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US-12617797-B2 - Substituted pyrazolo [1,5-a]pyrimidines having multimodal activity against pain

US12617797B2US 12617797 B2US12617797 B2US 12617797B2US-12617797-B2

Abstract

The present invention relates to pyrazolopyrimidine derivatives of Formula (I) having dual pharmacological activity towards both the α 2 δ subunit of the voltage-gated calcium channel and the sigma-1 (σ1) receptor, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.

Inventors

  • Ariadna FERNANDEZ-DONIS
  • José-Luís Díaz-Fernández
  • Carmen Almansa-Rosales
  • Mónica GARCIA-LOPEZ
  • Joan-Carles FERNANDEZ-COLLADO
  • Jordi GONZALEZ-GARCIA
  • Maria GARRIDO-MARTINEZ

Assignees

  • ESTEVE PHARMACEUTICALS, S.A.

Dates

Publication Date
20260505
Application Date
20210520
Priority Date
20200527

Claims (13)

  1. 1 . A compound of Formula (I): or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: X is a bond, —(CH 2 ) p —, —(CH 2 ) p —NR x —(CH 2 ) q —, —(CH 2 ) p —NR x —CH(CH 3 )—, or —(CH 2 ) p —O—(CH 2 ) q —; R x is H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR 13 R 13′ , O(haloalkyl), and OR 13 ; each R 13 is independently H or C 1-6 alkyl; each R 13′ is independently H or C 1-6 alkyl; R 1 is H, halogen, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NR 6 R 6′ , OR 6 , cycloalkyl, heterocyclyl, or aryl; wherein the C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR 11 R 11′ , O(haloalkyl), and OR 11 ; and wherein the cycloalkyl, heterocyclyl, or aryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1-6 alkyl, haloalkyl, alkyl(cycloalkyl), (CH 2 ) r NR 11 R 11′ , (CH 2 ) r OR 11 , C(CH 3 ) 2 OR 11 , C(O)R 11 , C(O)NR 11 R 11′ , C(O)OR 11 , NR 11 C(O)R 11′ , NR 11 C(O)NR 11′ R 11″ , NR 11 S(O) 2 R 11′ , NR 11 S(O) 2 NR 11′ R 11″ , O(haloalkyl), OCH 2 CH 2 OR 11 , ═O, SR 11 , S(O)R 11 , S(O) 2 R 11 , S(O) 2 NR 11 R 11′ , and heterocyclyl; R 6 is H, C 1-6 alkyl, alkyl(cycloalkyl), alkyl(heterocyclyl), alkyl(aryl), C 2-6 alkenyl, C 2-6 alkynyl, O(haloalkyl), cycloalkyl, heterocyclyl, or aryl; wherein the C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR 13 R 13′ , O(haloalkyl), and OR 13 ; and wherein the cycloalkyl of alkyl(cycloalkyl), heterocyclyl of alkyl(heterocyclyl), aryl of alkyl(aryl), cycloalkyl, heterocyclyl, or aryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1-6 alkyl, haloalkyl, alkyl(cycloalkyl), (CH 2 ) r NR 14 R 14′ , (CH 2 ) r OR 14 , C(CH 3 ) 2 OR 14 , C(O)R 14 , C(O)NR 14 R 14′ , C(O)OR 14 , NR 14 C(O)R 14′ , NR 14 C(O)NR 14′ R 14″ , NR 14 S(O) 2 R 14′ , NR 14 S(O) 2 NR 14′ R 14″ , O(haloalkyl), OCH 2 CH 2 OR 14 , ═O, SR 14 , S(O)R 14 , S(O) 2 R 14 , S(O) 2 NR 14 R 14′ , and heterocyclyl; each R 14 is independently H, C 1-6 alkyl, cycloalkyl, heterocyclyl, or aryl; each R 14′ is independently H, C 1-6 alkyl, cycloalkyl, heterocyclyl, or aryl; each R 14″ is independently H, C 1-6 alkyl, cycloalkyl, heterocyclyl, or aryl; R 6′ is H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR 13 R 13′ , O(haloalkyl), and OR 13 ; or R 6 and R 6′ , taken together with the nitrogen atom to which they are attached, form a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1-6 alkyl, haloalkyl, alkyl(cycloalkyl), (CH 2 ) r NR 14 R 14′ , (CH 2 ) r OR 14 , C(CH 3 ) 2 OR 14 , C(O)R 14 , C(O)NR 14 R 14′ , C(O)OR 14 , NR 14 C(O)R 14′ , NR 14 C(O)NR 14′ R 14″ , NR 14 S(O) 2 R 14′ , NR 14 S(O) 2 NR 14′ R 14″ , O(haloalkyl), OCH 2 CH 2 OR 14 , ═O, SR 14 , S(O)R 14 , S(O) 2 R 14 , S(O) 2 NR 14 R 14′ , and heterocyclyl; each R 11 is independently H, C 1-6 alkyl, alkyl(cycloalkyl), alkyl(heterocyclyl), alkyl(aryl), cycloalkyl, heterocyclyl, or aryl; each R 11′ is independently H, C 1-6 alkyl, alkyl(cycloalkyl), alkyl(heterocyclyl), alkyl(aryl), cycloalkyl, heterocyclyl, or aryl; each R 11″ is independently H, C 1-6 alkyl, alkyl(cycloalkyl), alkyl(heterocyclyl), alkyl(aryl), cycloalkyl, heterocyclyl, or aryl; R 2 is H, halogen, C 1-6 alkyl, alkyl(cycloalkyl), C 2-6 alkenyl, C 2-6 alkynyl, OR 7 , O(haloalkyl), or cycloalkyl; wherein the C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR 21 R 21′ , O(haloalkyl), and OR 21 ; and wherein the cycloalkyl of alkyl(cycloalkyl) or cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1-6 alkyl, haloalkyl, (CH 2 ) r NR 21 R 21′ , (CH 2 ) r OR 21 , C(CH 3 ) 2 OR 21 , C(O)R 21 , C(O)NR 21 R 21′ , C(O)OR 21 , NR 21 C(O)R 21′ , NR 21 C(O)NR 21′ R 21″ , NR 21 S(O) 2 R 21′ , NR 21 S(O) 2 NR 21′ R 21″ , O(haloalkyl), OCH 2 CH 2 OR 21 , ═O, SR 21 , S(O)R 21 , S(O) 2 R 21 , and S(O) 2 NR 21 R 21′ ; R 7 is H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR 13 R 13′ , O(haloalkyl), and OR 13 ; each R 21 is independently H or C 1-6 alkyl; each R 21′ is independently H or C 1-6 alkyl; each R 21″ is independently H or C 1-6 alkyl; R 3 is H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, OR 8 , or O(haloalkyl), wherein the C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR 31 R 31′ , O(haloalkyl), and OR 31 ; R 8 is H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR 13 R 13′ , O(haloalkyl), and OR 13 ; each R 31 is independently H or C 1-6 alkyl; each R 31′ is independently H or C 1-6 alkyl; R 4 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocyclyl, or aryl; wherein the C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR 41 R 41′ , O(haloalkyl), and OR 41 ; and wherein the cycloalkyl, heterocyclyl, or aryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1-6 alkyl, haloalkyl, (CH 2 ) r NR 41 R 41′ , (CH 2 ) r OR 41 , C(CH 3 ) 2 OR 41 , C(O)R 41 , C(O)NR 41 R 41′ , C(O)OR 41 , NR 41 C(O)R 41′ , NR 41 C(O)NR 41′ R 41″ , NR 41 S(O) 2 R 41′ , NR 41 S(O) 2 NR 41′ R 41″ , O(haloalkyl), OCH 2 CH 2 OR 41 , ═O, SR 41 , S(O)R 41 , S(O) 2 R 41 , and S(O) 2 NR 41 R 41′ ; each R 41 is independently H or C 1-6 alkyl; each R 41′ is independently H or C 1-6 alkyl; each R 41″ is independently H or C 1-6 alkyl; R 5 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or O(haloalkyl), wherein the C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR 51 R 51′ , O(haloalkyl), and OR 51 ; R 5′ is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or O(haloalkyl), wherein the C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NR 51 R 51′ , O(haloalkyl), and OR 51 ; each R 51 is independently H or C 1-6 alkyl; each R 51′ is independently H or C 1-6 alkyl; m is 1, 2, 3, or 4; n is 1 or 2; p is 0, 1, 2, 3, or 4; q is 0, 1, 2, 3, or 4; each r is independently 0, 1, 2, or 3; and t is 0 or 1; with the proviso that the following compound is excluded:
  2. 2 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4 is phenyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1-6 alkyl, haloalkyl, (CH 2 ) r NR 41 R 41′ , (CH 2 ) r OR 41 , C(CH 3 ) 2 OR 41 , C(O)R 41 , C(O)NR 41 R 41′ , C(O)OR 41 , NR 41 C(O)R 41′ , NR 41 C(O)NR 41′ R 41″ , NR 41 S(O) 2 R 41′ , NR 41 S(O) 2 NR 41′ R 41″ , O(haloalkyl), OCH 2 CH 2 OR 41 , ═O, SR 41 , S(O)R 41 , S(O) 2 R 41 , and S(O) 2 NR 41 R 41′ .
