3H), 2.74 (s, 3H).

ES-MS m/z 334.10 (M+H)+.

HPLC purity 96.1%.

Example 18 Preparation of 5,7-dimethyl-N-(4-(oxazol-4-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Using General Procedure B, the title compound was obtained as a white solid (18%).

¹ H NMR (400 MHz, CDCl3) δ 10.22 (br. s, 1H), 8.71 (s, 1H), 7.94 (s, 2H), 7.81-7.86 (m, 2H ), 7.75-7.79 (m, 2H), 6.78 (s, 1H), 2.83 (s, 3H), 2.74 (s, 3H).

ES-MS m/z 334.15 (M+H)+. HPLC purity 99.6%.

Example 19 Preparation of 5,7-dimethyl-N-(4-(oxazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Using General Procedure B, the title compound was obtained as a white solid (10%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.32 (br. s, 1H) 8.71 (s, 1H), 8.06 (d, J=8.62 Hz, 2H), 7.88 ( d, J=8.62 Hz, 2H), 7.70 (s, 1H), 7.22 (s, 1H), 6.79 (s, 1H), 2.83 (s, 3H), 2, 74 (s, 3H). ES-MS m/z 334.15 (M+H)+.

HPLC purity 97.9%.

Example 20 Preparation of N-(4-ethynylcyclohexyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

EDCI ( 955 mg, 6.16 mmol) and HOBt (277 mg, 2.05 mmol) and stirred at room temperature for 12 hours. The reaction mixture was quenched with water (30 ml), extracted with ethyl acetate (3x30 ml) and the combined organic layer was dried over sodium sulfate and concentrated to give the crude compound. The crude compound was purified by FCC (eluent, 20-25% ethyl acetate in hexane) to give t-butyl (4-(methoxy(methyl)carbamoyl)cyclohexyl)carbamate as a colorless liquid (133 mg, 68%).

¹ H NMR (400 MHz, CDCl3) δ 4.81 (br. s, 1H), 3.75-3.85 (m, 1H), 3.70 (s, 3H), 3.19 (s, 3H ), 2.69-2.81 (m, 1H), 1.85 (d, J=10.80 Hz, 2H), 1.59-1.74 (m, 6H), 1.45 (s, 9H).

ES-MS m/z 287.15 (M+H)+.

To a solution of tert-butyl (4-(methoxy(methyl)carbamoyl)-cyclohexyl)carbamate (1.2 g, 4.19 mmol) in THF (30 ml) was added in portions at -70°C lithium aluminum hydride (LAH) (1 .75 g, 4.60 mmol). The reaction mixture was warmed to room temperature and stirred for 5 h. The reaction mixture was quenched with 10% NaOH aqueous solution and extracted with ethyl acetate (3x25 ml). The combined organic layer was dried over sodium sulfate and concentrated to give the crude compound, which was purified by FCC (eluent, 15-20% ethyl acetate in hexanes) to give tert-butyl (4-22 041819 formylcyclohexyl) carbamate (647 mg, 68%) in in the form of a yellow thick oil, which was directly used in the next step.

To a solution of dimethyl(2-oxopropyl)phosphonate (219 mg, 1.32 mmol) in acetonitrile (20 ml) was added 4-methylbenzene sulfonylazide (260 mg, 1.32 mmol) and K ₂ CO ₃ (485 mg, 3 52 mmol) and stirred at room temperature for 12 h. tert-Butyl(4formylcyclohexyl)carbamate (200 mg, 0.88 mmol) was added to the resulting solution and stirred at room temperature for 12 h. The reaction mixture was concentrated in vacuo, diluted water (20 ml), was extracted with ethyl acetate (3x15 ml), dried over Na ₂ SO ₄ and concentrated under vacuum. The crude compound was purified by FCC (eluent, 15-20% ethyl acetate in hexane) to give tert-butyl(4ethynylcyclohexyl)carbamate as a colorless oil (133 mg, 68%).

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

5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid solution 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 4-ethynylcyclohexane-1-amine (92 mg, 0.75 mmol) was added and stirred for another 16 h at room temperature. The reaction mixture was diluted with water (10 ml), extracted with ethyl acetate (3x10 ml), dried over Na ₂ SO ₄ and concentrated under vacuum. The crude compound was purified by FCC (eluent, 2-4% methanol in DCM) to give the title compound as a white solid (120 mg, 65%).

1H NMR (400 MHz, CDCl ₃ ) 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), 1.341.43 (m, 2H), 1.22-1.31 (m, 2H). ES-MS m/z 297.25 (M+H) ⁺ .

HPLC purity 99.9%.

Example 21 Carboxamide

Preparation of N-(4-(isothiazol-4-yl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3B solution

5,7-dimethyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazolo[1,5

a]pyrimidine-3-carboxamide 6 (286 mg, 0.73 mmol) in DMF (5 ml) was added 4-bromoisothiazole (100 mg, 0.60 mmol), potassium acetate (179 mg, 1.8 mmol) and the adduct Pd(dppf)Cl ₂ -DCM (49 mg, 0.06 mmol) under argon at room temperature. The reaction mixture was heated to 100° C. for 16 hours. The reaction mixture was quenched with water (5 ml), extracted with ethyl acetate (3x10 ml) and concentrated in vacuo to give the crude compound. The crude compound was purified by FCC (eluent, 3-5% methanol in DCM) to give the title compound as an off-white solid (50 mg, 23%).

1H NMR (400 MHz, CDCl ₃ ) δ 10.24 (s, 1H), 8.79 (s, 1H), 8.71 (s, 1H), 8.68 (s, 1H), 7.84 ( d, J=8.57 Hz, 2H), 7.61 (d, J=8.57 Hz, 2H), 6.78 (s, 1H), 2.83 (s, 3H), 2.74 ( s, 3H). ES-MS m/z 350.20 (M+H)+.

HPLC purity 99.1%.

Example 22 Preparation of N-(4-(isoxazol-4-yl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide 5 (350 mg, 0.89 mmol), isoxazol-4-ylboric 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)Cl ₂ (73 mg, 0.08 mmol) and the solution was degassed for another 10 min in a sealed tube and heated to 50°C for 8 h. The reaction mixture was cooled to room temperature, diluted with water and stirred for 15 min. The solid that precipitated was filtered and dried to give the crude compound, which was purified by FCC (eluent, 2-4% methanol in DCM) to give the title compound as a light gray solid (45 mg, 15%).

¹ H NMR (400 MHz, CDCl ₃ ) 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%.

- 23 041819

Example 23 Preparation of N-(3-cyclonpropylisoxazol-5-yl)-5,7-dimethylpirazolo[1,5-a]pyrimidine-3carboxamide

To a solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (200 mg, 1.04 mmol) in DCM (5 ml) at 0 1 mmol). The reaction mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was concentrated in vacuo to give 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carbonyl chloride as a brown solid (210 mg, 95%) , which was directly used in the next step.

Chloride solution 5.7 -dimethylpyrazolo[1,5a]pyrimidine-3-carbonyl 2 (210 mg, 0.95 mmol) in THF (2 mL). The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was then quenched with water (2 ml) and extracted with ethyl acetate (3x10 ml). The combined organic layer was dried over sodium sulfate and concentrated in vacuo to give a crude product which was purified by preparative HPLC (YMC triart column; dimensions 20 x 250 mm x 5 µm; method: mobile phase A - 5 mM ammonium formate in water + 0.1% ammonia, mobile phase B - acetonitrile + 0.1% ammonia gradient from 10% B to 50% B) to give the title compound as an off-white solid (10 mg, 3%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.01 (s, 1H), 8.71 (s, 1H), 7.24 (s, 1H), 6.11 (s, 1H), 2 .77 (s, 3H), 2.68 (s, 3H), 2.03-1.94 (m, 1H), 1.05-0.98 (m, 2H), 0.84-0.76 (m, 2H). ES-MS m/z 298.30 (M+H) ⁺ .

HPLC purity 94.3%.

Example 24 Preparation of 5,7-dimethyl-N-(5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Solution of 5-(1-(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 atmosphere argon was added to a solution of 5,7dimethylpyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (210 mg, 0.95 mmol) in THF (2 ml). The reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was then quenched with water (2 ml) and extracted with ethyl acetate (3x10 ml). The combined organic layer was dried over sodium sulfate and concentrated in vacuo to give the crude product, which was purified by FCC (eluent, 15-20% ethyl acetate in hexanes) to give the title compound as an off-white solid (180 mg, 47%).

1H NMR (400 MHz, CDCl3) δ 10.63 (br. s, 1H), 8.67 (s, 1H), 7.23 (s, 1H), 6.80 (s, 1H), 2.83 (s, 3H), 2.72 (s, 3H), 1.51 (d, J=3.6 Hz, 2H), 1.47 (d, J=3.6 Hz, 2H). ES-MS m/z 365.95 (M+H)+.

HPLC purity 99.2%.

Example 25 Preparation of N-(4-(1H-n-pyrrol-2-yl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3carboxamide

(1-(tert-butoxycarbonyl) -1H-pyrrol-2-yl)boric acid (64 mg, 0.31 mmol), K2CO3 (105 mg, 0.76 mmol), Pd(PPh ₃ ) ₄ (29 mg, 0.025 mmol) and the mixture was degassed with argon in for 30 min and heated to 100°C for 30 hours 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 (10 ml) and brine (10 ml) and concentrated in vacuo to give the crude compound, which was purified by FCC (eluent, 5-10% methanol in DCM) to give the title compound as a white solid (50 mg, 59%).

1H NMR (400 MHz, DMSO-d6) δ 11.22 (br. s, 1H), 10.16 (s, 1H), 8.63 (s, 1H), 7.72 (d, J=8, 3 Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 7.20 (s, 1H), 6.84-6.80 (m, 1H), 6.47-6, 44 (m, 1H), 6.10 (d, J=2.2 Hz, 1H), 2.77 (s, 3H), 2.72 (s, 3H). ES-MS m/z 332.20 (M+H)+.

- 24 041819

HPLC purity 98.1%.

Example 26 Preparation of 5,7-dimethyl-N-(6-(oxazol-4-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3carboxamide

To a solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 1 (53 mg, 0.27 mmol) in DMF (1 ml) at 0 ), DIPEA (0.14 ml, 0.81 mmol) and 6-(oxazol-4yl)pyridine-3-amine (45 mg, 0.27 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with water (10 ml), extracted with ethyl acetate (3x10 ml) and the combined organic layer was dried over sodium sulfate and concentrated in vacuo to give the crude compound. The crude compound was purified by FCC (eluent, 1-3% methanol in DCM) to give the title compound as a white solid (18 mg, 19%).

1H NMR (400 MHz, CDCl3) δ 10.36 (br. s, 1H), 8.82 (s, 1H), 8.71 (s, 1H), 8.46 (d, J=7.94 Hz , 1H), 8.33 (br. s, 1H), 7.92-7.99 (m, 2H), 6.81 (s, 1H), 2.85 (s, 3H), 2.74 ( s, 3H). ES-MS m/z 335.35 (M+H)+.

HPLC purity 98.5%.

Example 27 Preparation of 5,7-dimethyl-N-(6-(thiophen-2-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3carboxamide

5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid solution 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 6-bromopyridine-3-amine (542 mg, 3.15 mmol) was added and stirred for another 16 h at room temperature. The reaction mixture was diluted with water (10 ml) and was extracted with ethyl acetate (3x10 ml), dried over Na ₂ SO ₄ and concentrated under vacuum. The crude compound was purified by FCC (eluent, 1-3% methanol in DCM) to give N-(6-bromopyridin-3-yl)5,7-dimethylpyrazolo-[1,5-a]pyrimidine-3-carboxamide as yellow solids (510 mg, 56%).

1H NMR (400 MHz, CDCl ₃ ) δ 10.24 (br. s, 1H), 8.65 (s, 1H), 8.54 (d, J=2.8 Hz, 1H), 8.24 ( dd, J=6 Hz, 11.6 Hz, 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) ⁺ .

4.4 ,5,5-tetramethyl-2-(thiophen-2-yl)-1,3,2-dioxaborolane (136 mg, 0.65 mmol), K ₂ CO ₃ (178 mg, 1.29 mmol), Pd ( PPh ₃ ) 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 (10 ml) and brine (10 ml) and concentrated in vacuo to give the crude compound, which was purified by trituration with methanol to give the title compound as an off-white solid (30 mg, 20%).

1H NMR (400 MHz, CDCl ₃ ) δ 10.28 (br. s, 1H), 8.65 (s, 1H), 8.62 (s, 1H), 8.42 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.49 (d, J=2.2 Hz, 1H), 7.29 (d, J=4.9 Hz, 1H), 7.04 (t, J=4.3 Hz, 1H), 6.72 (s, 1H), 2.76 (s, 3H), 2.65 (s, 3H). ES-MS m/z 350.30 (M+H) ⁺ .

