Substituted Pyrazolopyrimidines As

(19) TZZ Z_T

(11) EP 2 649 075 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 487/04 (2006.01) A61K 31/519 (2006.01) 25.04.2018 Bulletin 2018/17 A61P 43/00 (2006.01)

(21) Application number: 11810714.3 (86) International application number: PCT/US2011/063928 (22) Date of filing: 08.12.2011 (87) International publication number: WO 2012/078855 (14.06.2012 Gazette 2012/24)

(54) SUBSTITUTED PYRAZOLOPYRIMIDINES AS GLUCOCEREBROSIDASE ACTIVATORS SUBSTITUIERTE PYRAZOLOPYRIMIDINE ALS GLUCOCEREBROSIDASE AKTIVATOREN PYRAZOLOPYRIMIDINES SUBSTITUÉES COMME ACTIVATEURS DE LA GLUCOCEREBROSIDASE

(84) Designated Contracting States: (74) Representative: Agasse, Stéphane et al AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Cabinet GERMAIN & MAUREAU GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO B.P. 6153 PL PT RO RS SE SI SK SM TR 69466 Lyon Cedex 06 (FR)

(30) Priority: 08.12.2010 US 420946 P (56) References cited: WO-A1-2007/020194 WO-A1-2009/152083 (43) Date of publication of application: WO-A1-2010/086040 WO-A2-2004/089471 16.10.2013 Bulletin 2013/42 WO-A2-2005/113004 WO-A2-2006/087120 WO-A2-2007/048066 (73) Proprietor: The U.S.A. as represented by the Secretary, • DATABASE WPI Week 200471 Thomson Department of Health and Human Services Scientific, London, GB; AN 2004-721070 Bethesda, MD 20892-7660 (US) XP002670249, & JP 2004 277337 A (SUMITOMO SEIYAKU KK) 7 October 2004 (2004-10-07) -& JP (72) Inventors: 2004 277337 A (SUMITOMO PHARMA) 7 October • MARUGAN, Juan Jose 2004 (2004-10-07) Gaithersburg, Maryland 20878 (US) • DATABASECA [Online] CHEMICAL ABSTRACTS • SOUTHALL, Noel SERVICE, COLUMBUS, OHIO, US; 2009, Potomac MD 20584-4025 (US) GOLDFARB, DAVID SCOTT: "Method using • GOLDIN, Ehud lifespan-altering compounds for altering the Rockville, Maryland 20852 (US) lifespan of eukaryotic organisms, and screening • PATNAIK, Samarjit for such compounds", XP002670250, retrieved Gaithersburg, Maryland 20878 (US) from STN Database accession no. 2009:875997 • SIDRANSKY, Ellen -& US 2009/163545 A1 (GOLDFARB DAVID Bethesda, Maryland 20814 (US) SCOTT [US]) 25 June 2009 (2009-06-25) • MOTABAR, Omid Darnestown, Maryland 20878 (US) • WESTBROOK, Wendy Rockville, Maryland 20853 (US) • ZHENG, Wei Potomac, Maryland 20854 (US)