  3. 3 . The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: n is 1; and t is 0.
  4. 4 . The compound according to claim 1 , wherein the compound is of Formula (I′): or a pharmaceutically acceptable salt or stereoisomer thereof.
  5. 5 . The compound according to claim 1 , wherein the compound is of Formula (I 2′ ): or a pharmaceutically acceptable salt or stereoisomer thereof.
  6. 6 . The compound according to claim 1 , wherein the compound is of Formula (I 3 ): or a pharmaceutically acceptable salt or stereoisomer thereof.
  7. 7 . The compound according to claim 1 , wherein the compound is selected from the group consisting of: 7-(1-Benzylpiperidin-3-yl)-2-bromopyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-ethylpyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-3-bromopyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-3-bromo-2,6-dimethylpyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-3-bromo-6-methylpyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-3-bromo-2-methylpyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-3-bromo-2-ethylpyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-phenylpyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-(4-ethoxyphenyl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-(2-fluorophenyl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-(4-chlorophenyl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-(3,5-dichloropyridin-4-yl)pyrazolo[15-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidine, 4-(7-(1-Benzylpiperidin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)isothiazole, 7-(1-Benzylpiperidin-3-yl)-2-(1-methyl-1H-imidazol-5-yl)pyrazolo[1,5-a]pyrimidine, 4-(7-(1-Benzylpiperidin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)-N,N-dimethylaniline, 7-(1-Benzylpiperidin-3-yl)-2-(pyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine, 5-(7-(1-Benzylpiperidin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)pyridin-2-amine, 7-(1-Benzylpiperidin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-(2-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-(6-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-(2-methoxyphenyl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-(6-methoxypyridin-2-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-(5-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-(2-methoxypyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-(3-methoxypyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-(4-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-3-phenylpyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-3-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-3-(2-methoxypyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-3-(4-ethoxyphenyl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-3-(2-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-6-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-3-(2-methoxypyridin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-methyl-3-phenylpyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-3-(4-ethoxyphenyl)-2-methylpyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-3-(2-methoxypyridin-4-yl)-2-methylpyrazolo[1,5-a]pyrimidine, 4-(7-(1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-dimethylaniline, 7-(1-Benzylpiperidin-3-yl)-3-(2-fluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-methyl-3-(3-methylpyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-3-(2-fluoropyridin-4-yl)-2-methylpyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-methyl-3-(2-methylpyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-3-(3-fluoropyridin-4-yl)-2-methylpyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-methyl-3-(2-(trifluoromethyl)pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-3-(2-ethylpyridin-4-yl)-2-methylpyrazolo[1,5-a]pyrimidine, 3-(3-(7-(1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-5-methyl-1,2,4-oxadiazole, 2-(3-(7-(1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-5-methyl-1,3,4-oxadiazole, 7-(1-Benzylpiperidin-3-yl)-3-(3-methoxypyridin-4-yl)-2-methylpyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2,6-dimethyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2,5-dimethyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-ethyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 1-(1-(3-(7-(1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-1H-1,2,3-triazol-4-yl)-N-methylmethanamine, 1-(4-(7-(1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)-N-methylmethanamine, 7-(1-(2-Fluorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidine, 7-(1-Butylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidine, 7-(1-(2,6-Difluorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidine, 2-Methyl-7-(1-(pyridin-2-ylmethyl)piperidin-3-yl)pyrazolo[1,5-a]pyrimidine, 2-Methyl-7-(1-phenethylpiperidin-3-yl)pyrazolo[1,5-a]pyrimidine, 3-((3-(2-Methylpyrazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)methyl)phenol, 7-(1-Ethylpiperidin-3-yl)-2-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 2-Methyl-7-(1-propylpiperidin-3-yl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Isobutylpiperidin-3-yl)-2-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 2-Methyl-7-(1-(pyridin-2-ylmethyl)piperidin-3-yl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 6-Methyl-7-(1-phenethylpiperidin-3-yl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 6-Methyl-7-(1-(pyridin-2-ylmethyl)piperidin-3-yl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 