HPLC purity 99.5%.

Example 28 Preparation of N-([2,4'-bipyridine]-5-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Pyridine-4 -ylboric acid (40 mg, 0.32 mmol), K ₂ CO ₃ (111 mg, 0.80 mmol), Pd(PPh ₃ ) 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 water (10 ml) and brine (10 ml) and concentrated in vacuo to give the crude compound, which was purified by trituration with methanol to give the title compound as an off-white solid (30 mg, 32%).

- 25 041819 'H NMR (400 MHz, CDCI3) δ 10.41 (s, 1H), 8.79 (d, J=2.69 Hz, 1H), 8.61-8.68 (m, 3H) , 8.56 (dd, J=2.47,

8.75 Hz, 1H), 7.94 (d, J=6.28 Hz, 2H), 7.82 (d, J=8.53 Hz, 1H), 6.76 (s, 1H), 2 .78 (s, 3H), 2.69 (s, 3H). ES-MS m/z 345.35 (M+H)+.

HPLC purity 96.9%.

Example 29 Preparation of N-(6-(furan-2-yl)pyridin-3-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3carboxamide

Furan-2 -ylboric acid (77 mg, 0.65 mmol), K ₂ CO ₃ (178 mg, 1.29 mmol), Pd(PPh ₃ ) ₄ (49 mg, 0.042 mmol) and the mixture was degassed with argon for 30 min and heated to 100° C. for 30 hours. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate (10 ml). The filtrate was washed with ice water (10 ml) and brine (10 ml) and concentrated in vacuo to give the crude compound, which was purified by trituration with methanol to give the title compound as a brown solid (40 mg, 28%).

'H NMR (400 MHz, CDCI3) 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 9 6.9%.

Example 30 Preparation of 5,7-dimethyl-N-(6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)pyrazolo[1,5a]pyrimidine-3-carboxamide

1 -methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Hpyrazole (66 mg, 0.32 mmol), K ₂ CO ₃ (111 mg, 0, 80 mmol), Pd(PPh ₃ ) 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 (10 ml) and brine (10 ml) and concentrated in vacuo to give the crude compound, which was purified by trituration with methanol to give the title compound as an off-white solid (35 mg, 36%).

'H NMR (400 MHz, CDCl ₃ ) δ 10.23 (s, 1H), 8.64-8.59 (m, 2H), 8.41 (d, J=8.2 Hz, 1H), 7 .99 (br. s, 1H), 7.88 (s, 1H), 7.45 (d, J=8.7 Hz, 1H), 6.77 (s, 1H), 3.92 (s, 3H), 2.76 (s, 3H), 2.66 (s, 3H). ES-MS m/z 348.40 (M+H) ⁺ .

HPLC purity 97.9%.

Example 31 Preparation of 5,7-dimethyl-N-(4-(thiazol-4-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Into a solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide 5 (250 mg, 0.64 mmol) and thiazol-4-ylboric acid 2 (124 mg, 0 .96 mmol) in dioxane (10 ml) in a sealed tube was added a solution of CH ₃ CO ₂ K (126 mg, 1.28 mmol) in water (0.5 ml) and the mixture was degassed with argon for 30 min. Pd(dppf)Cl ₂ -DCM adduct (52 mg, 0.06 mmol) was added to the resulting solution and heated to 90° C. with stirring for 16 h. The reaction mixture was then filtered through a pad of celite and washed with excess DCM. The combined filtrate was concentrated in vacuo to give the crude compound, which was purified by FCC (eluent, 1-2% methanol in DCM) to give the title compound as a light brown solid (45 mg, 20%).

'H NMR (400 MHz, CDCl ₃ ) δ 8.07 (s, 1H), 7.29 (d, J=7.9 Hz, 2H), 6.64 (d, J=8.2 Hz, 2H ), 6.58 (s, 1H), 4.54 (s, 2H), 4.31 (s, 2H), 3.44 (s, 3H), 2.73 (s, 3H), 2.58 (s, 3H). ES-MS m/z 321.15 (M+H) ⁺ .

HPLC purity 98.9%.

Example 32 Preparation of N-(1H-benzo[d]imidazol-2-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

- 26 041819

To a solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (100 mg, 0.52 mmol) in DMF (2 ml) at 0 ), DIPEA (0.13 ml, 0.78 mmol) and 1Hbenzo[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 (3x10 ml) and the combined organic layer was dried over sodium sulfate and concentrated under vacuum to obtain the crude compound. The crude compound was purified by FCC (eluent, 1-3% methanol in DCM) to give the title compound as a white solid (20 mg, 13%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 11.18 (br.s, 1H), 11.09 (br.s, 1H), 8.71 (s, 1H), 7.66 (d, J= 7.50 Hz, 1H), 7.43 (d, J=7.50 Hz, 1H), 7.15-7.24 (m, 2H), 6.83 (s, 1H), 2.84 ( s, 3H), 2.77 (s, 3H). ES-MS m/z 307.15 (M+H)+.

HPLC purity 95.0%.

Example 33 Preparation of 5,7-dimethyl-N-(4-(3-(piperidin-1-yl)prop-1-yn-1-yl)phenyl)pyrazolo[1,5a]pyrimidine-3-carboxamide

A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5-a]-pyrimidine-3-carboxamide 5 (200 mg, 0.51 mmol), prop-2-yn-1-ol (0, 04 ml, 0.61 mmol), CuI (10 mg, 0.05 mmol) and Pd(PPh3)4 (58 mg, 0.005 mmol) in piperidine (3 ml) were heated in a sealed tube at 45°C for 16 h The reaction mixture was then diluted with water (5 ml), extracted with ethyl acetate (3x10 ml), dried over Na ₂ SO ₄ and concentrated under vacuum to give the crude compound, which was purified by FCC (eluent, 0-3% methanol in DCM) to obtain N-(4-(3-hydroxyprop-1-yn-1-yl)phenyl)-5,7dimethylpyrazolo[1,5-a]-pyrimidine-3-carboxamide as an off-white solid (60 mg, 37% ).

1H NMR (400 MHz, CDCl ₃ ) 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) ⁺ .

Into a solution of N-(4-(3-hydroxyprop-1-in-1-yl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide (120 mg, 0.37 mmol) in DMF (5 ml) was added piperidine (0.04 ml, 0.44 mmol), PPh ₃ (146 mg, 0.55 mmol) and DIAD (112 mg, 0.55 mmol) and the mixture was heated to 40°C for 16 hours The reaction mixture was extinguished with water (10 ml), was extracted with ethyl acetate (3x15 ml), dried over Na ₂ SO ₄ and concentrated under vacuum. The crude compound was purified by FCC (eluent, 0-3% methanol in DCM) to give an off-white solid (22 mg, 15%).

1H NMR (400 MHz, CDCl ₃ ) δ 10.13 (s, 1H), 8.61 (s, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 6.70 (s, 1H), 3.48 (s, 2H), 2.75 (s, 3H), 2.65 (s, 3H), 2.61- 2.51 (m, 4H), 1.69-1.59 (m, 6H). ES-MS m/z 388.35 (M+H) ⁺ .

HPLC purity 95.4%.

Example 34 Preparation of N-(4-(3-(dimethylamino)prop-1-yn-1-yl)phenyl)-5,7-dimethylpyrazolo[1,5a]pyrimidine-3-carboxamide

A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide 5 (100 mg, 0.25 mmol), 3-bromoprop-1-in (91 mg, 0. 76 mmol), CuI (5 mg, 0.02 mmol) and PdCl ₂ (PPh ₃ ) ₂ (10 mg, 0.01 mmol) in 2M solution of N,N-dimethylamine in THF (5 ml) were heated in a sealed tube at 60°C for 16 hours Then, the reaction mixture was diluted with water (5 ml) and was extracted with ethyl acetate (3x10 ml). The combined organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude compound, which was purified by FCC (eluent, 0-3% methanol in DCM) to give the title compound as a light brown solid (56 mg, 63% ).

¹ H NMR (400 MHz, DMSO-d ₆ ) 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)+ hell

- 27 041819 duct.

HPLC purity 98.8%.

Example 35 Preparation of 5,7-dimethyl-N-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A solution of N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide 5 (300 mg, 0.76 mmol), 3-bromoprop-1-ine (0.21 ml, 2.29 mmol), CuI (29 mg, 0.15 mmol) and PdCl ₂ (PPh ₃ ) ₂ (54 mg, 0.07 mmol) in a 2M solution of morpholine in THF (10 ml) were heated in a sealed tube at 60° C for 4 hours Then the reaction mixture was diluted with water (10 ml) and was extracted with ethyl acetate (3x15 ml). The combined organic layer was dried over sodium sulfate and concentrated in vacuo to give the crude compound, which was purified by FCC (eluent, 0-3% methanol in DCM) to give the title compound as an off-white solid (60 mg, 20%).

¹ H NMR (400 MHz, CDCl3) δ 10.21 (s, 1H), 8.69 (s, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.44 (d, J=7.9 Hz, 2H), 6.77(s, 1H), 3.85-3.68(m, 4H), 3.52(s, 2H), 2.83(s, 3H), 2.72 (s, 3H), 2.69-2.53 (m, 4H). ES-MS m/z 390.35 (M+H) ⁺ .

HPLC purity 99.9%.

Example 36 Carboxamide

Obtaining N-(4-( 1 H-imidazol-2-yl)phenyl)-5,7-dimethylpyrazolo [1,5-a] pyrimidin-3 -

Into a solution of 5,7-dimethyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazolo[1,5a]pyrimidine-3-carboxamide 6 (440 mg, 1.12 mmol) in DMF (5 ml) was added 2-bromo-1H-imidazole (150 mg, 1.02 mmol), potassium carbonate (422 mg, 3.06 mmol) and the mixture was degassed with argon for 15 minutes. To the resulting solution was added Pd(PPh ₃ ) ₄ (117 mg, 0.10 mmol) and the reaction mixture was degassed for another 10 min and heated at 100°C for 15 h. Then the reaction mixture was diluted with water (10 ml), extracted ethyl acetate (3x10 ml) and the combined organic layer was dried over sodium sulfate and concentrated in vacuo to give the crude compound. The crude compound was purified by FCC (eluent, 1-3% methanol in DCM) to give the title compound as a white solid (40 mg, 12%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.48 (br. s, 1H), 10.27 (s, 1H), 8.65 (s, 1H), 7.93 (d, J=8 .87 Hz, 2H), 7.82 (d, J=8.87 Hz, 2H), 7.07-7.24 (m, 3H), 2.78 (s, 3H), 2.73 (s , 3H). ES-MS m/z 333.35 (M+H) ⁺ .

HPLC purity 98.3%.

Example 37 Preparation of 5,7-dimethyl-N-(4-(piperidin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3carboxamide

Piperidine (0.06 ml , 0.61 mmol), bis(dibenzylideneacetone)palladium(0) (2 mg, 0.002 mmol), and the mixture was degassed with argon for 30 min. DavePhos (2 mg, 0.005 mmol) and KOtBu (114 mg, 1.02 mmol) were added and the mixture was heated to 90° C. for 16 h. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate (3x10 ml). The combined filtrate was washed with water, dried over sodium sulfate and concentrated in vacuo to give the crude compound, which was purified by FCC (eluent, 1-2% methanol in DCM) to give the title compound as a white solid (160 mg, 47%) .

1H NMR (400 MHz, DMSO-d ₆ ) 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). ESMS m/z 350.25 (M+H) ⁺ .

HPLC purity 96.7%.

Example 38 Preparation of 5,7-dimethyl-N-(4-(piperazin-1-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

- 28 041819

tert-Butylpiperazine-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 were added tBuOK (286 mg, 2.55 mmol) and DavePhos (5 mg, 0.01 mmol) and the mixture was heated to 90° C. for 16 h. 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 (3x10 ml) and the combined organic layer was dried over sodium sulfate and concentrated in vacuo to give the crude compound, which was then purified by FCC (eluent, 1-3% methanol in DCM) and triturated with methanol to give t-butyl-4 -(4-(5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamido)phenyl)piperazine-1-carboxylate as an off-white solid (380 mg, 36%). ES-MS m/z 451.40 (M+H)+.

To a solution of tert-butyl 4-(4-(5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamido)phenyl)piperazine-1-carboxylate (280 mg, 0.62 mmol) in DCM (8 ml) TFA (1.5 ml) was added and stirred at room temperature for 12 h. Then the reaction mixture was diluted with water (10 ml), extracted with ethyl acetate (3x10 ml), dried over Na ₂ SO ₄ and concentrated under vacuum to obtain the crude compound, which was then purified by FCC (eluent, 1-3% methanol in DCM) and triturated with methanol to give the title compound as an off-white solid (58 mg, 16%).