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 649 075 B1

Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 649 075 B1

• DATABASECA [Online] CHEMICAL ABSTRACTS • DATABASECA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2009, SERVICE, COLUMBUS, OHIO, US; 2009, GOLDFARB, DAVID SCOTT: "Method using GOLDFARB, DAVID SCOTT: "Method using lifespan-altering compounds for altering the lifespan-altering compounds for altering the lifespan of eukaryotic organisms, and screening lifespan of eukaryotic organisms, and screening for such compounds", XP002670251, retrieved for such compounds", XP002670257, retrieved from STN Database accession no. 2009:875996 & from STN Database accession no. 2009:846110 & US 2009/163545 A1 (GOLDFARB, DAVID SCOTT) US 2009/163545 A1 (GOLDFARB, DAVID SCOTT) 25 June 2009 (2009-06-25) 25 June 2009 (2009-06-25) • DATABASECA [Online] CHEMICAL ABSTRACTS • DATABASECA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2009, SERVICE, COLUMBUS, OHIO, US; 2009, GOLDFARB, DAVID SCOTT: "Method using GOLDFARB, DAVID SCOTT: "Method using lifespan-altering compounds for altering the lifespan-altering compounds for altering the lifespan of eukaryotic organisms, and screening lifespan of eukaryotic organisms, and screening for such compounds", XP002670252, retrieved for such compounds", XP002670258, retrieved from STN Database accession no. 2009:875995 & from STN Database accession no. 2009:846109 & US 2009/163545 A1 (GOLDFARB, DAVID SCOTT) US 2009/163545 A1 (GOLDFARB, DAVID SCOTT) 25 June 2009 (2009-06-25) 25 June 2009 (2009-06-25) • DATABASECA [Online] CHEMICAL ABSTRACTS • DATABASECA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2009, SERVICE, COLUMBUS, OHIO, US; 2009, GOLDFARB, DAVID SCOTT: "Method using GOLDFARB, DAVID SCOTT: "Method using lifespan-altering compounds for altering the lifespan-altering compounds for altering the lifespan of eukaryotic organisms, and screening lifespan of eukaryotic organisms, and screening for such compounds", XP002670253, retrieved for such compounds", XP002670259, retrieved from STN Database accession no. 2009:846114 & from STN Database accession no. 2009:846108 & US 2009/163545 A1 (GOLDFARB, DAVID SCOTT) US 2009/163545 A1 (GOLDFARB, DAVID SCOTT) 25 June 2009 (2009-06-25) 25 June 2009 (2009-06-25) • DATABASECA [Online] CHEMICAL ABSTRACTS • DATABASECA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2009, SERVICE, COLUMBUS, OHIO, US; 2009, GOLDFARB, DAVID SCOTT: "Method using GOLDFARB, DAVID SCOTT: "Method using lifespan-altering compounds for altering the lifespan-altering compounds for altering the lifespan of eukaryotic organisms, and screening lifespan of eukaryotic organisms, and screening for such compounds", XP002670254, retrieved for such compounds", XP002670260, retrieved from STN Database accession no. 2009:846113 & from STN Database accession no. 2009:846107 & US 2009/163545 A1 (GOLDFARB, DAVID SCOTT) US 2009/163545 A1 (GOLDFARB, DAVID SCOTT) 25 June 2009 (2009-06-25) 25 June 2009 (2009-06-25) • DATABASECA [Online] CHEMICAL ABSTRACTS • DATABASECA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2009, SERVICE, COLUMBUS, OHIO, US; 2009, GOLDFARB, DAVID SCOTT: "Method using GOLDFARB, DAVID SCOTT: "Method using lifespan-altering compounds for altering the lifespan-altering compounds for altering the lifespan of eukaryotic organisms, and screening lifespan of eukaryotic organisms, and screening for such compounds", XP002670255, retrieved for such compounds", XP002670261, retrieved from STN Database accession no. 2009:846112 & from STN Database accession no. 2009:846106 & US 2009/163545 A1 (GOLDFARB, DAVID SCOTT) US 2009/163545 A1 (GOLDFARB, DAVID SCOTT) 25 June 2009 (2009-06-25) 25 June 2009 (2009-06-25) • DATABASECA [Online] CHEMICAL ABSTRACTS • DATABASECA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2009, SERVICE, COLUMBUS, OHIO, US; 2009, GOLDFARB, DAVID SCOTT: "Method using GOLDFARB, DAVID SCOTT: "Method using lifespan-altering compounds for altering the lifespan-altering compounds for altering the lifespan of eukaryotic organisms, and screening lifespan of eukaryotic organisms, and screening for such compounds", XP002670256, retrieved for such compounds", XP002670262, retrieved from STN Database accession no. 2009:846111 & from STN Database accession no. 2009:846105 & US 2009/163545 A1 (GOLDFARB, DAVID SCOTT) US 2009/163545 A1 (GOLDFARB, DAVID SCOTT) 25 June 2009 (2009-06-25) 25 June 2009 (2009-06-25)

2 (Cont. next page) EP 2 649 075 B1

• DATABASECA [Online] CHEMICAL ABSTRACTS • DATABASECA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2009, SERVICE, COLUMBUS, OHIO, US; 2005, GOLDFARB, DAVID SCOTT: "Method using DALINGER, IGOR L. ET AL: "Liquid-phase lifespan-altering compounds for altering the synthesis of combinatorial libraries based on lifespan of eukaryotic organisms, and screening 7-trifluoromethyl-substituted for such compounds", XP002670263, retrieved pyrazolo[1,5-a]pyrimidine scaffold", from STN Database accession no. 2009:846104 & XP002670268, retrieved from STN Database US 2009/163545 A1 (GOLDFARB, DAVID SCOTT) accession no. 2005:118953 & DALINGER, IGOR 25 June 2009 (2009-06-25) L. ET AL: "Liquid-phase synthesis of • DATABASECA [Online] CHEMICAL ABSTRACTS combinatorial libraries based on SERVICE, COLUMBUS, OHIO, US; 2009, 7-trifluoromethyl-substituted GOLDFARB, DAVID SCOTT: "Method using pyrazolo[1,5-a]pyrimidine scaffold", JOURNAL lifespan-altering compounds for altering the OF COMBINATORIAL CHEMISTRY, CODEN: lifespan of eukaryotic organisms, and screening JCCHFF; ISSN: 1520-4766, vol. 7, no. 2, 2005, for such compounds", XP002670264, retrieved pages 236-245, XP002494988, from STN Database accession no. 2009:846103 & • HUPPATZ J L: "Systemic Fungicides. The US 2009/163545 A1 (GOLDFARB, DAVID SCOTT) synthesis of Pyrazolo[1,5-a]pyrimidine 25 June 2009 (2009-06-25) Analogues of Carboxin", AUSTRALIAN • DATABASECA [Online] CHEMICAL ABSTRACTS JOURNAL OF CHEMISTRY, CSIRO, AU, vol. 38, SERVICE, COLUMBUS, OHIO, US; 2009, no.1, 1 January 1985 (1985-01-01), pages 221-230, GOLDFARB, DAVID SCOTT: "Method using XP009072127, ISSN: 0004-9425 cited in the lifespan-altering compounds for altering the application lifespan of eukaryotic organisms, and screening • DATABASE REGISTRY [Online] CHEMICAL for such compounds", XP002670265, retrieved ABSTRACTS SERVICE, COLUMBUS, OHIO, US; from STN Database accession no. 2009:846101 & 29 April 2007 (2007-04-29), chemical library; US 2009/163545 A1 (GOLDFARB, DAVID SCOTT) Supplier: aurora fine chemicals: XP002670270, 25 June 2009 (2009-06-25) Database accession no. 933237-02-6 • DATABASECA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2009, GOLDFARB, DAVID SCOTT: "Method using lifespan-altering compounds for altering the lifespan of eukaryotic organisms, and screening for such compounds", XP002670266, retrieved from STN Database accession no. 2009:846100 & US 2009/163545 A1 (GOLDFARB, DAVID SCOTT) 25 June 2009 (2009-06-25) • DATABASECA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2009, GOLDFARB, DAVID SCOTT: "Method using lifespan-altering compounds for altering the lifespan of eukaryotic organisms, and screening for such compounds", XP002670267, retrieved from STN Database accession no. 2009:846099 & US 2009/163545 A1 (GOLDFARB, DAVID SCOTT) 25 June 2009 (2009-06-25)