2-Methyl-7-(1-(2-methylbenzyl)piperidin-3-yl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 2-Methyl-7-(1-(4-methylbenzyl)piperidin-3-yl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 2-Methyl-7-(1-(3-methylbenzyl)piperidin-3-yl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine, 2-((7-(1-Benzylpiperidin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)(methyl)amino)ethanol, N 1 -(7-(1-Benzylpiperidin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)-N 1 -methylethane-1,2-diamine N 1 -(7-(1-Benzylpiperidin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)-N 1 ,N 2 -dimethylethane-1,2-diamine, 7-(1-Benzylpiperidin-3-yl)-N-methyl-N-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-2-amine, N 1 -(7-(1-Benzylpiperidin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)-N 2 -methylethane-1,2-diamine, (R)-1-(7-((R)-1-Benzylpiperidin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)-N-methylpyrrolidin-3-amine, (S)-1-(7-((S)-1-Benzylpiperidin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)-N-methylpyrrolidin-3-amine, (S)-1-(7-((R)-1-Benzylpiperidin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)-N-methylpyrrolidin-3-amine, (R)-1-(7-((S)-1-Benzylpiperidin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)-N-methylpyrrolidin-3-amine, 7-(1-Benzylpiperidin-3-yl)-3-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-methyl-3-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-amine, 7-(1-Benzylpiperidin-3-yl)pyrazolo[1,5-a]pyrimidine-2-carbonitrile, 1-(7-(1-Benzylpiperidin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)-N,N-dimethylmethanamine, 1-(7-(1-Benzylpiperidin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)-N-methylmethanamine, N-Benzyl-1-(7-(1-benzylpiperidin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)methanamine, (7-(1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methanol, 1-(7-(1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-methylmethanamine, N-((7-(1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)-2-phenylethanamine, N-Benzyl-1-(7-(1-benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methanamine, (7-(1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methanamine, 7-(1-Benzylpiperidin-3-yl)-2-methyl-3-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyrimidine, 3-((Benzyloxy)methyl)-7-(1-benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidine, 7-(1-Benzylpiperidin-3-yl)-2-methyl-3-(phenoxymethyl)pyrazolo[1,5-a]pyrimidine, 3-(7-(1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)propan-1-amine, 7-(1-Benzylpiperidin-3-yl)pyrazolo[1,5-a]pyrimidin-2-ol, 7-(1-Benzylpiperidin-3-yl)-3-bromopyrazolo[1,5-a]pyrimidin-2-ol, (S)-2-((R)-3-(2-Methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)-2-phenylethanol, (S)-2-((S)-3-(2-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)-2-phenylethanol, (R)-2-((S)-3-(2-Methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)-2-phenylethanol, (R)-2-((R)-3-(2-Methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)-2-phenylethanol, 2-Bromo-7-(1-(4-chlorobenzyl)piperidin-3-yl)pyrazolo[1,5-a]pyrimidine, 2-Bromo-7-(1-(3-chlorobenzyl)piperidin-3-yl)pyrazolo[1,5-a]pyrimidine, 2-Bromo-7-(1-(3,4-dichlorobenzyl)piperidin-3-yl)pyrazolo[1,5-a]pyrimidine, 2-Bromo-7-(1-(3,4-difluorobenzyl)piperidin-3-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-(2-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine, 3-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)pyridin-2-ol, 7-(1-(3-Chlorobenzyl)piperidin-3-yl)-2-(2-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine, 3-(7-(1-(3-Chlorobenzyl)piperidin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)pyridin-2-ol, 7-(1-(3,4-Dichlorobenzyl)piperidin-3-yl)-2-(2-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-(3,4-Difluorobenzyl)piperidin-3-yl)-2-(2-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidine, 1-(2-Bromo-7-(1-(4-chlorobenzyl)piperidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, 7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-(3-Chlorobenzyl)piperidin-3-yl)-2-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-(3,4-Dichlorobenzyl)piperidin-3-yl)-2-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-(2,4-Dichlorobenzyl)piperidin-3-yl)-2-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-(3,4-Difluorobenzyl)piperidin-3-yl)-2-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 2-Methyl-3-(pyridin-4-yl)-7-(1-(4-(trifluoromethyl)benzyl)piperidin-3-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-Isopentylpiperidin-3-yl)-2-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 3-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-dimethylbenzamide, 4-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)benzamide, 7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methyl-3-(pyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine, 5-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)pyrimidin-2-amine, 7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methyl-3-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine, 4-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-3,5-dimethylisoxazole, (4-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)methanol, (5-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-ye)pyridin-2-yl)methanol, 7-(1-(4-Chlorobenzyl)piperidin-3-yl)-3-(2-ethoxypyridin-4-yl)-2-methylpyrazolo[1,5-a]pyrimidine, 7-(1-(4-Chlorobenzyl)piperidin-3-yl)-3-(2-(cyclopropylmethoxy)pyridin-4-yl)-2-methylpyrazolo[1,5-a]pyrimidine, 