¹ H NMR (400 MHz, DMSO-d6) δ 9.97 (br.s, 1H), 8.59 (s, 1H), 7.59 (d, J=7.20 Hz, 2H), 7, 18 (s, 1H), 6.96 (d, J=6.96 Hz, 2H), 3.10-2.97 (m, 4H), 2.76 (s, 3H), 2.69 (s , 3H), 1.33-1.23 (m, 4H), 0.87 (br. s, 1H). ES-MS m/z 351.25 (M+H)+. HPLC purity 97.7%.

Example 39 Preparation of N-(4-(1H-pyrazol-3-yl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3carboxamide

NH

Into a solution of 5,7-dimethyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazolo[1,5a]pyrimidine-3-carboxamide 6 (320 mg, 0.80 mmol) in propanol/water (4:1 ml) was added 5-bromo1H-pyrazole (100 mg, 0.60 mmol), Ce ₂ CO ₃ (585 mg, 1.80 mmol), and the mixture was degassed with argon for 15 min. PdCl ₂ (dppf) (49 mg, 0.60 mmol) was added to the resulting solution, and the resulting solution was degassed for another 10 min and then heated at 100° C. for 16 h. The reaction mixture was then diluted with water (10 ml), extracted with ethyl acetate (3x10 ml), dried over sodium sulfate and concentrated in vacuo to give the crude compound, which was then purified by FCC (eluent, 1-3% methanol in DCM) and triturated with methanol to give the title compound as a brown solid (25 mg, 11%).

1H NMR (400 MHz, DMSO-d6) δ 12.81 (br.s, 1H), 10.24 (br.s, 1H), 8.65 (s, 1H), 7.43-7.89 ( m, 6H), 7.21 (s, 1H), 2.78 (s, 3H), 2.73 (s, 3H). ES-MS m/z 333.25 (M+H)+.

HPLC purity 92.4%.

Example 40 Preparation of 5,7-dimethyl-N-(4-(pentyloxy)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (300 mg, 1.56 mmol) in DMF (10 ml) at 0 ), DIPEA (0.82 ml, 4.70 mmol) and 4-aminophenol (205 mg, 1.88 mmol). Then, the reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with water (2 ml), extracted with ethyl acetate (3x10 ml), dried over Na ₂ SO ₄ and concentrated under vacuum to obtain the crude product, which was then purified by the method FCC (eluent, 5% methanol in DCM) to give N-(4-hydroxyphenyl)5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide as an off-white solid (284

- 29 041819 mg, 64%).

1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.26 (s, 1H), 8.58 (s, 1H), 7.51 (d, J=7.9 Hz , 2H), 7.16 (s, 1H), 6.77 (d, J=7.9 Hz, 2H), 2.76 (s, 3H), 2.68 (s, 3H). ES-MS m/z 283.15 (M+H)+.

To a solution of N-(4-hydroxyphenyl)-5,7-dimethylpyrazolo-[1,5-a]pyrimidine-3-carboxamide (140 mg, 0.49 mmol) in DMF was added K ₂ CO ₃ (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 hours Then the reaction mixture was diluted with water (2 ml) and was extracted with ethyl acetate (3x10 ml). The combined organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give a crude product which was then purified by preparative HPLC (YMC triart column; dimensions 20x250 mmx5 μm); method: mobile phase A - 5 mM ammonium formate in water + 0.1% ammonia, mobile phase B - acetonitrile + 0.1% ammonia; gradient: 10% B to 50% B) to give the title compound as a white solid (50 mg, 29%).

1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.61 (s, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.18 (s , 1H), 6.94 (d, J=8.8 Hz, 2H), 3.95 (t, J=6.4 Hz, 2H), 2.77 (s, 3H), 2.69 (s , 3H), 1.77-1.66 (m, 2H), 1.46-1.31 (m, 4H), 0.90 (t, J=7.1 Hz, 3H). ES-MS m/z 353.30 (M+H) ⁺ .

HPLC purity 99.8%.

Example 41 Preparation of 5,7-dimethyl-N-(4-(prop-2-yn-1-yl-oxy)phenyl)pyrazolo[1,5-a]pyrimidine-3carboxamide/(A-o n

Potassium carbonate (36 mg, 0 .26 mmol) and 80% propargyl bromide (0.04 ml, 0.26 mmol) at room temperature and 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 (3x10 ml ), dried over Na ₂ SO ₄ and concentrated in vacuo to give the crude compound, which was then purified by PREP HPLC (YMC triart column; dimensions 20x250 mmx5 µm; method: mobile phase A - 5 mM ammonium formate in water+0.1% ammonia, mobile phase B - acetonitrile+0.1% ammonia gradient: 10% B to 50% B) to give the title compound as a white solid (34 mg, 61%).

1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.61 (s, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.18 (s , 1H), 7.01 (d, J=8.8 Hz, 2H), 4.79 (s, 2H), 3.56 (s, 1H), 2.77 (s, 3H), 2.70 (s, 3H). ES-MS m/z 321.20 (M+H) ⁺ .

HPLC purity 99.7%.

Example 42 Preparation of 4-(4-(5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamido)phenyl)butanoic acid

To a solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (200 mg, 1.04 mmol) in DMF (5 ml) was added EDC-HCl (240 mg, 1.25 mmol), HOBT (170 mg, 1.25 mmol), triethylamine (0.43 ml, 3.14 mmol) and stirred at room temperature for 30 minutes. 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 16 hours. The reaction mixture was then quenched with ice water (50 ml) and stirred for another 30 min. The solid was collected by filtration and washed with water then n-hexane and dried to give the corresponding ether 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) ⁺ .

To a solution of the ether in MeOH:THF (8 ml; 1:1) was added a solution of LiOH (46 mg, 1.09 mmol) in water (4 ml) and stirred at room temperature for 3 h. The reaction mixture was then concentrated in vacuo to dryness , and the residue was diluted with water and acidified (pH=1) with 2N HCl solution. The resulting solution was stirred at room temperature for 30 minutes. The solid was filtered, washed with water then n-hexane and dried to give the title compound as a white solid (160 mg, 43% over 2 steps).

1H NMR (400 MHz, DMSO-d ₆ ) 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-MSm/z 353.40 (M+H) ⁺ .

HPLC purity 99.3%.

Example 43 Preparation of N-(4-(1-hydroxyethyl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3carboxamide

- 30 041819

To a solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (100 mg, 0.52 mmol) in DMF (5 mL) was added EDCI (122 mg, 0.78 mmol), HOBT ( 36 mg, 0.26 mmol) and triethylamine (0.1 ml, 0.78 mmol) and stirred for 15 min at room temperature. To the resulting solution was added 1-(4-aminophenyl)ethan-1-ol (86 mg, 0.63 mmol) and the mixture was stirred for another 16 h. Then the reaction mixture was diluted with water (10 ml), extracted with ethyl acetate (3x10 ml) and the combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give the crude compound, which was then purified by preparative TLC to give the title compound as an off-white solid (49 mg, 30%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.12 (br. s, 1H), 8.61 (s, 1H), 7.67 (d, J=7.50 Hz, 2H), 7 .34 (d, J=7.94 Hz, 2H), 7.18 (s, 1H), 5.11 (br.s, 1H), 4.69-4.72 (m, 1H), 2, 76 (s, 3H), 2.70 (s, 3H), 1.33 (d, J=6.17 Hz, 3H). ES-MS m/z 310.3 (M+H)+.

HPLC purity 99.2%.

Example 44 Preparation of 3-(4-(5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamido)phenyl)propanoic acid

To a solution of 5,7-dimethylpyrazolo[1,5-a]n-pyrimidine-3-carboxylic acid 2 (250 mg, 1.31 mmol) in DMF (5 mL) was added EDC-HCl (304 mg, 1.96 mmol), HOBT (299 mg, 1.96 mmol), NEt ₃ (0.54 ml, 3.93 mmol) and stirred at room temperature for 30 minutes. 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 water (50 ml) and stirred for another 30 min. . The precipitated solid was collected by filtration, washed with water then n-hexane and dried to give methyl 3-(4-(5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamido)phenyl)propanoate as light brown solid (350 mg, 76%), which was used in the next step without further purification.

1H NMR (400 MHz, CDCl ₃ ) δ 10.10 (s, 1H), 8.70 (s, 1H), 7.68 (d, J=8.33 Hz, 2H), 7.21 (d, J=8.33Hz, 2H), 6.77(s, 1H), 3.69(s, 3H), 2.96(t, J=7.67Hz, 2H), 2.83(s, 3H), 2.71 (s, 3H), 2.62-2.68 (m, 2H). ES-MS m/z 353.25 (M+H) ⁺ .

To a solution of methyl 3-(4-(5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamido)phenyl)propanoate in THF:H ₂ O (10:10 ml) was added a solution of LiOH (51 mg, 2.13 mmol) and stirred at room temperature for 3 hours. The reaction mixture was then concentrated in vacuo, diluted with water and stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration, washed with water then n-hexane and dried to give the title compound as a white solid (170 mg, 71%).

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.11 (br. s, 1H), 10.11 (s, 1H), 8.62 (s, 1H), 7.64 (d, J=8 .33 Hz, 2H), 7.23 (d, J=8.33 Hz, 2H), 7.19 (s, 1H), 2.78-2.83 (m, 2H), 2.76 (s , 3H), 2.70 (s, 3H), 2.53-2.57 (m, 2H). ES-MS m/z 339.20 (M+H) ⁺ . HPLC purity 99.5%.

Example 45 Preparation of N-(4-azidophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Λν-ν

AH O

HE

N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide solution 5 (50 mg, 0.13 mmol), CuI (2 mg, 0.01 mmol), NaN ₃ (17 mg, 0.26 mmol) and sodium ascorbate (2 mg, 0.01 mmol) in EtOH:H ₂ O (2 ml) were degassed with argon for 15 min. N,N-dimethylethylenediamine (0.002 ml, 0.02 mmol) was added and the mixture was heated to 100° C. for 50 minutes in a microwave oven. The reaction mixture was diluted with water (2 ml), extracted with ethyl acetate (3x10 ml), dried over sodium sulfate and concentrated under vacuum to give the crude compound, which was then purified by SFC (column: silica gel with 2-ethylpyridine; dimensions: 30x250 mm, size 5 µm particles, method: mobile phase A - CO2, mobile phase B - 5 mM ammonium formate in MeOH; gradient: 10% co-solvent to 50% maximum) to give the title compound as a brown solid (24 mg, 62%) .

- 31 041819 ¹ H NMR (400 MHz, CDCI3) δ 10.08 (br.s, 1H), 8.62 (s, 1H), 7.68 (d, J=8.0 Hz, 2H), 6 .96 (d, J=8.1 Hz,

2H), 6.70 (s, 1H), 2.75 (s, 3H), 2.65 (s, 3H). ES-MS m/z 308.05 (M+H)+.

HPLC purity 95.9%.

Example 46 Preparation of 5,7-dimethyl-N-(4-(thiophen-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

4,4,5, 5-tetramethyl-2-(thiophen-2-yl)-1,3,2-dioxaborolane (64 mg, 0.31 mmol), K ₂ CO ₃ (105 mg, 0.76 mmol) and Pd(PPh ₃ ) 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 then filtered through a pad of celite and washed with ethyl acetate (10 ml). The filtrate was washed with ice water (10 ml) and brine (10 ml) and concentrated in vacuo to give the crude compound, which was then purified by FCC (eluent, 5-10% methanol in DCM) to give the title compound as a brown solid ( 40 mg, 45%).

1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 8.63 (s, 1H), 7.70 (d, J=8.6 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.21 (d, J=3.5 Hz, 1H), 7.17 (d, J=5.1 Hz, 1H), 7.00 (dd, J=3 .6, 5.0 Hz, 1H), 6.69 (s, 1H), 2.75 (s, 3H), 2.65 (s, 3H). ES-MS m/z 349.10 (M+H)+.

HPLC purity 98.9%.

Example 47 Preparation of 5,7-dimethyl-N-(2-methyl-1H-indol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a stirred solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.26 mmol), HATU (148 mg, 0.39 mmol) and DIPEA (0.09 ml, 0.52 mmol) 2methyl-1H-indole-5-amine (45 mg, 0.31 mmol) was added to 1 ml of DMF. The reaction mixture was stirred at room temperature for 16 hours to complete the reaction. The resulting crude product was purified by preparative HPLC (MeCN/10 mM NH4HCO3) to give the title compound as a yellow solid (13.1 mg, 15.6%).

1H NMR (400 MHz, DMSO) δ 10.87 (s, 1H), 10.04 (s, 1H), 8.61 (s, 1H), 7.86 (s, 1H), 7.25 (d , J=1.2 Hz, 2H), 7.19 (s, 1H), 6.12 (s, 1H), 2.78 (s, 3H), 2.72 (s, 3H), 2.38 (s, 3H). ES-MS m/z: 320 [M+H] ⁺ . Purity by LC-MS (214 nm): >99%; tR=1.71 min.