3 EP 2 649 075 B1

Description

STATEMENT OF GOVERNMENT SUPPORT

5 [0001] This invention was made in part with government support from the National Institutes of Health. The government has certain rights in this invention.

BACKGROUND

10 [0002] Gaucher disease is a rare disease affecting 1 in 40,000 babies born with a particular high frequency in the Ashkenazi Jews of eastern European descent (about 1 in 800 live births). It is caused by inherited genetic mutations in the GBA (glucosidase, beta acid) gene, which result in reduced activity of glucocerebrosidease (GCase or acid beta- glucocerebrosidase), an enzyme present in cellular organelles called lysosomes, responsible for the breakdown of a fatty material called glucocerebroside (or glucosyl ceramide). The accumulation of this lipid inside cells causes them to 15 swell abnormally creating problems throughout the body. The disease has been categorized into three types: Neuron- opathic (types 2, 3) and non-neuronopathic (type 1) with mild to severe symptoms that can appear at anytime from infancy to adulthood. Clinical manifestations include enlarged spleen/liver, anemia, lack of platelets, neurodegeneration, and bone disease with varying severity depending on the type of disease and time of diagnosis. The reduction in GCase activity has been attributed to the lack of protein in the lysosome. After production in the endoplasmic reticulum (ER) 20 proteins that do not fold properly are degraded in the ER and not transported to the lysosome where they can hydrolyze glucocerebroside. [0003] Existing treatment options for Gaucher disease include enzyme replacement (CEREZYME) or substrate reduction therapy (ZAVESCA) which cost between $100,000 to >$200,000 per year. The development of the iminosugar isofagomine (PLICERA) as a molecular chaperone was halted after Phase 2 clinical trials showed an increase in the 25 amount of GCase in white blood cells but a lack in the reduction of visceral symptoms. Thus there is an unmet need for the development of novel chaperone therapy for Gaucher disease. The present disclosure fulfills this need and provides additional advantages set forth in the following disclosure. [0004] WO 2009/152083 A1 discloses 5H-pyrrolo [2, 3-B] pyrazine derivatives for kinase modulation, and indications therefor. This international application reports activity of the disclosed compounds as an Fms inhibitor. 30 SUMMARY

[0005] Described herein are substituted pyrazolopyrimidines and dihydropyrazolopyrimidines and related compounds, their methods of manufacture, compositions containing the described compounds, and methods of use of the described 35 compounds. It is disclosed a compound of Formula (I) and the pharmaceutically acceptable salts of a compound of Formula (I)

wherein the ring

55 is a ring system of the formula

(i)

4 EP 2 649 075 B1

in which R5 is an optionally substituted alkylidene group and R6 and R7 carry the definitions set forth below, or

10 (ii)

in which R5, R6, and R7 carry the definitions set forth below. 20

[0006] R1 is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (mono- or bicyclic carbocycle)C0-C4alkyl or (mono- or bicyclic heterocycle)C0-C4alkyl, each of which R1 is unsubstituted or substituted with one or more substituents independently chosenfrom halogen, hydroxyl, cyano, nitro, amino, -CHO, -COOH, C 1-C6alkyl,C 2-C6alkenyl,C 2-C6alkynyl,C 1-C6alkoxy, C2-C6alkanoyl, (mono- or di- 1-C C6alkylamino)C0-C4alkyl, mono- or di-C1-C6alkylcarboxamide, C1-C6alkylester, 25 C1-C6alkylthio, C1-C6alkylsulfonyl, C1-C2haloalkyl, and C1-C2haloalkoxy, and with 0 or 1 substituents chosen from Y- Z- where Z is a covalent bond, C1-C4alkylene, -S-, -O-, -NR-, -C(O)-, -NHC(O)-, or -C(O)NH-, where R is hydrogen or C1-C4alkyl, and Y is phenyl or pyridyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently chosen from halogen, hydroxyl, cyano, nitro, amino, C1-C4alkyl, C1-C4alkoxy, trifluoromethyl, difluoromethyl, and trifluoromethoxy; and R2 is hydrogen, C1-C6alkyl, C3-C7cycloalkyl, and (phenyl)C0-C2alkyl. 30 [0007] Or, R1 and R2 are joined to form a 5- to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatoms chosen from N, O, and S, which 5- to 7-membered heterocycloalkyl ring is optionally fused to a phenyl or pyridyl; which 5- to 7-membered heterocycloalkyl ring is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, C1-C2alkyl, and C1-C2alkoxy. [0008] R3 is hydrogen or C1-C2alkyl. 35 [0009] R5 is halogen, hydroxyl, amino, cyano, C1-C4alkyl, vinyl, cyclopropyl, cyclopropylidenyl, C1-C4alkoxy, difluoromethyl, trifluoromethyl, or phenyl. [0010] R6 is halogen, hydroxyl, C1-C4alkyl, or C1-C4alkoxy. [0011] R7 is halogen, hydroxyl, amino, cyano, C 1-C4alkyl, C1-C4alkoxy, difluoromethyl, or trifluoromethyl, or R7 is phenyl or a 5- to 7-membered heterocycloalkyl ring having 1 or 2 heteroatoms chosen from N, O, and S, each of 40 which R7 is directly attached via a covalent bond or attached via a C 1-C4 alkyl, C1-C4alkoxy, or C1-C4alkylamino group, and each of which R 7 is unsubstituted or substituted with 1 to 3 substituents independently chosen from halogen, hydroxyl, C1-C4alkyl, C1-C4alkxoy, (mono- and di-C1-C2alkylamino)C0-C4alkyl, C1-C2haloalkyl, and C1-C2haloalkoxy; or R6 and R7 are taken together to form a 5- or 6-membered carbocyclic ring with no additional points of unsaturation, which ring is unsubstituted or substituted with 1 to 3 substituents independently chosen from C 1-C2alkyl and C 1-C2alkoxy. 45 [0012] In certain embodiments R1 is not unsubstituted phenyl, dihydroindenyl, benzy[b][1,4]dioxolyl, benzo[d][1,3] dioxol-5-yl, cyclohexyl, pyridyl, or phenyl substituted with 1 or 2 substituents independently chosen from chloro, fluoro,