7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methyl-3-(1-methyl-1H-imidazol-5-yl)pyrazolo[1,5-a]pyrimidine, 7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methyl-3-(pyrimidin-4-yl)pyrazolo[1,5-a]pyrimidine, 4-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)pyrimidin-2-amine, 7-(1-(4-Chlorobenzyl)piperidin-3-yl)-N,N,2-trimethylpyrazolo[1,5-a]pyrimidin-3-amine, 7-(1-Benzylpiperidin-3-yl)-N,N,2-trimethylpyrazolo[1,5-a]pyrimidin-3-amine, N-Benzyl-7-(1-benzylpiperidin-3-yl)-N,2-dimethylpyrazolo[1,5-a]pyrimidin-3-amine, N-Benzyl-1-(7-(1-(4-chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methanamine, N-Benzyl-1-(7-(1-(4-chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-methylmethanamine, 1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-(4-fluorobenzyl)methanamine, (4-((((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)amino)methyl)phenyl)methanol, 1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-(pyridin-4-ylmethyl)methanamine, 1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-(thiophen-2-ylmethyl)methanamine, 1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((5-methylthiophen-2-yl)methyl)methanamine, 1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((1-methyl-1H-pyrazol-3-yl)methyl)methanamine, 1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)methanamine, N-((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)-2-phenylethan-1-amine, N-((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)-2-(4-methoxyphenyl)ethan-1-amine, N-((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)ethanamine, N-((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)-2,2,2-trifluoroethan-1-amine, 1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-(cyclopropylmethyl)methanamine, 2-(((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)amino)ethan-1-ol, N-((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)propan-2-amine, N-((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)-2-methylpropan-1-amine, N-((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)-3-methylbutan-1-amine, N-((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)-2-isopropoxyethan-1-amine, N-((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)-4-methoxybutan-1-amine, (2S,6R)-4-((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)-2,6-dimethylmorpholine, 4-((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)morpholine, N-((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)-2-morpholinoethan-1-amine, 4-((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)thiomorpholine, 4-((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)thiomorpholine 1,1-dioxide, 7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methyl-3-(piperidin-1-ylmethyl)pyrazolo[1,5-a]pyrimidine, 7-(1-(4-Chlorobenzyl)piperidin-3-yl)-3-((4-(methoxymethyl)piperidin-1-yl)methyl)-2-methylpyrazolo[1,5-a]pyrimidine, 1-((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)piperidine-4-carboxamide, 1-((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)piperidine-4-carbonitrile, 4-((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)piperazin-2-one, 1-(4-((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)piperazin-1-yl)ethan-1-one, 7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methyl-3-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyrimidine, 1-(3-(((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)amino)propyl)pyrrolidin-2-one, 1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)methanamine, N-((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-amine, 1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((1-(methylsulfonyl)piperidin-4-yl)methyl)methanamine, 1-(4-((((7-(1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)amino)methyl)piperidin-1-yl)ethan-1-one, 1-(7-(1-(3-Fluorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, 1-(7-(1-(3,4-Difluorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, 4-((3-(2-Methyl-3-((((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)methyl)benzonitrile, 1-(2-Methyl-7-(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, 1-(2-Methyl-7-(1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, 1-(7-(1-(2,4-Dichlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-dimethylmethanamine, 1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-ethylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, 1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, 1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, 1-(2-Chloro-7-(1-(4-chlorobenzyl)piperidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, 1-(2-Chloro-7-(1-isopentylpiperidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, 1-(4-((((2-Chloro-7-(1-isopentylpiperidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)methyl)amino)methyl)piperidin-1-yl)ethan-1-one, (S)-1-(4-((((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)amino)methyl)piperidin-1-yl)ethan-1-one, (R)-1-(4-((((7-(1-(4-chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)amino)methyl)piperidin-1-yl)ethan-1-one, (R)—N-((7-((R)-1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)-1-phenylethan-1-amine, (R)—N-((7-((S)-1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)-1-phenylethan-1-amine, (S)—N-((7-((R)-1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)-1-phenylethan-1-amine, (S)—N-((7-((S)-1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)-1-phenylethan-1-amine, (S)-1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, (R)-1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, (+/−)-1-(7-((R/S)-1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N—(((S/R)-tetrahydrofuran-3-yl)methyl)methanamine, 