Example 48 Preparation of N-(1H-indazol-5-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To a stirred solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.26 mmol), HATU (57 mg, 0.39 mmol) in DMF/NMM (1 mL/ 0.1 ml) was added 1H-indazol-5-amine (42 mg, 0.314 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then quenched with water (2 ml), stirred at room temperature for 0.5 h and then filtered. The solid was washed with water (1 ml), DCM (2 ml), Et ₂ O (2 ml) and dried to give the title compound (20 mg, 25.0%) as a white solid.

1H NMR (400 MHz, DMSO) δ 13.03 (s, 1H), 10.20 (s, 1H), 8.64 (s, 1H), 8.28 (s, 1H), 8.07 (d , J=1.1 Hz, 1H), 7.56 (s, 2H), 7.19 (s, 1H), 2.77 (s, 3H), 2.72 (s, 3H). ES-MSm/z: 307.2 [M+H] ⁺ . Purity by LC-MS (254 nm): >98%; t _R \u003d 1.54 min.

Example 49 Preparation of N-(1H-indazol-6-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To a stirred solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (70 mg, 0.37 mmol), HATU (209 mg, 0.55 mmol) and DIPEA (0.13 ml, 0.74 mmol) 1 Nindazol-6-amine (59 mg, 0.44 mmol) was added to 1 ml of DMF. The reaction mixture was stirred at room temperature for

- 32 041819 for 16 hours to complete the reaction. The solid was collected by filtration, washed with H2O, DCM and diethyl ether to give the title compound (51 mg, 63.7%) as a brown solid.

¹ H 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]+. Purity by LC-MS (214 nm): >97%; tR=1.45 min.

Example 50 Preparation of N-(2H-1,3-benzodioxol-5-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3carboxamide

To a stirred solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.26 mmol), HATU (148 mg, 0.39 mmol) and DIPEA (0.09 ml, 0.52 mmol) 2H1,3-benzodioxol-5-amine (42 mg, 0.31 mmol) was added to 1 ml of DMF. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was purified by preparative HPLC (MeCN/NH4HCO ₃ ) to give the title compound as a white solid (16.8 mg, 23%).

¹ H 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, 1H), 6 .03 (s, 2H), 2.77 (s, 3H), 2.70 (s, 3H). ES-MS m/z: 311.0 [M+H] ⁺ .

Purity by LC-MS (214 nm): > 99%; tR=1.72 min.

Example 51 Preparation of N-(2-methyl-1,3-benzodioxol-6-yl)-5,7-dimethylpyrazolo[1,5-a]n-pyrimidine3-carboxamide

To a stirred solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.262 mmol), 2-methyl-1,3-benzoxazole-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 h until the reaction was complete. The suspension was diluted with H ₂ O (3 ml) and the precipitated solid was collected by filtration, washed with a minimum amount of DCM and Et ₂ O and dried under vacuum to give the title compound (60 mg, 71%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 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] ⁺ .

Purity by LC-MS (254 nm): >99%; tR=1.74 min.

Example 52 Preparation of 5,7-dimethyl-N-(2-methyl-1H-1,3-benzodiazol-6-yl)pyrazolo[1,5-a]n-pyrimidine-3-carboxamide

To a stirred solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.262 mmol), 2-methyl-1H-1,3-benzodiazol-6-amine (57 mg, 0.314 mmol) and HATU (149 mg, 0.393 mmol) in DMF (1 ml) was added DIPEA (0.14 ml, 0.786 mmol) and the reaction mixture was stirred at room temperature for 16 h until the reaction was complete. The suspension was diluted with H ₂ O (3 mL) and the precipitated solid was collected by filtration, washed with minimal DCM and Et ₂ O, and purified by preparative HPLC (MeCN/10 mM NH ₄ HCO ₃ ) to give the title compound (28 mg, 33 %) as a white solid.

'H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 10.18 (d, J=31.2 Hz, 1H), 8.63 (s, 1H), 8.09 ( d, J=53.2 Hz, 1H), 7.49-7.16 (m, 3H), 2.78 (s, 3H), 2.72 (s, 3H), 2.49 (s, 3H ). ES-MS m/z: 321.1 [M+H] ⁺ .

Purity by LC-MS (254 nm): 99%; tR=1.46 min.

Example 53 Preparation of 5,7-dimethyl-N-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

- 33 041819

To a mixture of 6-nitro-1,2,3,4-tetrahydroquinoline (200 mg, 0.772 mmol) and TEA (156 mg, 1.544 mmol) in ₆ ml dioxane and ₁ ml H mmol) and the reaction mixture was stirred at room temperature for 2 h and concentrated under vacuum. Saturated sodium bicarbonate aqueous solution was added to the residue, and the mixture was extracted with DCM. The organic layer was washed with brine, dried over anhydrous Mg ₂ SO ₄ and concentrated to give crude tert-butyl 6-nitro-1,2,3,4-tetrahydroquinoline-2-carboxylate (220 mg, 100%) which was used directly at the next stage. ES-MS m/z: 223 (M-55) ⁺ . Purity by LC-MS (254 nm): >98%; tR=2.00 min.

To a suspension of tert-butyl-6-nitro-1,2,3,4-tetrahydroquinoline-2-carboxylate (220 mg, 0.772 mmol) and NH4Cl (330 mg, 6.176 mmol) in 6 ml EtOH and 4 ml H ₂ O was added portions of Fe powder (173 mg, 3.088 mmol). The reaction mixture was stirred at 70°C for 2 h, cooled 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 preparative HPLC (MeCN/10 mM NH4HCO3) to give tert-butyl-6-amino-1,2,3,4-tetrahydroquinoline-2-carboxylate as an oil (150 mg, 78% over 2 steps) .

1H NMR (400 MHz, CDCl ₃ ) 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).

To a stirred solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (65 mg, 0.340 mmol), tert-butyl-6-amino-1,2,3,4-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 h until the reaction was complete . The crude product was purified by preparative HPLC (MeCN/10 mM NH4HCO3) to give the boc-protected title compound intermediate (64 mg, 47%) as a white solid. ES-MS m/z: 422.0 [M+H] ⁺ . Purity by LC-MS (254 nm): 96%; t _R \u003d 1.93 min. This boc-protected derivative of the title compound was converted to the title compound using the procedure below.

To the boc-protected derivative of the title compound (64 mg, 0.152 mmol) obtained by the above procedure was added TFA (0.5 ml) at 0°C. The mixture was stirred at room temperature for 2 h, diluted with DCM and basified to pH ~8 with saturated aqueous NaHCO ₃ . The resulting mixture was separated and the aqueous phase was extracted with DCM. The combined organic phases were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a residue which was then purified by preparative HPLC (MeCN/10 mM NH4HCO3) to give the title compound (24 mg, 51%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.60 (s, 1H), 8.46-8.44 (m, 2H), 7.18 (s, 1H) , 7.00 (d, J=8.0 Hz, 1H), 3.81 (s, 2H), 2.94 (t, J=5.6 Hz, 2H), 2.76 (s, 3H) , 2.70-2.69 (m, 5H). ES-MS m/z: 322.0 [M+H] ⁺ . Purity by LC-MS (254 nm): 99%; t _R \u003d 1.51 min.

Example 54 Preparation of N-(1,2-benzoxazol-5-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To an ice-cold stirred solution of SnCl ₄ (1.828 g, 7.02 mmol) in 12M HCl (0.5 ml) was added 5-nitro-1,2-benzoxazole (140 mg, 0.86 mmol) in one portion at 0°C . After 5 minutes, a solution of SnCl ₂ -2H ₂ O (792 mg, 3.51 mmol) in 12 M HCl (0.5 ml) at 0° C. was added dropwise, then another 1.0 ml of 12 M HCl was added.

The reaction mixture was then stirred at room temperature for 3 h and extracted with Et ₂ O. The aqueous layer was basified to pH ~8 with saturated aqueous NaHCO ₃ and extracted with EtOAc. The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered, concentrated and dried in vacuo to give 1,2-benzoxazol-5-amine as a colorless solid (110 mg, 95%).

Ή NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 6.94 (dd, J=8.4 Hz, 2.0 Hz, 1H), 6.91 (d, J=2.0 Hz, 1H) ES-MS m/z: 135.1 [M+H] ⁺ .

Purity by LC-MS (214 nm): 90%; tR=1.32 min.

DIPEA (136 mg, 1.048 mmol) and the reaction mixture was stirred at room temperature for 2 h to complete the reaction. The suspension was diluted

- 34 041819 with H2O (3 mL) and the precipitated solid was collected by filtration, washed with a minimum of DCM and Et2O, and dried under vacuum to give the compound ester (105 mg, 65%) as a white solid. ES-MS m/z: 310.0 [M+H]+. Purity by LC-MS (254 nm): 88%; t _R \u003d 1.61 min. The ester of the compound was used in the next step. To a suspension of the ester of the compound from the previous step (105 mg, 0.340 mmol) in DMF (0.5 ml) was added a solution of 1,2-benzoxazol-5-amine (46 mg, 0.340 mmol) in DMF (0.5 ml). The reaction mixture was stirred at room temperature for 2 hours to complete the reaction and quenched by adding TFA (5 drops). The precipitated solid was collected by filtration, suspended in DCM, basified with saturated aqueous NaHCO ₃ to pH ~8. The aqueous layer was extracted with DCM, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a residue. The residue was purified by preparative HPLC (MeCN/H ₂ O) to give the title compound (40 mg, 38%) as a white solid.

1H NMR (400 MHz, CDCl ₃ ) 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 \u003d 9.36 min.

Example 55 Preparation of N-[2-(furan-2-yl)-1H-1,3-benzodiazol-5-yl]-5,7-dimethylpyrazolo[1,5a]pyrimidine-3-carboxamide

A mixture of 4-nitrobenzene-1,2-diamine (1.53 g, 10 mmol), furan-2-carbaldehyde (1.22 g, 13.0 mmol), pbenzoquinone (1.19 g, 11 mmol) and 2- propanol (15 ml) in a sealed tube was refluxed for 2 hours. The reaction mixture was diluted with water, filtered and dried under vacuum to give 2-(furan-2-yl)-5-nitro-1H-1,3-benzodiazole as a yellow solid (1.2 g, 52%). LC-MS m/z: 234 (M+H) ⁺ . Purity by LC-MS (214 nm): >90%.

A suspension of 2-(furan-2-yl)-5-nitro-1H-1,3-benzodiazol (1.2 g, 5.15 mmol) and 10% Pd/C (120 mg) in EtOH (10 mL) was stirred at room temperature under H ₂ for 2 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified on a silica gel column (MeOH/DCM=1/10) to give 2-(furan-2-yl)-1H-1,3-benzodiazol-5-amine as a yellow solid (870 mg, 83%) .

¹ H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 7.85 (d, J=1.2 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.01 (d, J=3.2 Hz, 1H), 6.67 (m, 2H), 6.53 (q, J=2.0 Hz, 1H), 4.93 (s, 2H). LC-MS m/z: 204 (M+H) ⁺ .

Purity by LC-MS (214 nm): > 95%.

To a stirred solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.262 mmol), 2-(furan-2-yl)-1H-1,3-benzodiazol-5- amine (57 mg, 0.314 mmol) and HATU (149 mg, 0.393 mmol) in DMF (1 ml) was added DIPEA (0.14 ml, 0.786 mmol) and the reaction mixture was stirred at room temperature for 16 h until the reaction was complete. The suspension was diluted with H ₂ O (3 ml) and the precipitated solid was collected by filtration, washed with a minimum amount of DCM and Et ₂ O and dried under vacuum to give the title compound (73 mg, 75%) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) 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). ESMSm/z: 373.0 [M+H] ⁺ .

Purity by LC-MS (254 nm): 96%; t _R \u003d 1.62 min.

Example 56 Preparation of N-(2-methyl-1,3-benzothiazol-6-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3carboxamide

To a stirred solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.262 mmol), 2-methyl-1,3-benzothiazol-6-amine (51 mg, 0.314 mmol) and HATU (149 mg, 0.393 mmol) in DMF (1 ml) DIPEA (0.1 ml, 0.524 mmol) was added and the reaction mixture was stirred at room temperature for 16 h until the reaction was complete. The suspension was diluted with H ₂ O (3 ml) and the precipitated solid was collected by filtration, washed with a minimum amount of DCM and Et ₂ O and dried under vacuum to give the title compound as a white solid (53 mg, 60%).

1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.66 (s, 1H), 8.54 (d, J=1.2 Hz, 1H), 7.90 (d , J=8.8 Hz, 1H), 7.74 (dd, J=8.8 Hz, 1.2 Hz, 1H), 7.21 (s, 1H), 2.78 (s, 6H), 2.74 (s, 3H). ES-MS m/z: 338.1 [M+H] ⁺ .