C1-C4alkyl, C1-C2alkoxy, acetyl, and trifluoromethyl, when R6 is hydrogen, R5 and R7 are both methyl, or when R6 is hydrogen and one R5 and R7 is methyl and the other is phenyl. Also R1 is not 1-(4-fluorobenzyl)-1H-pyrazol-4-yl when R6 is hydrogen and one R5 and R7 is methyl and the other is phenyl. 50 [0013] It is disclosed a pharmaceutical composition comprising a compound of Formula I, or salt thereof, together with a pharmaceutically acceptable carrier. The invention concerns a pharmaceutical composition according to any one of claims 1 to 3 and 6. The invention concerns compound or pharmaceutically acceptable salt thereof as claimed in claims 4 and 5. The invention concerns a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in treating 55 Gaucher disease in a patient or preventing the symptoms of Gaucher disease in a patient having a GBA gene mutation as claimed in claim 7. [0014] It is disclosed a method of treating Gaucher disease in a patient or preventing or reducing the severity of the symptoms of Gaucher disease in a patient having a GBA gene mutation comprising providing an effective amount of a

5 EP 2 649 075 B1

compound of Formula (I) or pharmaceutically acceptable salt thereof to the patient. [0015] It is disclosed a method of increasing the amount of beta glucocerebrosidase in the white blood cells of patient having a GBA gene mutation, comprising providing an effective amount of a compound of Formula (I) to the patient.

5 DETAILED DESCRIPTION

[0016] Described herein are substituted pyrazolopyrimidines and dihydropyrazolopyrimidines and related compounds useful as chaperones of glucocerebrosidase. Certain substituted pyrazolopyrimidines and dihydropyrazolopyrimidines and related compounds disclosed in this application are potent and selective activators of glucocerebrosidase. These 10 compounds are useful in treating Gaucher disease and preventing the symptoms of Gaucher disease in persons who have a mutated GBA gene.

TERMINOLOGY

15 [0017] Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. [0018] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items. The term "or" means "and/or". The terms "comprising", "having", "including", and "containing" are 20 to be construed as open-ended terms (i.e., meaning "including, but not limited to"). Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted 25 by context. The use of any and all examples, or exemplary language (e.g., "such as"), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention as used herein. Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. 30 [0019] All compounds are understood to include all possible isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include 11C, 13C, and 14C. [0020] The term "substituted" means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom’s normal valence is not exceeded. When 35 the substituent is oxo (i.e., =O), then 2 hydrogens on the atom are replaced. When aromatic moieties are substituted by an oxo group, the aromatic ring is replaced by the corresponding partially unsaturated ring. For example a pyridyl group substituted by oxo is a pyridone. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent 40 formulation into an effective therapeutic agent. [0021] Suitable groups that may be present on an "optionally substituted" position include, but are not limited to, e.g.,

halogen, cyano, hydroxyl, amino, nitro, oxo, azido, alkanoyl (such as a C2-C6 alkanoyl group such as acyl or the like); carboxamido; alkylcarboxamide; alkyl groups, alkoxy groups, alkylthio groups including those having one or more thioether linkages, alkylsulfinyl groups including those having one or more sulfinyl linkages, alkylsulfonyl groups including 45 those having one or more sulfonyl linkages, mono- and di-aminoalkyl groups including groups having one or more N atoms, all of the foregoing optional alkyl substituents may have one or more methylene groups replaced by an oxygen or -NH-, and have from about 1 to about 8, from about 1 to about 6, or from 1 to about 4 carbon atoms, cycloalkyl; phenyl; phenylalkyl with benzyl being an exemplary phenylalkyl group, phenylalkoxy with benzyloxy being an exemplary phenylalkoxy group. 50 [0022] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. [0023] "Alkyl" includes both branched and straight chain saturated aliphatic hydrocarbon groups, having the specified number of carbon atoms. The term C 1-C2alkyl means an alkyl group having from 1 to about 2 carbon atoms, e.g., methyl and ethyl, respectively Likewise "alkenyl" is a branched or straight chain unsaturated hydrocarbon group having the specified number of carbon atoms and at least one carbon-carbon double bond and alkynyl is a branched or straight 55 chain unsaturated hydrocarbon group having the specified number of carbon atoms and at least one carbon-carbon triple bond. [0024] "Alkylene"is a straight orbranched saturatedbivalent carbon chain having theindicated number of carbon atoms. [0025] "Alkylester" is an alkyl group as defined above attached through an ester linkage. The ester linkage may be in