1-(7-((R)-1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N—(((R)-tetrahydrofuran-3-yl)methyl)methanamine, 1-(7-((S)-1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N—(((S)-tetrahydrofuran-3-yl)methyl)methanamine, (S)-1-(7-(1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, (R)-1-(7-(1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, (S)-1-(7-(1-(4-Fluorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, (R)-1-(7-(1-(4-Fluorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, (S)-3-((3-(2-Methyl-3-((((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)methyl)benzonitrile, (R)-3-((3-(2-Methyl-3-((((tetrahydro-2H-pyran-4-yl)methyl)amino)methyl)pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-1-yl)methyl)benzonitrile, (S)-1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-dimethylmethanamine, (R)-1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-dimethylmethanamine, (R)-1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-methylmethanamine, (S)-1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-methylmethanamine, ((S)-1-(7-(1-Benzylpiperidin-3-yl)-2-chloropyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, ((R)-1-(7-(1-Benzylpiperidin-3-yl)-2-chloropyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, (S)-1-(4-((((7-(1-Benzylpiperidin-3-yl)-2-chloropyrazolo[1,5-a]pyrimidin-3-yl)methyl)amino)methyl)piperidin-1-yl)ethan-1-one, (R)-1-(4-((((7-(1-benzylpiperidin-3-yl)-2-chloropyrazolo[1,5-a]pyrimidin-3-yl)methyl)amino)methyl)piperidin-1-yl)ethan-1-one, 4-((((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)amino)methyl)piperidine-1-carboxamide, (7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methanamine, 1-(7-(1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)methanamine, (+/−)-1-(7-((R/S)-1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N—(((R/S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)methanamine, (1-(7-((R)-1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N—(((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)methanamine, (1-(7-((S)-1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N—(((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)methanamine, (+/−)-(R/S)—N-((7-((R/S)-1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)-1-(tetrahydro-2H-pyran-4-yl)ethan-1-amine, (S)—N-((7-((R)-1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)-1-(tetrahydro-2H-pyran-4-yl)ethan-1-amine, (R)—N-((7-((S)-1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)-1-(tetrahydro-2H-pyran-4-yl)ethan-1-amine, (R)-1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-(cyclopropylmethyl)-N-methylmethanamine, (S)-1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-(cyclopropylmethyl)-N-methylmethanamine, 1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-(2,6-difluorobenzyl)-N-methylmethanamine, (4-((((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)(methyl)amino)methyl)phenyl)methanol, 1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, N-((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)propan-2-amine, N-((7-(1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)-N-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)propan-2-amine, 1-(7-(1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-(cyclopropylmethyl)-N-methylmethanamine, N-((7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)-2,2,2-trifluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)ethan-1-amine, 2-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-dimethylethan-1-amine, 1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2,6-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, 1-(7-(1-(4-Chlorobenzyl)piperidin-3-yl)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, (S)-1-(7-(1-(2-Fluorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, (S)-1-(7-(1-(2,4-Difluorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, (S)-1-(7-(1-(3,5-Difluorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, 1-(7-(1-(4-Methoxybenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, (R)-4-((((7-((S)-1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)amino)methyl)-1-methylpiperidin-2-one, (S)-4-((((7-((S)-1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)amino)methyl)-1-methylpiperidin-2-one, (R)-5-((((7-((S)-1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)amino)methyl)piperidin-2-one, (S)-5-((((7-((S)-1-Benzylpiperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)amino)methyl)piperidin-2-one, (S)-1-(4-((((7-(1-(3,4-Difluorobenzyl)piperidin-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)amino)methyl)piperidin-1-yl)ethan-1-one, 1-(7-(1-Benzylpiperidin-3-yl)-2-methoxypyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, 7-((1-(4-Chlorobenzyl)piperidin-3-yl)methyl)-2-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 7-((1-(3-Chlorobenzyl)piperidin-3-yl)methyl)-2-methyl-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine, 1-(7-((1-(4-Chlorobenzyl)piperidin-3-yl)methyl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-dimethylmethanamine, 1-(7-((1-(3-Chlorobenzyl)piperidin-3-yl)methyl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-dimethylmethanamine and 1-(7-(1-(4-Chlorobenzyl)azepan-3-yl)-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)methanamine, or a pharmaceutically acceptable salt thereof.