Purity by LC-MS (254 nm): 99%; tR=1.75 min.

- 35 041819

Example 57 Preparation of N-(2-3-dihydro-1H-inden-5-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3carboxamide

To a stirred solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.262 mmol), 2,3-dihydro-1H-inden-5-amine (42 mg, 0.314 mmol) and HATU (149 mg, 0.393 mmol) in DMF (1 ml) was added DIPEA (0.1 ml, 0.524 mmol) and the reaction mixture was stirred at room temperature for 16 h 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.

1H NMR (400 MHz, DMSO-d ₆ ) 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]+. Purity by LC-MS (254 nm): >99%; tR=1.98 min.

Example 58 Preparation of N-{4-chloro-3-[(pyridin-3-yloxy)methyl]phenyl}-5,7-dimethylpyrazolo[1,5a]pyrimidine-3-carboxamide

2-Chloro-5-nitrobenzaldehyde (10 g, mmol) was dissolved in 150 ml of methanol and cooled to 0°C. Then a solution of NaBH ₄ (3.33 g, mmol) in 30 ml of water was added dropwise over 90 min while maintaining the temperature below 10°C. The resulting reaction mixture was then stirred for 1 h, acidified with 2N HCl and stirred 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.

1H NMR (400 MHz, DMSO-d ₆ ) 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 (br.s, 1H), 4.63 (s, 2H).

Purity by LC-MS (254 nm): > 98%; tR=1.60 min.

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 CBr ₄ (3.26 d, 9.8 mmol). The reaction mixture was stirred at room temperature for 24 hours and then diluted with DCM, washed with water and brine. The organic layer was separated, dried (MgSO ₄ ), filtered and concentrated in vacuo to give a residue. The residue was purified on a silica gel column (EA/PE: 1/10) to give 2-(bromomethyl)-1-chloro-4-nitrobenzene (1.56 g, 64%).

1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J=2.8 Hz, 1H), 8.13 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7, 59 (d, J=8.8 Hz, 1H), 4.62 (s, 2H). Purity by LC-MS (254 nm): > 80%; tR=1.95 min.

To an ice-cold suspension of NaH (60%, 110 mg, 2.75 mmol) in anhydrous DMF (1 ml) was added dropwise a solution of 3-hydroxypyridine (250 mg, 2.65 mmol) in DMF (2 ml). The mixture was then stirred at 0° C. for 15 min and a solution of 2-(bromomethyl)-1-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 1 hour, quenched with water and then partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous (MgSO4), filtered, and concentrated in vacuo to give a residue. The residue was purified on a silica gel column (EA/PE: 1/1) to give 3-[(2-chloro-5nitrophenyl)methoxy]pyridine (350 mg, 54%) as an off-white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.50 (d, J=2.8 Hz, 1H), 8.45 (d, J=2.8 Hz, 1H), 8.32 (dd, J=4.8 Hz, 1.2 Hz, 1H), 8.18 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H ), 7.36-7.33 (m, 1H), 7.30-7.26 (m, 1H), 5.26 (s, 2H). ES-MS m/z: 265 (M+H) ⁺ .

Purity by LC-MS (254 nm): > 97%; tR=1.80 min.

_{Fe powder} ( 272 mg, 4.85 mmol). The reaction mixture was stirred at 80°C for 3 h, cooled 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 aqueous NaHCO ₃ . The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under vacuum. The residue was purified on a silica gel column (EA/PE: 3/1) to give 4-chloro-3-[(pyridin-3-yloxy)methyl)]aniline (167 mg, 59%) as a white solid.

1H NMR (400 MHz, DMSO-d6): δ 8.41 (dd, J=2.8 Hz, 0.8 Hz, 1H), 8.25 (d, J=4.4 Hz, 2.0 Hz , 1H), 7.267.23 (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 (br.s, 2H).

- 36 041819

To a stirred solution of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.262 mmol), 4-chloro-3-[(pyridin-3-yloxy)methyl)]aniline (73 mg, 0.314 mmol) and HATU (149 mg, 0.393 mmol) in DMF (1 ml) was added DIPEA (0.1 ml, 0.524 mmol) and the reaction mixture was stirred at room temperature for 16 h, at 45°C for 2 h and at 60°C for 2 h to complete the reaction. The suspension was diluted with H ₂ O (3 ml) and the precipitated solid was collected by filtration, washed with a minimum amount of DCM and Et ₂ O and dried under vacuum to give the title compound (57 mg, 53%) as a pale white solid.

1H NMR (400 MHz, DMSO-d ₆ ) 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]+.

Purity by LC-MS (254 nm): 99%; t _R \u003d 1.89 min.

Example 59 Preparation of 5,7-dimethyl-N-{4-methyl-3-(1,3-oxazol-2-yl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

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(PPh ₃ ) ₄ (115 mg, 0.1 mmol) in dioxane (2 mL) was stirred at 100° C. for 3 h under argon in a microwave synthesis unit to give the crude product. The crude product was purified by preparative HPLC (MeCN/10 mM NH4HCO3) to give 4-methyl-3-(1,3-oxazol-2-yl)aniline (92 mg, 52%) as an oil. ES-MS m/z: 175.2 [M+H] ⁺ .

Purity by LC-MS (254 nm): >99%; t _R \u003d 1.31 min.

A mixture of 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid 2 (50 mg, 0.26 mmol), 4-methyl3-(1,3-oxazol-2-yl)aniline (55 mg, 0.314 mmol) and HATU (57 mg, 0.39 mmol) in DMF/NMM (1 ml/0.1 ml) were stirred at room temperature for 12 h. Water (2 ml) was added to the reaction mixture, stirred at room temperature for 0.5 h and then filtered. The resulting solid was washed with water (1 ml), DCM (2 ml), Et ₂ O (2 ml) and dried under vacuum to obtain the title compound (62 mg, 68.0%) as a white solid.

'H 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] ⁺ .

Purity by LC-MS (254 nm): > 99%; tR=1.91 min.

Example 60 Preparation of 5,7-dimethyl-N-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (64 mg, 0.31 mmol), K ₂ CO ₃ (105 mg, 0.76 mmol) , Pd(PPh ₃ ) 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 water (10 ml) and brine (10 ml) and concentrated in vacuo to give the crude compound. The crude compound was purified by FCC (eluent, 5-10% methanol in DCM) to give the title compound as an off-white solid (35 mg, 39%).

'H NMR (400 MHz, CDCI3) δ 10.29 (s, 1H), 10.08 (s, 1H), 8.63 (s, 1H), 7.69 (d, J=7.1 Hz, 2H), 7.54 (s, 1H), 7.40 (d, J=8.4 Hz, 2H), 6.70 (s, 1H), 3.90 (s, 3H), 2.75 ( s, 3H), 2.65 (s, 3H). ES-MS m/z 347.20 (M+H) ⁺ .

HPLC purity 91.1%.

Example 61 Preparation of N-(4-(furan-2-yl)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3carboxamide

Furan-2-ylboric acid (34 mg, 0.31 mmol), K ₂ CO ₃ (105 mg, 0.76 mmol), Pd(PPh ₃ ) ₄ (29 mg, 0.025 mmol) and the reaction mixture was degassed with argon for 30 min and

- 37 041819 was heated to 100°C for 30 hours the Reaction mixture was filtered through a layer of celite and washed with ethyl acetate (10 ml). The filtrate was washed with ice water (10 ml) and brine (10 ml) and concentrated in vacuo to give the crude compound, which was purified by FCC (eluent, 5-10% methanol in DCM) to give the title compound as a yellow solid (30 mg, 35%).

1H NMR (400 MHz, CDCb) δ 10.11 (s, 1H), 8.61 (s, 1H), 7.70 (d, J=8.6 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 7.38 (d, J=1.2 Hz, 1H), 6.68 (s, 1H), 6.52 (d, J=3.3 Hz, 1H), 6.40 (dd, J=1.8, 3.3 Hz, 1H), 2.73 (s, 3H), 2.64 (s, 3H). ES-MS m/z 333.10 (M+H)+.

HPLC purity 99.0%.

Example 62 Preparation of 5,7-dimethyl-N-(4-(pyridin-4-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Pyridine-4-ylboric acid (37 mg, 0.31 mmol), K ₂ CO ₃ (105 mg, 0.76 mmol), Pd(PPh ₃ ) ₄ (29 mg, 0.025 mmol), and the reaction mixture was degassed with argon for 30 min and heated to 100°C for 30 hours Then, the reaction mixture was filtered through a layer of celite and washed with ethyl acetate (10 ml). The filtrate was washed with ice water (10 ml) and brine (10 ml) and concentrated in vacuo to give the crude compound, which was purified by FCC (eluent, 5-10% methanol in DCM) to give the title compound as a white solid (40 mg, 46%).

1H NMR (400 MHz, CDCl3) δ 10.26 (s, 1H), 8.64 (s, 1H), 8.58 (d, J=6.1 Hz, 2H), 7.85 (d, J = 8.6 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H), 7.55 (d, J=6.1 Hz, 2H), 6.73 (s, 1H), 2.77 (s, 3H), 2.68 (s, 3H). ES-MS m/z 344.15 (M+H)+.

HPLC purity 92.4%.

Example 63 Preparation of additional pyrazolo[1,5-a]pyrimidine-3-carboxamides

Additional pyrazolo[1,5-a]pyrimidine-3-carboxamide compounds were prepared using the general procedures described in section I below. Examples of procedures for the preparation of specific amine compounds used in the preparation of specific compounds are given in section II below. Examples of procedures for the preparation of specific carboxylic acid compounds used in the preparation of specific compounds are given in section III below. Specific pyrazolo[1,5-a]pyrimidine-3-carboxamide compounds prepared according to general procedures are given in section IV below.

Section I. General Methods

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

An amine compound (1. 25-2.0 eq.). The reaction mixture was stirred at room temperature for 4-16 h and then washed with saturated aqueous NaHCO3 (5 ml/0.2 mmol), aqueous citric acid (5 ml/0.2 mmol) and brine (5 ml/0 .2 mmol). The combined extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting crude material was purified by silica gel column chromatography or preparative HPLC to give an amide compound.

General Procedure B. Conversion of a Carboxylic Acid Ester Compound to a Carboxylic Acid Compound

NaOH (2.0-5.0 eq.) and the mixture was heated at 80°C for 2 h and then concentrated. A 6N HCl solution was added to the concentrate to adjust the pH to 5~6, and then the mixture was stirred for 10 minutes and filtered. The resulting solid was collected and dried to give a carboxylic acid compound.

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

To a solution of the carboxylic acid compound (1.0 equivalent) in DCM (3 ml/0.5 mmol) was added DMF (1 drop) and oxalyl chloride (2.0 equivalent). 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), then the amine compound (5.0 eq.) and triethylamine (2.0 eq.) were added. The reaction mixture was stirred at room temperature for 2 h and then diluted with DCM (10 ml/0.5 mmol). The organic solution was washed successively with H2O (10 ml/0.5 mmol) and brine (10 ml/0.5 mmol), then dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by preparative HPLC or silica gel chromatography to give the amide compound.

Section II. Obtaining specific amine compounds

Examples of procedures for the preparation of specific amine compounds used in the preparation of specific pyrazolo[1,5-a]pyrimidine-3-carboxamide compounds are given below.

-(4,4-Difluorocyclohexyl)ethane-1-amine

To a solution of 4,4-difluorocyclohexane-1-carboxylic acid (1.64 g, 10 mmol) and DIPEA (2.58 g, 20 mmol) in DMF (10 ml) was added HATU (5.7 g, 15 mmol) and the reaction mixture was stirred at 0° C. for 30 min, then N,O-dimethylhydroxylamine hydrochloride (970 mg, 10 mmol) was added. The reaction mixture was warmed to room temperature and stirred overnight, then quenched with saturated aqueous NaHCO ₃ and separated. The aqueous phase was extracted with EtOAc (100 mlx3) and the combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (PE/EtOAc; 4:1) to give 4,4-difluoro-N-methoxy-N-methylcyclohexane-1-carboxamide (880 mg, 42%) as a colorless oil. LC-MS m/z: 208.0 [M+H]+. LCMS: tR=1.58 min.

To a solution of 4,4-difluoro-N-methoxy-N-methylcyclohexane-1-carboxamide (880 mg, 4.25 mmol) in THF (12 ml) was added dropwise a solution of MeLi in 1,2-diethoxyethane (3 mol/l , 2 ml) at 0°C. After the addition was complete, the reaction mixture was warmed to room temperature and stirred overnight, then quenched with saturated aqueous NH4Cl and separated. The aqueous phase was extracted with EtOAc (120 mlx3) and the combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (PE/EA=4:1) to give 1-(4,4-difluorocyclohexyl)ethan-1-one (400 mg, 43%) as a light yellow oil.