6 EP 2 649 075 B1

either orientation, e.g., a group of the formula -O(C=O)alkyl or a group of the formula -(C=O)Oalkyl. [0026] "Alkylester" is an alkyl group as defined above attached through an ester linkage. The ester linkage may be in either orientation, e.g., a group of the formula -O(C=O)alkyl or a group of the formula -(C=O)Oalkyl. [0027] "Alkylester" is an alkyl group as defined above attached through an ester linkage. The ester linkage may be in 5 either orientation, e.g., a group of the formula -O(C=O)alkyl or a group of the formula -(C=O)Oalkyl. [0028] "Alkanoyl" is an alkyl group as defined above, attached through a keto (-(C=O)-) bridge. Alkanoyl groups have the indicated number of carbon atoms, with the carbon of the keto group being included in the numbered carbon atoms.

For example a C2alkanoyl group is an acetyl group having the formula CH 3(C=O)-. [0029] "Alkylsulfonyl" is a group of the formula alkyl-(SO 2)-, where the alkyl group is an alkyl group as defined above 10 having the defined number of carbon atoms. An exemplary alkylsulfonyl group is methylsulfonyl. [0030] "Alkylthio" indicates an alkyl group as defined above attached through a sulfur linkage, i.e. a group of the formula alkyl-S-. Examples include ethylthio and pentylthio. [0031] "Alkoxy" means an alkyl group, as defined above, with the indicated number of carbon atoms attached via an oxygen bridge. 15 [0032] "Cycloalkyl" is a saturated hydrocarbon ring group, having the specified number of carbon atoms, usually from 3 to about 7 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl as well as bridged or caged saturated ring groups such as norborane or adamantane. [0033] A "mono- or bicyclic carbocycle" is a 3- to 8-membered saturated, partially unsaturated, or aromatic ring containing only carbon ring atoms or a 6 to 11 membered saturated, partially unsaturated, or aromatic bicyclic carbocyclic 20 ring system containing only carbon ring atoms. Unless otherwise indicated, the carbocyclic group may be attached to its pendant group at any carbon atom that results in a stable structure. When indicated the carbocyclic rings described herein may be substituted on any available ring carbon if the resulting compound is stable. Carbocyclic groups include cycloalkyl groups, such as cyclopropyl and cyclohexyl; cycloalkenyl groups, such as cyclohexenyl, bridged cycloalkyl groups; and aryl groups, such as phenyl. 25 [0034] "Halo" or "halogen" means fluoro, chloro, bromo, or iodo. [0035] "Heterocycloalkyl" is a saturated cyclic group having the indicated number of ring atoms containing from 1 to about 3 heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. Examples of heterocycloalkyl groups include tetrahydrofuranyl and pyrrolidinyl groups. [0036] "Mono- or bicyclic-heterocycle" is a 5- to 8-membered saturated, partially unsaturated, or aromatic ring con- 30 taining from 1 to about 4 heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon, or a 7 to 11 membered bicyclic saturated, partially unsaturated, or aromatic heterocylic ring system, each containing at least 1 heteroatom in the multiple ring system chosen from N, O, and S and containing up to about 4 heteroatoms independently chosen from N, O, and S in each ring of the multiple ring system. Unless otherwise indicated, the heterocyclic ring may be attached to the group it substitutes at any heteroatom or carbon atom that results in a stable structure. When indicated 35 the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen atom in the heterocycle may optionally be quaternized. It is preferred that the total number of heteroatoms in a heterocyclic groups is not more than 4 and that the total number of S and O atoms in a heterocyclic group is not more than 2, more preferably not more than 1. Examples of heterocyclic groups include, pyridyl, indolyl, pyrimidinyl, pyridizinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, q uin- 40 olinyl, pyrrolyl, pyrazolyl, benz[ b]thiophenyl, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, dihydroisoindolyl, 5,6,7,8-tetrahydroisoquinoline, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, morpholinyl, piper - azinyl, piperidinyl, and pyrrolidinyl. [0037] "Mono- and/ or di-alkylamino" means secondary or tertiary alkyl amino groups, wherein the alkyl groups are as defined above and have the indicated number of carbon atoms. The point of attachment of the alkylamino group is 45 on the nitrogen. The alkyl groups are independently chosen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino.