  8. 8 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, adjuvant, or vehicle and the compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.
  9. 9 . A method for treating pain in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.
  10. 10 . The method according to claim 9 , wherein the pain is selected from the group consisting of acute pain, allodynia, cancer pain, chronic pain, hyperalgesia, inflammatory pain, medium to severe pain, migraine, neuropathic pain, and visceral pain.
  11. 11 . A process for the production of the compound of Formula (I) according to claim 1 , wherein the process comprises any one of the following steps: (1) treating a compound of formula VI: wherein: A is —C(R 5 R 5′ ) m —R 4 ; Y is halogen; and R 2 , R 3 , R 4 , R 5 , R 5′ , m, n, and t are defined as in claim 1 ; with a compound of formula VII: wherein: X and R 1 are defined as in claim 1 ; in the presence of a Pd catalyst, a base, and a solvent; or (2) alkylating a compound of formula Ia: wherein: A is H; and X, R 1 , R 2 , R 3 , n, and t are defined as in claim 1 ; with a compound of formula XI: Z-T XI wherein: T is —C(R 5 R 5′ ) m —R 4 ; Z is Cl, Br, or I; and R 4 , R 5 , R 5′ , and m are defined as in claim 1 .
  12. 12 . A process for the production of the compound of Formula (I) according to claim 1 , wherein XR 1 is —CH 2 NR 6 R 6′ , wherein the process comprises any one of the following steps: (1) reacting a compound of formula VI: wherein: A is —C(R 5 R 5′ ) m —R 4 ; Y is an acid functionality; and R 2 , R 3 , R 4 , R 5 , R 5′ , m, n, and t are defined as in claim 1 ; with a compound of formula IX: wherein: R 6 and R 6′ are defined as in claim 1 ; or (2) reacting a compound of formula VI: wherein: A is —C(R 5 R 5′ ) m —R 4 ; Y is halogen; and R 2 , R 3 , R 4 , R 5 , R 5′ , m, n, and t are defined as in claim 1 ; with a compound of formula X: wherein: R 6 and R 6′ are defined as in claim 1 ; or in the presence of a Pd catalyst, a base, a phosphine ligand, and a solvent; or (3) reacting a compound of formula VIII: wherein: A is —C(R 5 R 5′ ) m —R 4 ; and R 2 , R 3 , R 4 , R 5 , R 5′ , m, n, and t are defined as in claim 1 ; with a compound of formula IX: wherein: R 6 and R 6′ are defined as in claim 1 ; in the presence of a reducing agent, a solvent, and optionally, an acid; or (4) alkylating a compound of formula Ib: wherein: A is H; and R 2 , R 3 , R 6 , R 6 ′, n, and t are defined as in claim 1 ; with a compound of formula XI: Z-T XI wherein: T is —C(R 5 R 5′ ) m —R 4 ; Z is Cl, Br, or I; and R 4 , R 5 , R 5′ , and m are defined as in claim 1 .
  13. 13 . A compound selected from the group consisting of: or a pharmaceutically acceptable salt or stereoisomer thereof.