1H NMR (500 MHz, CDCl3) δ 2.44 (m, 1H), 2.19 (s, 3H), 2.13-2.16 (m, 2H), 1.96-1.98 (m, 2H), 1.74-1.83 (m, 4H).

A mixture of 1-(4,4-difluorocyclohexyl)ethan-1-one (200 mg, 1.23 mmol), NH ₄ OAc (1.9 g, 24.6 mmol) and NaBH ₃ CN (388 mg, 6.15 mmol) in i-PrOH (15 ml) was stirred at room temperature for 4 h and then at 90°C for 2 h. The reaction mixture was then poured into water (15 ml), extracted with CH ₂ Cl ₂ (30 ml , x3) and dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (EtOAc/MeOH; 10:1) to give 1-(4,4difluorocyclohexyl)ethane-1-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

_NH2

MgBrMe (3M in THF, 5 ml, 15 mmol) was added dropwise at room temperature to a solution of 1-(4-chlorophenyl)ethan-1-one (1.54 g, 10 mol) in Et ₂ O (60 ml). After the addition was complete, the reaction mixture was stirred at room temperature for 12 h and then quenched by careful addition of saturated aqueous NH ₄ Cl (30 ml). The resulting mixture was stirred for 1 h and then was extracted with EtOAc (100 ml x 3). The combined organic layers were dried over Na ₂ SO 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.

1H NMR (400 MHz, CDCl ₃ ) 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).

A mixture of 2-(4-chlorophenyl)propan-2-ol (1.36 g, 8 mmol), TMSN3 (2.4 g, 16 mmol) and BF ₃ -Et ₂ O (16 ml) in CH ₂ Cl ₂ ( 20 ml) was stirred at room temperature for 2 h and extinguished with saturated aqueous NaHCO ₃ . The resulting mixture was separated and the aqueous phase was extracted with CH ₂ Cl ₂ (30 mlx3). The combined organic phases were dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo to give the title compound 1-(2-azidopropan-2-yl)-4-chlorobenzene as a colorless oil, which was used in the next step without further purification. LC-MS m/z: 153.0 [M - N ₃ ] ⁺ . LCMS: purity (254 nm): 44%; t _R \u003d 1.44 min.

The crude azide from the previous step was dissolved in THF (15 ml) at room temperature and trimethylphosphine (16 ml, 1.0 M in THF) was added. After 15 min, 3 ml of water was added and the resulting mixture was stirred at room temperature for 2 h until the reaction was complete (monitored by LC/MS.) The solvent was removed under vacuum and the residue was diluted with water (75 ml), extracted with CH ₂ Cl ₂ , dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the resulting residue was purified by reverse phase chromatography.

- 39 041819 (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-NH ₂ ] ⁺ . LCMS: purity (214 nm): 98%; tR=1.71 min.

Section III. Obtaining specific compounds of carboxylic acids

Examples of procedures for the preparation of specific carboxylic acid compounds used in the preparation of specific substituted pyrazolo[1,5-a]pyrimidine compounds are given below.

7-Chloro-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid

CI

Αγ

And he is about

To a solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (10 g, 64.5 mmol) in HOAc (50 ml) was added 4-methylenexetan-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 give ethyl 7-hydroxy-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (8.0 g, 57%) and ethyl -5-hydroxy-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (3.1 g, 21%) as white solids. 7-hydroxy product: LC-MS m/z: 221.0 [M+H] ⁺ , purity (214 nm): >90%, tR=1.26 min; 5hydroxy product: LC-MS m/z: 221.0 [M+H] ⁺ , purity (214 nm): >92%, tR=1.46 min.

A solution of ethyl 7-hydroxy-5-methylpirazolo[1,5-a]pyrimidine-3-carboxylate (4.4 g, 20 mmol) in POCl ₃ (30 ml) was stirred at 95°C for 1 h and concentrated under vacuum. The residue was dissolved in EtOAc (20 ml) and basified with saturated aqueous NaHCO ₃ (20 ml) to pH~7. The resulting mixture was separated and the aqueous phase was extracted with EtOAc (15 mlx3). The combined organic phases were dried over anhydrous Na ₂ SO 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 7chloro-5-methylpirazolo[1,5-a]n-pyrimidine-3-carboxylate (1.0 g, 21% ) as a white solid. LC-MS m/z: 239.0 [M+H] ⁺ , purity (254 nm): >82%, tR=1.55 min.

(Bu ₃ Sn) ₂ O (5 .0 g, 8.36 mmol). The reaction mixture was stirred at 120°C for 2 days and concentrated under vacuum. The residue was dissolved in EtOAc (10 ml) and basified with saturated aqueous NaHCO ₃ (10 ml) to pH~8-9. The aqueous phase was separated and acidified with 6N HCl solution (10 ml) to pH~5. The solution was extracted with EtOAc (10 mlx3). The organic phases were dried over anhydrous Na ₂ SO 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 7-chloro-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (230 mg, 26%) as white solid. LC-MS m/z: 211.0 [M+H] ⁺ , purity (214 nm): >97%, t _R = 1.23 min.

5-Chloro-7-methylpyrazolo[1,5-a]-pyrimidine-3-carboxylic acid

A solution of ethyl 5-hydroxy-7-methylpyrazolo[1,5-a]-pyrimidine-3-carboxylate (2.8 g, 12.6 mmol) in POCl ₃ (30 ml) was stirred at 70°C for 2 h and concentrated under vacuum. The resulting residue was dissolved in EtOAc (20 ml) and basified with saturated aqueous NaHCO ₃ (15 ml) to pH~7. The resulting mixture was separated and the aqueous phase was extracted with EtOAc (10 mlx3). The combined organic phases were dried over anhydrous Na ₂ SO 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[1,5-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.

(Bu 3 Sn) 2 O (Bu ₃ Sn) ₂ O ( 5.0 g, 8.36 mmol). The reaction mixture was stirred at 120°C for 2 days and concentrated under vacuum. The resulting residue was dissolved in EtOAc (10 ml) and basified with saturated aqueous NaHCO ₃ (10 ml) to pH~8-9. The aqueous phase was separated and acidified with 6N HCl solution (10 ml) to pH~5. The solution was extracted with EtOAc (10 mlx3). The organic phases were dried over anhydrous Na ₂ SO 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 5chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (330 mg, 37%) as white solid. LC-MS m/z: 211.0 [M+H] ⁺ , purity (214 nm): >97%, t _R = 1.28 min.

Section IV. Pyrazolo[1,5-a]pyrimidine-3-carboxamide compounds prepared according to general procedures

- 40 041819

The following compounds were obtained in accordance with the General methods described in section I above.

5,7-Dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazolo-[1,5-a]pyrimidine-3-carboxamide

Following General Procedure A and using 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40 mg, 0.21 mmol) and 1,2,3,4-tetrahydronaphthalene-1-amine, the title compound (37 mg, 55%) as a yellow solid.

¹ H NMR (500 MHz, CDCl ₃ ): 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%; tR=8.26 min.

5,7-Dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo-[1,5-a]pyrimidine-3-carboxamide

Following General Procedure A and using 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (24 mg, 0.125 mmol) and (1R,4R)-4-(pentyloxy)cyclohexane-1-amine, we obtained the title compound (29 mg, 64%) as a white solid.

¹ H NMR (400 MHz, MeOD-d4): δ 8.37 (s, 1H), 8.27 (d, J=7.6 Hz, 1H), 6.91 (s, 1H), 3.90 (br.s, 1H), 3.47 (t, J=6.8 Hz, 2H), 3.34 (br.s, 1H), 2.71 (s, 3H), 2.61 (s, 3H), 2.10-2.06 (m, 4H), 1.55 (t, J=6.4 Hz, 2H), 1.481.41 (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 (214 nm): >99%; t _R \u003d 9.262 min.

(S)-N-(1-(2-Fluorophenyl)ethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following General Procedure A and using 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40 mg, 0.21 mmol) and (S)-1-(2-fluorophenyl)ethan-1-amine , gave the title compound (34.3 mg, 49%) as a white solid.

¹ H NMR (400 MHz, MeOD-d4) δ 9.02 (d, J=7.5 Hz, 1H), 8.49 (s, 1H), 7.48-7.43 (m, 1H), 7.34-7.28(m, 1H), 7.19-7.10(m, 2H), 7.03(s, 1H), 5.52-5.47(m, 1H), 2, 79 (d, J=0.4 Hz, 3H), 2.69 (s, 3H), 1.62 (d, J=7.2 Hz, 3H). LC-MS m/z: 313.2 [M+H]+. HPLC: purity (214 nm): >99%; t _R \u003d 9.85 min.

(S)-N-(1-(2-Methoxyphenyl)ethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following General Procedure A and using 5,7-dimethylpyrαzolo[1,5-a]pyrimidine-3-carboxylic acid (25 mg, 0.13 mmol) and (S)-1-(2-methoxyphenyl)ethane-1-amine , gave the title compound (21.6 mg, 51%) as a yellow solid.

¹ H NMR (500 MHz, CDCl3): δ 8.77 (d, J=8.5 Hz, 1H), 8.61 (s, 1H), 7.36 (d, J=6.0 Hz, 1H ), 7.23 (t, J=8.0 Hz, 1H), 6.94-6.90 (m, 2H), 6.70 (s, 1H), 5.63-5.59 (m, 1H), 3.93 (s, 3H), 2.78 (s, 3H), 2.67 (s, 3H), 1.58 (d, J=7.0 Hz, 3H). LC-MS m/z: 325.0 [M+H]+. HPLC: purity (214 nm): >93%; t _R \u003d 9.82 min.

(R)-N-(1-(2-Methoxyphenyl)ethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

- 41 041819

Following General Procedure A and using 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (30 mg, 0.15 mmol) and (R)-1-(2-methoxyphenyl)ethan-1-amine , gave the title compound (19.7 mg, 40%) as a pink solid.

1H NMR (500 MHz, DMSO-d ₆ ): 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 \u003d 9.82 min.

(S)-N-(1-(3-Chlorophenyl)ethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following General Procedure A and using 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40 mg, 0.21 mmol) and (S)-1-(3-chlorophenyl)ethan-1-amine , gave the title compound (26.1 mg, 38%) as a white solid.

1H NMR (400 MHz, MeOD-d ₄ ) 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 (kv, 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 \u003d 10.24 min.

(R)-N-(1-(4-Chlorophenyl)ethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following General Procedure A and using 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (38 mg, 0.20 mmol) and (R)-1-(4-chlorophenyl)ethan-1-amine , gave the title compound (18 mg, 26%) as a white solid.

1H NMR (500 MHz, DMSO-d6): δ 8.49 (s, 1H), 8.47 (s, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.41 ( d, J=8.5 Hz, 1H), 7.14 (s, 1H), 5.20-5.14 (m, 1H), 2.74 (s, 1H), 2.63 (s, 1H ), 1.51 (d, J=6.0 Hz, 3H). LC-MS m/z: 329.1 [M+H] ⁺ . HPLC: purity (214 nm): >99%; t _R \u003d 10.32 min.

(R)-N-( 1 -(4-Fluorophenyl)ethyl)-5,7-dimethylpyrazolo [1,5-a]pyrimidine-3-carboxamide

Following General Procedure A and using 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (30 mg, 0.16 mmol) and (R)-1-(4-fluorophenyl)ethan-1-amine , gave the title compound (26.7 mg, 53%) as a white solid.

1H NMR (500 MHz, CDCl ₃ ): 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-MSm/z: 313.2 [M+H] ⁺ . HPLC: purity (214 nm): >99%; t _R \u003d 9.82 min.

N-(1-(4,4-Difluorocyclohexyl)ethyl)-5,7-dimethylpyrazolo[1,5-а]pyrimidine-3-carboxamide

Following General Procedure A and using 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (20 mg, 0.1 mmol) and 1-(4,4-difluorocyclohexyl)ethan-1-amine, named

- 42 041819 compound (10 mg, 30%) as a white solid.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.63 (s, 1H), 8.14 (d, J=8.5 Hz, 1H), 6.73 (s, 1H), 4.29-4 .27 (m, 1H), 2.82 (s, 3H), 2.66 (s, 3H), 2.20-2.14 (m, 2H), 1.98-1.95 (m, 1H ), 1.87-1.56 (m, 6H), 1.29 (d, J=6.5 Hz, 3H). LC-MS m/z:

337.2 [M+H]+. HPLC: purity (254 nm): >99%; tR=7.95 min.

N-(2-(4-Chlorophenyl)propan-2-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A and using 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40 mg, 0.21 mmol) and 2-(4-chlorophenyl)propan-2-amine, the title compound was obtained. (23.5 mg, 33%) as a white solid.