[0038] "Mono- or di-alkylcarboxamide" is a group of the formula -(C=O)Nalkyl 1alkyl2, where the alkyl 1 and alkyl 2 groups are independently chosen alkyl groups as defined herein, attached through a carboxamide linkage. The carboxamide linkage may be in either orientation, e.g., -NH(C=O)- or -(C=O)NH-. 50 [0039] "Haloalkyl" means both branched and straight-chain alkyl groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms, generally up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl. [0040] "Haloalkoxy" indicates a haloalkyl group as defined above attached through an oxygen bridge (oxygen of an alcohol radical). 55 [0041] "Pharmaceutical compositions" means compositions comprising at least one active agent, such as a compound or salt of Formula I, and at least one other substance, such as a carrier. Pharmaceutical compositions meet the U.S. FDA’s GMP (good manufacturing practice) standards for human or non-human drugs. [0042] "Carrier" means a diluent, excipient, or vehicle with which an active compound is administered. A "pharmaceu-

7 EP 2 649 075 B1

tically acceptable carrier" means a substance, e.g., excipient, diluent, or vehicle, that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable carrier" includes both one and more than one such carrier. 5 [0043] A "patient" means a human or non-human animal in need of medical treatment. Medical treatment can include treatment of an existing condition, such as a disease or disorder, prophylactic or preventative treatment, or diagnostic treatment. In some embodiments the patient is a human patient. [0044] "Providing" means giving, administering, selling, distributing, transferring (for profit or not), manufacturing, compounding, or dispensing. 10 [0045] "Treatment" or "treating" means providing an active compound to a patient in an amount sufficient to measurably reduce any symptom of a beta-glucocerebrosidase mediated disorder, e.g., cause regression of the disorder, liver function, reduce anemia, increase platelet count, or decrease the rate of neurodegeneration or bone degeneration. In certain embodiments treatment of Gaucher disease may be commenced before the patient presents symptoms of the disease. 15 [0046] A "therapeutically effective amount" of a pharmaceutical composition means an amount effective, when administered to a patient, to provide a therapeutic benefit such as an amelioration of symptoms, e.g., an amount effective to decrease the symptoms of Gaucher disease. [0047] A significant change is any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student’s T-test, where p < 0.05. 20 CHEMICAL DESCRIPTION

[0048] Compounds of formula I may contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like, e.g., asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric 25 forms. These compounds can be, for example, racemates or optically active forms. For compounds with two or more asymmetric elements, these compounds can additionally be mixtures of diastereomers. For compounds having asymmetric centers, all optical isomers in pure form and mixtures thereof are encompassed. In these situations, the single enantiomers, i.e., optically active forms can be obtained by asymmetric synthesis, synthesis from optically pure precur- sors, or by resolution of the racemates. Resolution of the racemates can also be accomplished, for example, by con- 30 ventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column. All forms are contemplated herein regardless of the methods used to obtain them. [0049] All forms (for example solvates, optical isomers, enantiomeric forms, polymorphs, free compound and salts) of an active agent may be employed either alone or in combination. [0050] The term "chiral" refers to molecules, which have the property of non-superimposability of the mirror image 35 partner. [0051] "Stereoisomers" are compounds, which have identical chemical constitution, but differ with regard to the ar- rangement of the atoms or groups in space. [0052] A "diastereomer" is a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral 40 properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis, crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column. [0053] "Enantiomers" refer to two stereoisomers of a compound, which are non-superimposable mirror images of one another. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there 45 has been no stereoselection or stereospecificity in a chemical reaction or process. [0054] Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dic- tionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, 50 the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. [0055] A "racemic mixture" or "racemate" is an equimolar (or 50:50) mixture of two enantiomeric species, devoid of optical activity. A racemic mixture may occur where there has been no stereoselection or stereospecificity in a chemical 55 reaction or process. [0056] "Pharmaceutically acceptable salts" include derivatives of the disclosed compounds in which the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical

8 EP 2 649 075 B1

methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media such as ether, 5 ethyl acetate, ethanol, isopropanol, or acetonitrile are used, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts. [0057] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the 10 parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, 15 HOOC-(CH2)n-COOH where n is 0-4, and the like. Lists of additional suitable salts may be found, e.g., in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985). [0058] Small molecules which activate the GCase enzyme are disclosed herein. The data suggests these small molecules may be acting as chaperones which help the misfolded enzyme to fold properly and be trafficked from the endoplasmic reticulum to the lysosome. Most small molecule chaperones described in literature are inhibitors of GCase 20 and thus can potentially inhibit enzyme activity in the lysosome. The present chemical series is advantageous as the compounds do not inhibit, but rather activate GCase. The chemical class of pyrazolo[1, 5-a] pyrimidine-3carboxamides is also structurally distinct from iminosugars, often described as chaperones in literature, and holds promise towards selectivity against other glycosidases. [0059] In addition to compounds of Formula (I) shown above in the SUMMARY section, Compounds of II and III, which 25 are subformulae of Formula I, and compounds in which the variables, e.g., R 1-R7 carry the following definitions are also disclosed.

[0060] In Formula III, it is disclosed that R5a is hydrogen, C1-C4alkyl, C3-C7cycloalkyl, or 4-to 7-membered carbon attached heterocycloalkyl, having 1 or 2 heteroatoms independently chosen from N, S, and O. 40 [0061] In certain embodiments of Formula III, it is disclosed that R 5a is hydrogen or cyclopropyl. [0062] Included herein are compounds and salts for Formula II in which:

R2 is hydrogen or methyl.