Description

FIELD OF THE INVENTION The present invention relates to compounds having dual pharmacological activity towards both the α2δ subunit of the voltage-gated calcium channel, and the sigma-1 (σ1) receptor. More particularly, the present invention relates to pyrazolo[1,5-a]pyrimidine-derivatives having this pharmacological activity, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain. BACKGROUND OF THE INVENTION The adequate management of pain constitutes an important challenge, since currently available treatments provide in many cases only modest improvements, leaving many patients unrelieved (Turk D C, Wilson H D, Cahana A. Lancet; 2011, 377, 2226-2235). Pain affects a big portion of the population with an estimated prevalence of 20% and its incidence, particularly in the case of chronic pain, is increasing due to the population ageing. Additionally, pain is clearly related to comorbidities, such as depression, anxiety and insomnia, which leads to important productivity losses and socio-economical burden (Goldberg D S, McGee S J, BMC Public Health, 2011, 11, 770). Existing pain therapies include non-steroidal anti-inflammatory drugs (NSAIDs), opioid agonists, calcium channel blockers and antidepressants, but they are much less than optimal regarding their safety ratio. All of them show limited efficacy and a range of secondary effects that preclude their use, especially in chronic settings. Voltage-gated calcium channels (VGCC) are required for many key functions in the body. Different subtypes of voltage-gated calcium channels have been described (Zamponi et al., Pharmacol. Rev. 2015, 67, 821-70). The VGCC are assembled through interactions of different subunits, namely α1 (Cavα1), β (Cavβ) α2δ (Cavα2δ) and γ (Cavγ). The α1 subunits are the key porous forming units of the channel complex, being responsible for the Ca2+ conduction and generation of Ca2+ influx. The α2δ, β, and γ subunits are auxiliary, although very important for the regulation of the channel, since they increase the expression of the α1 subunits in the plasma membrane as well as modulate their function, resulting in functional diversity in different cell types. Based on their physiological and pharmacological properties, VGCC can be subdivided into low voltage-activated T-type (Cav3.1, Cav3.2, and Cav3.3), and high voltage-activated L-(Cav1.1 through Cav1.4), N—(Cav2.2), P/Q-(Cav2.1), and R—(Cav2.3) types, depending on the channel forming Cavα subunits. All of these five subclasses are found in the central and peripheral nervous systems. Regulation of intracellular calcium through activation of these VGCC plays obligatory roles in: 1) neurotransmitter release, 2) membrane depolarization and hyperpolarization, 3) enzyme activation and inactivation, and 4) gene regulation (Perret and Luo, Neurotherapeutics 2009, 6, 679-92; Zamponi et al., 2015 supra; Neumaier et al., Prog. Neurobiol. 2015, 129, 1-36). A large body of data has clearly indicated that VGCC are implicated in mediating various disease states including pain processing. Drugs interacting with the different calcium channel subtypes and subunits have been developed. Current therapeutic agents include drugs targeting L-type Cav1.2 calcium channels, particularly 1,4-dihydropyridines, which are widely used in the treatment of hypertension. T-type (Cav3) channels are the target of ethosuximide, widely used in absence epilepsy. Ziconotide, a peptide blocker of N-type (Cav2.2) calcium channels, has been approved as a treatment of intractable pain (Perret and Luo, 2009, supra; Vink and Alewood, Br. J. Pharmacol. 2012, 167, 970-89). The Cav1 and Cav2 subfamilies contain an auxiliary α2δ subunit, which is the therapeutic target of the gabapentinoid drugs of value in certain epilepsies and chronic neuropathic pain. To date, there are four known α2δ subunits, each encoded by a unique gene and all possessing splice variants. Each α2δ protein is encoded by a single messenger RNA and is posttranslationally cleaved and then linked by disulfide bonds. Four genes encoding α2δ subunits have now been cloned. α2δ-1 was initially cloned from skeletal muscle and shows a fairly ubiquitous distribution. The α2δ-2 and α2δ-3 subunits were subsequently cloned from brain. The most recently identified subunit, α2δ-4, is largely nonneuronal. The human α2δ-4 protein sequence shares 30, 32 and 61% identity with the human α2δ-1, α2δ-2 and α2δ-3 subunits, respectively. The gene structure of all α2δ subunits is similar. All α2δ subunits show several splice variants (Davies et al., Trends Pharmacol. Sci. 2007, 28, 220-8; Dolphin A C, Nat Rev Neurosci. 2012, 13, 542-55, Biochim. Biophys. Acta 2013, 1828, 1541-9). The Cavα2δ-1 subunit may play an important role in neuropathic pain development (Perret and Luo, 2009, supra; Vink and Alewood, 2012, supra). Biochemical data have indicated a significant Cavα2δ-1, but n