¹ H NMR (500 MHz, DMSO-d6): δ 8.58 (s, 1H), 8.42 (s, 1H), 7.44 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 7.16 (s, 1H), 2.76 (s, 3H), 2.63 (s, 3H), 1.73 (s, 6H). LC-MS m/z: 343.1 [M+H] ⁺ . HPLC: purity (214 nm): >99%; tR=8.99 min.

7-Chloro-N-(2-(4-chlorophenyl)propan-2-yl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following General Procedure C and using 7-chloro-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (100 mg, 0.47 mmol) and 2-(4-chlorophenyl)propan-2-amine, the title compound (40 mg, 23%) as a white solid.

¹ H NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.44 (s, 1H), 7.60 (s, 1H), 7.44 (d, J=9.0 Hz, 2H), 7.36(d, J=8.5Hz, 2H), 2.65(s, 3H), 1.73(s, 6H). LC-MS m/z: 362.2 [M+H]+.

HPLC purity (214 nm): >99%; t _R \u003d 9.02 min.

5-Chloro-N-(2-(4-chlorophenyl)propan-2-yl)-7-methylpyrazolo[1,5-а]pyrimidine-3-carboxamide

Following General Procedure C and using 5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (100 mg, 0.47 mmol) and 2-(4-chlorophenyl)propan-2-amine, the title compound (60 mg, 35%) as a white solid.

¹ H NMR (500 MHz, DMSO-d ₆ ) 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 \u003d 9.44 min.

N-(2-(2,4-Difluorophenyl)propan-2-yl)-5,7-dimethylpyrazolo[1,5-а]pyrimidine-3-carboxamide

Following General Procedure A and using 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (19 mg, 0.1 mmol) and 2-(2,4-difluorophenyl)propan-2-amine, the title compound (20 mg, 58) as a white solid.

¹ H NMR (500 MHz, CDCl3) δ 8.66 (s, 1H), 8.56 (s, 1H), 7.49-7.44 (m, 1H), 6.86-6.82 (m , 1H), 6.76-6.73 (m, 1H), 6.74 (s, 1H), 2.81 (s, 3H), 2.67 (s, 3H), 1.92 (s, 6H). LC-MS m/z: 345.1 [M+H] ⁺ . HPLC: Purity (254 nm): >99%; tR=8.62 min.

N-(2-((1R,4R)-4-Methoxycyclohexyl)propan-2-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide and N-(2-((1S, 4S)-4-methoxycyclohexyl)propan-2-yl)-5,7-dimethylpyrazolo[1,5-a]-pyrimidine-3carboxamide

Following General Procedure A and using 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (50 mg, 0.26 mmol) and 2-(4-methoxycyclohexyl)propan-2-amine, N- (2-43 041819 ((1R,4R)-4-methoxycyclohexyl)propan-2-yl)-5,7-dimethylpyrαzolo[1,5-a]pyrimidine-3-carboxamide (7.2mg) and N-( 2-((1S,4S)-4-methoxycyclohexyl)propan-2-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3carboxamide (8.4 mg) as white solids.

N-(2-((1R,4R)-4-Methoxycyclohexyl)propan-2-yl)-5,7-dimethylpyrαzolo[1,5-a]pyrimidine-3carboxamide: 1H NMR (500 MHz, MeOD-d4) 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). LCMS m/z: 345.2 [M+H]+. HPLC: purity (214 nm): 99.52%; t _R = 8.08 min.

N-(2-((1S,4S)-4-Methoxycyclohexyl)-propan-2-yl)-5,7-dimethylpyrαzolo[1,5-a]pyrimidine-3-carboxamide: ¹ H NMR (500 MHz, DMSO4) δ 8.46 (s, 1H), 8.44 (s, 1H), 7.02 (s, 1H), 3.51-3.50 (m, 1H), 3.35 (s, 3H), 2.80 (s, 3H), 2.69 (s, 3H), 2.10-2.07 (m, 2H), 1.99-1.96 (m, 1H), 1.87-1, 66 (m, 2H), 1.54-1.48 (m, 6H), 1.48 (s, 6H), 0.87 (d, J=7.0 Hz, 1H). LC-MS m/z: 345.2 [M+H] ⁺ . HPLC: purity (214 nm): 95.63%; t _R = 8.46 min.

Example 64 Preparation of additional pyrazolo[1,5-a]pyrimidine-3-carboxamides

The following additional pyrazolo[1,5-a]pyrimidine-3-carboxamide compounds were prepared according to the procedures described above:

Example 65 Evaluation of Biological Activity

The ability of exemplary compounds to activate glucocerebrosidase (Gcase) was evaluated. Experimental procedures and results are shown below.

Part I. Research methodology

An aliquot of 484 μl of a solution of phosphatidylserine (PS) (Sigma P7769) with a concentration of 1.0 mg/ml in chloroform was evaporated in a stream of nitrogen for 1 h. The lipid film was dissolved for 4 min with vigorous shaking in a mixture of 40 ml of 176 mM K2HPO4/50 mM citric acid (pH 4.7) containing 7.5 μl Triton X-100 resulting in a mixed micellar preparation containing 0.32 mM Triton X-100 and 0.37 mole % PS. Dissolved in a micellar solution of 4-methyllumbelliferyl-beta-D-glucopyranoside (ACROS-337025000) to a final concentration of 2 mm for use as a reaction substrate.

Stock solutions containing 10 mM of test compounds were diluted to the required concentrations with dimethyl sulfoxide (DMSO) and 0.41 µl of the compound in DMSO mixture was added to 100 µl of a micellar solution containing 10 nM GCase and 100 nM saposin C (Enzo ALX-201-262 -C050). A pre-incubation was carried out for 30 min at room temperature, after which the reaction was initiated by combining 25 μl of the substrate solution with 25 ml of the compound/bSaee/saposin mixture. The reaction was carried out for 15 min at room temperature and stopped by adding 150 μl of 1M glycine, pH 12.5. The completion of the reaction was monitored by measuring the fluorescence intensity (excitation: 365 nm, emission: 440 nm) on a SpectraMax i3 instrument (Molecular Devices). Test compounds were screened at a final concentration of 1.0 and 0.1 μM, and then 8-point dose-response curves were plotted using 3-fold dilutions, based on a maximum final concentration of 5 μM.

Part II. results

The values of activation Gcase for the tested compounds are given below in table. 1 and 2, along with cLogP, PSA, and water solubility of the compounds. For experiments in which the test compound was used at a concentration of 1.0 μM, the + symbol indicates Gcase activation less than 30%, the ++ symbol indicates Gcase activation in the range of 30% to 60%, and the +++ symbol indicates Gcase activation greater than 60%. . For experiments in which the test compound was used at a concentration of 0.1 μM, the symbol * denotes Gcase activations less than 10%, the symbol ** denotes Gcase activations in the range of 10% to 20%, and the symbol *** denotes Gcase activations greater than 20% .

- 44 041819

Table 1

Connection No. Connection structure cLogP PSA Compound solubility in water (µg/mL) Gcase activation percentage 1 µM test compound 0.1 µM test compound III-1 XX f / '0 16 69.4 <1.5 ++ * III-2 χβ IS 0 Η 1.4 69.4 <1.5 + * III-3 l" A •A 0 x'N 0 H 3.7 57.1 <1.5 ++ * * * III-4 HCH a* A' N 0 H 2.4 66.2 <1.5 + + + ** III-5 0XX0H 3, 6 66, 3 <1.5 ++ * * * III-6 000H 1.3 72.6 <1.5 + * III-7 1 is _{i ' CN 0 H 2.8 69.4 <1.5 + + + * * III-8 0? 0H0 2.1 66, 3 <1.5 ++ * * III-9 at 0 0N0H 2.5 78.6 <1.5 + + + * III-10 0 0H 2.0 78.6 <1.5 + + + * * %s v~~N 0 H 2.0 78.6 <1.5 + + + * * III-12 αχο A-n 0H 2, 6 78.6 <1.5 + *

- 45 041819

III-13 70' An 0 H 1.8 57.1 26.0 + * III-14 70'0H 1.8 57.1 17, 6 + * III-15 AA0H 1.8 57.1 8.0 + * III-16 ,s 7% 0H 2.7 69.4 <1.5 + + + * * III-17 0 <X N 0H 2.1 78.6 <1.5 + * II1-18 And Λ''00-! 0H 2.4 78.6 2, 6 + * III-19 Hell AY Ύ An 0 H 1.2 91.1 thirty + * III-20 III-21 III-22 III-23 III-24 III-25 /a A Axf A ^N oA π Ы Άν 0 H AA An OH «5 (0 An 0 H a / ^N •or A 2.7 1.7 2.0 1.3 1.3 2.0 69.4 81.8 78.6 85.0 73.9 61.6 <1.5 <1.5 <1.5 <1.5 >64.0 54.0 + + + + + + + * III-26 0%H 2.0 61.6 39.0 + *

- 46 041819

- 47 041819

III-42 An 0 Η 1.8 81.4 0.4 + * III-43 0% .J ^Jk-OMe Αν 0 Η 1.4 87.9 N/A N/A N/A III-44 ifi' Αν 0 Η 16 78.6 0.3 + * III-45 Αν 0 Η 1.5 81.4 1.2 + * III-46 Al An 0 Η 1.5 69, 1 33.4 + * III-47 % t* _λ Αν 0 Η 1.5 78.6 0.9 + * III-48 D? Αν 0 Η 2.2 91.0 0.3 N/A N/A III-49 <ly 2.4 90.1 0.4 + * III-50 An % An A A/ $ An O Η 2.3 69.4 2.3 ++ * III-51 Αχ J-N o/A ^{0 n} AJ 3.0 78.6 0.06 + + + ** III-52 -Aa 0 N 2, 6 78.6 0.05 + + + ** III-53 Dy-N A ‘S.A 0 N 2.2 78.6 <0.05 + + + 9g 9g III-54 .N t A oX 2.1 72.7 2, 1 ++ * III-55 oA 2.8 66, 3 <1.5 + + + * * * III-56 /.-:-7 0 n 2.5 69.4 <1.5 + * III-57 .A A A-N 0 n 2.7 69, 1 <1.5 + **

-48041819

III-58 Pro 3, 6 57.1 2b + + + *** III-59 ^0 \ 3.3 bb, 3 7.1 + + + * * III-60 ΛΑ oO F 3, 1 57.1 7.2 + + + * III-61 OD at ό 2.9 bb, 3 1.4 + + + * * III-62 :U° i -Lo -Ld ² 2.9 bb, 3 2.5 + + + * III-63 III-64 οθ ^Η /LO CI Ad lz ^LL~ ^C| 3.7 3.7 57.1 57.1 11.9 0.7 + + + + + + ** III-65 Hell AD o+ ⁿ yes 3, 1 57.1 27b ++ * III-66 O ₍ ^Ν V OX F 0 N Vdr thirty 57.1 20b + * III-67 L< OO 4.1 57.1 2.2 + + + A A III-68 CI Hell .A 2, 6 57.1 2.1 + + + * * III-69 Al “OO 4.3 57.1 5, 1 + + + * * * III-70 L< F A ^; -T 3b 57.1 2.0 + + + A A III-71 2.7 bb, 3 21.4 ++ *

- 49 041819

III-72 Y-N to Yes ₀ >NV%OMe 2.7 6 6.3 15, 1 + + + * III-73 D' w o A / J 3, 9 81.4 34.0 + * III-74 OH Η 3.7 27, 6 0.2 + * III-75 %Ν O V Ί ^{0 n} V/ 4.2 78.6 0, 1 + + + III-76 A AH 0 HE 3.2 56, 7 0.01 ++ ** III-77 Dchd o n 2.8 69, 1 4.2 + + + *** III-78 'ΝΗ- %V HE 2.8 69, 1 <1.5 + ** III-79 Yes HE 3, 1 57.1 0.8 *** ** Compound No. IV-1 IV-2 IV-3 IV-4 Connection structure d'pi HE A A AA He V R Άν o n LA A >Ν 0 N Tab cLogP 2.2 2.5 thirty 1.7 faces 2 PSA 57.1 60.3 60.3 75.5 Compound solubility in water (µg/mL) <1.5 5, 1 <1.5 0.6 1 µM test 7 + + 7 connections i and o n R o s o -----o> m e ω w th 0.1 µM X-X-X-ίS connections IV-5 L V 0 N 3, 1 57.1 0.5 + + + **

- 50 041819

Inclusion in the description of the present application of the content of cited literary sources by reference to them

The contents of each of the patent documents and each of the scientific publications mentioned in the description of the present application are in all cases included in the description of the present application by reference to them.

Equivalents

The invention can be implemented in other specific forms without deviating from its essence or main characteristics. The above embodiments are to be considered in all respects only as illustrations and not as limitations to the invention. Accordingly, the scope of the invention is defined in the appended claims and not in the above description of the invention, and it is intended that all changes that are defined by the concept of equivalence and the range of equivalence are covered by the claims.