45 [0063] Further included herein are compounds and salts for Formula II in which:

R5 and R7 are both methyl; or

one of R5 and R7 is methyl and the other is phenyl; or 50 one of R5 and R7 is methyl and the other is difluoromethyl.

[0064] Included herein are compounds and salts of formula II in which:

R1 is (phenyl)C0-C4alkyl, (pyridyl)C0-C4alkyl, (pyrimidinyl) 0 C-C4alkyl, (C3-C7cycloalkyl)C0-C4alkyl, (pyra- 55 zolyl)C0-C2alkyl, (pyrrolyl)C0-C2alkyl, (imidazolyl)C0-C2alkyl, (thienyl)C0-C2alkyl, (furanyl)C0-C2alkyl, (oxazolyl)C0-C2alkyl, (thiazolyl)C0-C2alkyl, pyrolidinyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydrofuranyl, piperazinyl, morpholinyl, piperidinyl, thiomorpholinyl, dihydroindenyl, benzo[b][1,4]dioxinyl, or benzo[d][1,3]dioxolyl, each of which is unsubstituted or substituted with one or

9 EP 2 649 075 B1

more substituents independently chosen from halogen, hydroxyl, cyano, nitro, amino, -CHO, -COOH, C1-C6alkyl, C2-C6alkanoyl, mono- or di-1-C 6alkylamino, C mono- or 1-C di-C6alkylcarboxamide, 1 C-C6alkylthio, C1-C6alkylsulfonyl, C1-C2haloalkyl, and C1-C2haloalkoxy, and with 0 or 1 substituents chosen from Y-Z- where Z is a covalent bond, C 1-C4alkylene, -S-, -O-, -NR-, -C(O)-, -NHC(O)-, or -C(O)NH-, where R is hydrogen or C 1-C4alkyl, 5 and Y is phenyl or pyridyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently chosen

from halogen, hydroxyl, cyano, nitro, amino, C 1-C4alkyl, and C1-C4alkoxy.

[0065] Further included herein are compounds and salts of Formula II in which R1 is cyclohexyl, substituted with at least one trifluoromethyl, C3-C6alkyl. 10 [0066] Compounds and salts of Formula I, II, and III are disclosed in which:

R2 is hydrogen or methyl; and R 7 is C1-C4alkyl, difluoromethyl, or phenyl. In some embodiments it is disclosed that R7 is difluoromethyl.

15 [0067] Compounds and salts of Formula I, II, and III are disclosed in which:

R2 is hydrogen or methyl; and R 7 is methyl or difluoromethyl; and R1 is (phenyl)C0-C2alkyl, (pyridyl)C0-C2alkyl, (cyclohexyl)C0-C2alkyl, pyrazolyl, furanylnaphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl tetrahydrofuranyl, morpholinyl, piperidinyl, 20 piperazinyl, thiomorpholinyl, dihydroindenyl, benzo[b][1,4]dioxinyl, or benzo[d][1,3]dioxolyl, each of which is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, cyano, nitro, amino, -CHO, -COOH, C1-C4alkyl, C1-C4alkoxy, C2-C4alkanoyl, mono- or di- 1 C-C4alkylamino, mono- or di- C1-C4alkylcarboxamide, C1-C4alkylester, C1-C2alkylsulfonyl, trifluoromethyl, trifluoromethoxy, and difluoromethyl, and with 0 or 1 substituents chosen from Y-Z- where Z is a covalent bond, C1-C4alkylene, -S-, -O-, -NR-, -C(O)-, 25 -NHC(O)-, or -C(O)NH-, where R is hydrogen or C 1-C4alkyl, and Y is phenyl or pyridyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently chosen from halogen, hydroxyl, C 1-C2alkyl, and C1-C2alkoxy.

[0068] Compounds of Formula I have the following tautomeric formulas:

PHARMACEUTICAL PREPARATIONS 40 [0069] The substituted pyrazolopyrimidines and dihydropyrazolopyrimidines disclosed herein can be administered as the neat chemical, but are specifically administered as a pharmaceutical composition, for example a pharmaceutical formulation comprising a substituted pyrazolopyrimidines or dihydropyrazolopyrimidine compound of Formula I or pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier. The pharmaceutical 45 composition can be is formulated as an injectable fluid, an aerosol, a cream, a gel, a tablet, a pill, a capsule, a syrup, or a transdermal patch. [0070] The substituted pyrazolopyrimidines and dihydropyrazolopyrimidines may be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, via buccal administration, rectally, as an ophthalmic solution, or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers. 50 The pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution. Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active com- ponents, e.g., an effective amount to achieve the desired purpose. [0071] Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to 55 render them suitable for administration to the patient being treated. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. [0072] Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disinte-

10 EP 2 649 075 B1

grants, emulsifiers, flavorings, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin, talc, and vegetable oils. Optional active and/or inactive agents may be 5 included in the pharmaceutical compositions, provided that such agents do not substantially interfere with the activity of the hydrazone and diacyl hydrazine compounds used in the pharmaceutical compositions. The optional active is an additional active agent that is not a compound or salt of Formula I. [0073] The pharmaceutical compositions can be formulated for oral administration. These compositions contain between 0.1 and 99 weight % (wt.%) of a hydrazone or a diacyl hydrazine compound and usually at least about 5 wt.% of 10 a hydrazone or a diacyl hydrazine compound. Some embodiments contain from about 25 wt.% to about 50 wt. % or from about 5 wt.% to about 75 wt.% of the hydrazone or diacyl hydrazine compound.