Claims (51)

CLAIM 1. Pharmaceutical composition having the ability to activate glucocerebrosidase (Gcase) containing a compound of formula I (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein R ¹ is independently at each occurrence C _1-4 alkyl, C _1-4 haloalkyl, C ₁ - ₄ alkoxy, cyclopropyl, cyano, chlorine or fluorine; R ² is hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, -(C _1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, chlorine, fluoro or -N (H)(R ³ ); R ³ is independently at each occurrence hydrogen or C _1-4 alkyl; R ⁴ is independently at each occurrence hydrogen, C _1-4 alkyl or —C(O)R ³ ; X ¹ is one of the following: (a) a carbonyl-containing linker selected from -C(O)N(H)-ψ and -C(O)N(H) (C _1-6 alkylene)ψ, where ψ is a bond to A ¹ , or ( b) an amine-containing linker selected from -(C _1-4 alkylene)-N(H)-ψ and -(C _1-4 alkylene)-N(H)(C _1-4 αkylene)-ψ; A ¹ is C _3-10 cycloalkyl which is substituted 1 or 2 times with Y ¹ and 0, 1, 2 or 3 times with Y ² ; Y ¹ is independently in each case one of the following: 2-8 membered heteroalkyl optionally substituted with 6-10 membered aryl or 3-10 membered heterocyclyl; 3-10 membered heterocyclyl, 6-10 membered aryl, -O-(3-6 membered heterocyclyl), -O-(6-10 membered aryl) or -O-(C _2-6 alkynyl); or C _2-6 alkynyl, -C=C-(C _1-6 alkylene)-OR ⁴ , -C=C-(C1-6 alkylene)-N(R ³ )2, -(C _2-4 alkynylene)- (5-6 membered heteroaryl) or C _2-6 alkenyl; Y ² is independently at each occurrence C1-6 alkyl, C3-6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, C2-4 alkynyl, cyano, azido, -N(R ³ )2, -(C _1-6 alkylene)-(5-6 membered heterocyclyl), -(C _1-6 alkylene)-CO ₂ R ³ or C _1-6 haloalkyl-substituted C _3-6 cycloalkyl and n is 1, 2 or 3, where the term heteroalkyl refers to an alkyl group in which at least one carbon atom has been replaced by an O or S atom, where the term heterocyclyl refers to a saturated, partially unsaturated or aromatic ring structure comprising from one to four heteroatoms, selected from nitrogen, oxygen and sulfur; and where the term heteroaryl refers to an aromatic ring structure that includes at least one ring heteroatom selected from nitrogen, oxygen and sulfur. 2. Pharmaceutical composition according to claim 1, where R ¹ represents methyl. 3. Pharmaceutical composition according to claim 1 or 2, where n is 2. 4. Pharmaceutical composition according to claim 3, wherein the R ¹ groups are located at positions 5 and 7 of the pyrazolo[1,5-a]pyrimidinyl. 5. Pharmaceutical composition according to any one of claims 1 to 4, wherein R ² is hydrogen. 6. Pharmaceutical composition according to any one of claims 1-5, where R ³ and R ⁴ each represents - 51 041819 is independently in each case hydrogen, methyl or ethyl. 7. Pharmaceutical composition according to any one of claims 1-6, where X ¹ represents -C(O)N(H)-ψ. 8. Pharmaceutical composition according to any one of claims 1 to 7, wherein in any case Y ² is independently C _1-6 alkyl, C _3-6 cycloalkyl, halogen, C _1-6 haloalkyl or hydroxyl. 9. Pharmaceutical composition according to any one of claims 1-7, wherein in any case Y ² is independently C _1-3 alkyl. 10. A pharmaceutical composition according to any one of claims 1-9, wherein Y ¹ is a 2-8 membered heteroalkyl. 11. Pharmaceutical composition according to any one of claims 1-9, wherein Y ¹ is -O-(C _1-7 alkyl). 12. A pharmaceutical composition according to any one of claims 1 to 9, wherein Y ¹ is -O-butyl, -O-pentyl or -O-hexyl. 13. A pharmaceutical composition according to any one of claims 1 to 12, wherein A ¹ is C _5-1 o cycloalkyl which is substituted 1 or 2 times with Y ¹ and 0, 1, 2 or 3 times with Y ² . 14. A pharmaceutical composition according to any one of claims 1 to 12, wherein A ¹ is C ₃ . ₇ cycloalkyl substituted once with Y ¹ and 0-1 times with Y ² . 15. Pharmaceutical composition according to claim 1, where the compound is represented by formula I-A ^R1 (I-A) or a pharmaceutically acceptable salt thereof, wherein R ¹ is independently methyl, cyclopropyl or isopropyl; R ² is hydrogen; R ³ is independently at each occurrence hydrogen or C _1-4 alkyl; A ¹ is C ₃ . ₁₀ cycloalkyl which is substituted 1 or 2 times with Y ¹ and 0, 1, 2 or 3 times with Y ² ; Y ¹ is independently in each occurrence a 2-8 membered heteroalkyl and Y ² is independently in each occurrence C1-6 alkyl, C3.6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, azido, -N(R ³ )2, - (C _1-6 alkylene)-(5-6 membered heterocyclyl), -(C1.6 αkylene)-CO ₂ R ³ or C1-6 haloalkyl-substituted C3-6 cycloalkyl. 16. Pharmaceutical composition according to claim 15, where R ¹ is methyl. 17. A pharmaceutical composition according to claim 15 or 16, wherein in any case Y ² is independently C _1-3 alkyl, halogen or C _1-3 haloalkyl. 18. Compound of formula IIa (Na) or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are each independently at each occurrence hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, -(C _1-4 alkylene)-(2-6 membered heteroalkyl ), cyclopropyl, cyano, chlorine or fluorine; R ³ is independently at each occurrence hydrogen or C _1-4 alkyl; X ¹ is one of the following: (a) a carbonyl-containing linker selected from -6(Ο)Ν(H)-ψ and -C(O)N(H)( _C1.6 alkylene)-ψ, where ψ is a bond to A ¹ ; or (b) an amine-containing link selected from -(C _1-4 alkylene)-N(H)-ψ and -(C _1-4 alkylene)-N(H)(C _1-4 alkylene)-ψ; A ¹ is C _3-10 cycloalkyl which is substituted with (a) 1, 2 or 3 halogens and (b) 0, 1, 2 or 3 times with Y ² ; Y ² is independently in each occurrence C1-6 alkyl, C3.6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, cyano, azido, -N(R ³ )2, - (C _1-6 alkylene)-(5-6 membered heterocyclyl), -(C 1-6 αkylene)-CO ₂ R ³ or C 1-6 haloalkyl-substituted C 3-6 cycloalkyl and n is 1, 2 or 3, where the term heteroalkyl refers to to an alkyl group in which at least one carbon atom has been replaced by an O or S atom, and where the term heterocyclyl refers to a saturated, partially unsaturated or aromatic - 52 041819 ring structure comprising from one to four heteroatoms selected from nitrogen, oxygen and sulfur. 19. A compound according to claim 18 wherein R ¹ is independently at each occurrence C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, cyclopropyl, cyano, chlorine or fluoro. 20. A compound according to claim 18 wherein R ¹ is methyl. 21. A compound according to any one of claims 18-20, where n is 2. 22. A compound according to claim 21 wherein the R ¹ groups are located at positions 5 and 7 of the pyrazolo[1,5a] pyrimidinyl. 23. A compound according to any one of claims 18-22, wherein X ¹ is -C(O)N(H)-v. 24. A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof. 25. The compound according to claim 24, where the compound is or a pharmaceutically acceptable salt thereof. 26. The compound according to claim 24, where the compound is or a pharmaceutically acceptable salt thereof. 27. The compound according to claim 24, where the compound is or a pharmaceutically acceptable salt thereof. - 53 041819 28. The compound according to claim 24, where the compound is 29. The compound according to claim 24, where the compound is 30. The compound according to claim 24, where the compound is 31. Pharmaceutical composition having the ability to activate glucocerebrosidase (Gcase), containing a compound according to any one of claims 18-30 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 32. Compound of formula I or a pharmaceutically acceptable salt thereof, wherein R ¹ is independently at each occurrence C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, cyclopropyl, cyano, chlorine or fluorine; R ² is hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, -(C _1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, chlorine, fluoro or -N (H)(R ³ ); R ³ is independently at each occurrence hydrogen or C _1-4 alkyl; X ¹ is one of the following: (a) a carbonyl-containing linker selected from -C(O)N(H)-ψ and -C(O)N(H)(C _1-6 alkylene)-ψ, where ψ is a bond to A ¹ , or (b) an amine-containing link selected from -(C _1-4 alkylene)-N(H)-ψ and -(C _1-4 alkylene)-N(H)(C _1-4 alkylene)-ψ; A ¹ is C _3-10 cycloalkyl which is substituted 1 or 2 times with Y ¹ and 0, 1, 2 or 3 times with Y ² ; Y ¹ is -O-(C ₁ .7 alkyl); Y ² is independently in each occurrence C1-6 alkyl, C3_6 cycloalkyl, halogen, C1-6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, C1-6 alkoxy, C2.4 alkynyl, cyano, azido, -N(R ³ ) 2, -(C1-6 alkylene)-(5-6 membered heterocyclyl), -(C _1-6 alkylene)-CO ₂ R ³ or C _1-6 haloalkyl-substituted C ₃ _ ₆ cycloalkyl and n is 1, 2 or 3, wherein the term heteroalkyl refers to an alkyl group in which at least one carbon atom has been replaced by an O or S atom, and wherein the term heterocyclyl refers to a saturated, partially unsaturated, or aromatic ring structure comprising one to four heteroatoms selected from from nitrogen, oxygen and sulfur. 33. A compound according to claim 32, wherein R ¹ is methyl. 34. A compound according to claim 32 or 33, where n is 2. 35. A compound according to any one of claims 32-34, wherein the R ¹ groups are located at the 5 and 7 positions of the pyrazolo[1,5-a]pyrimidinyl. 36. A compound according to any one of claims 32-35, wherein R ² is hydrogen. 37. A compound according to any one of claims 32-36, wherein R ³ is independently in each occurrence hydrogen, methyl or ethyl. 38. A compound according to any one of claims 32-37, wherein X ¹ is -C(O)N(H)-ψ. 39. A compound according to any one of claims 32-38, wherein in any case Y ² is independently C _1-6 alkyl, C ₃ _ ₆ cycloalkyl, halogen, C _1-6 haloalkyl, or hydroxyl. 40. A compound according to any one of claims 32-39, wherein in any case Y ² is independently C1. ₃ alkyl. 41. The compound according to any one of claims 32-40, where Y ¹ represents -O-butyl, -O-pentyl or - 54 041819 -O-hexyl. 42. The compound according to any one of claims 32-41, wherein A ¹ is C ₅ . cycloalkyl which is substituted 1 or 2 times with Y and 0, 1.2 or 3 times with Y ² . 43. A compound according to any one of claims 32-42, wherein A ¹ is C3.7 cycloalkyl substituted once with Y ¹ and 0-1 times with Y ² . 44. The compound according to claim 32, where the compound is represented by formula I-A ^R1 (I-A) or a pharmaceutically acceptable salt thereof, wherein R ¹ is independently methyl, cyclopropyl or isopropyl; R ² is hydrogen; R ³ is independently at each occurrence hydrogen or C alkyl; A ¹ is C ₃ .u cycloalkyl which is substituted 1 or 2 times with Y ¹ and 0, 1.2 or 3 times with Y ² ; Y ¹ is -O-(Ci_ ₇ alkyl) and Y ² is independently in each occurrence Ci.6 alkyl, C3.6 cycloalkyl, halogen, Ci.6 haloalkyl, C1-6 hydroxyalkyl, hydroxyl, Ci.6 alkoxy, cyano, azido, -N(R ³ )2, - (Ci_ ₆ alkylene)-(5-6 membered heterocyclyl), -(Ci. ₆ alkylene)-CO ₂ R ³ or Ci. ₆ haloalkyl-substituted C ₃ . ₆ cycloalkyl. 45. A compound according to claim 44, wherein R ¹ is methyl. 46. A compound according to claim 44 or 45, wherein in any case Y ² is independently Ci. ₃ alkyl, halogen or Ci. ₃ haloalkyl. 47. A method of treating a disease selected from the group consisting of Gaucher's disease, Parkinson's disease and Lewy body disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of paragraphs. 18-30 and 32-46 or a pharmaceutical composition according to any one of claims 1-17 and 31 for the treatment of a disease. 48. The method of claim 47, wherein the disease is Gaucher's disease. 49. The method of claim 47 wherein the disease is Parkinson's disease. 50. The method of claim 47 wherein the disease is Lewy body disease. 51. The method according to any one of claims 47-50, wherein the patient is a human.