TREATMENT METHODS

15 [0074] The compounds of Formula I or a salt thereof, as well as pharmaceutical compositions comprising the compounds, are useful for treating lysosomal storage diseases, including Gaucher disease. The compounds of Formula I or a salt thereof, as well as pharmaceutical compositions comprising the compounds, are also useful for preventing the occurrence of symptoms of a lysosomal storage disorder, such as Gaucher disease, in a patient having GBA gene mutation. It is disclosed that the method of treating a lysosomal storage disease in a patient comprises providing to the 20 patient an effective amount of a compound or salt of Formula I: In an embodiment the patient is a mammal, specifically a primate, more specifically a human. An effective amount of a pharmaceutical composition may be an amount sufficient to inhibit the progression of a disease or disorder; or cause a regression of a disease or disorder. [0075] An effective amount of a compound or pharmaceutical composition described herein will also provide a sufficient concentration of a substituted pyrazolopyrimidines or dihydropyrazolopyrimidines compound when administered to a 25 patient. A sufficient concentration is a concentration of the compound or salt of Formula I in the patient’s body necessary to prevent or combat the disorder. Such an amount may be ascertained experimentally, for example by assaying blood concentration of the compound, or theoretically, by calculating bioavailability. [0076] It is disclosed that methods of treatment include providing certain dosage amounts of a substituted pyrazolopyrimidine or dihydropyrazolopyrimidine compound or salt to a patient. Dosage levels of each compound of from about 30 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of compound that may be combined with the carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of each active compound. In certain embodiments 25 mg to 500 mg, or 25 mg to 200 mg of a compound of Formula I are provided daily to a patient. Frequency 35 of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most diseases and disorders, a dosage regimen of 4 times daily or less can be used and in certain embodiments a dosage regimen of 1 or 2 times daily is used. [0077] It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time 40 of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy. [0078] It is disclosed a method of treating a lysosomal storage disorder in a patient identified as in need of such treatment,the method comprising providing tothe patient an effective amount of a compound of Formula I. Thecompounds and salts of Formula I provided herein may be administered alone, or in combination with one or more other active agent. 45 [0079] These disclosed methods of treatment are also useful for treatment of mammals other than humans, including for veterinary applications such as to treat horses and livestock e.g. cattle, sheep, cows, goats, swine and the like, and pets (companion animals) such as dogs and cats. [0080] For diagnostic or research applications, a wide variety of mammals will be suitable subjects including rodents (e.g. mice, rats, hamsters), rabbits, primates, and swine such as inbred pigs and the like. Additionally, for in vitro appli- 50 cations, such as in vitro diagnostic and research applications, body fluids (e.g., blood, plasma, serum, cellular interstitial fluid, saliva, feces and urine) and cell and tissue samples of the above subjects will be suitable for use.

EXAMPLES

55 [0081] The following Examples are offered by way of illustration and not by way of limitation. Unless otherwise specified, all reagents and solvent are of standard commercial grade and are used without further purification. Starting materials are available from commercial suppliers, such as Sigma-Aldrich (St. Louis, MO), or are synthesized using procedures that are known in the art.

11 EP 2 649 075 B1

EXAMPLE 1. SYNTHETIC SCHEME FOR PREPARING SUBSTITUTED PYRAZOLOPYRIMIDINES AND DIHYDRO- PYRAZOLOPYRIMIDINES

[0082] The synthetic sequence (Scheme 1) used to generate the substituted pyrazolopyrimidines and dihydropyra- 5 zolopyrimidines provided herein starts with the condensation of a 1,3-diketone6 with ethyl 3-amino-1H-pyrazole-4- carboxylate 7 in acetic acid. Such reactions have been reported previously. See for example WO 2008/134035 and Huppatz, J. L. Aust. J. Chem. 1985, 38, 221-230. Initial efforts to simplify the evaluation of the amide SAR centered on

the use of acetylacetone as the diketone to eliminate the formation of regioisomers (R 1=R2=CH3). With unsymmetrical ketones a mixture of regioisomers (8, 9) forms which is typically separated by chromatography. Ester hydrolysis then 10 provides an acid, which is coupled with amines or anilines to generate compounds (10, 11) for biological analysis.

EXAMPLE 2. SYNTHESIS OF N-(4-ETHYNYLPHENYL)-5,7-DIMETHYLPYRAZOLO[1,5-A]PYRIMIDINE-3-CARBOX- AMIDE

30 Step 1. Synthesis of 5,7-Dimethylpyrazolo [1,5-a]pyrimidine-3-carboxylic acid ( 12)

[0083]

[0084] Pentane-2,4-dione (1.46 ml, 14.2 mmol), ethyl 3-amino-1H-pyrazole-4-carboxylate (2.00 g, 12.9 mmol) were heated in a sealed tube with acetic acid (10 ml) at 110 °C overnight. The reaction reached completion by LCMS (LC- 45 MS: rt (min) = 3.08). The acetic acid was removed by blowing air with the flask being heated to 75 °C. The crude residue of ethyl 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylate (assumed to be 12.89 mmol) was suspended in MeOH (15 ml) and treated with 7.2 M sodium hydroxide (5.37 ml, 38.7 mmol). The mixture was heated to 80 °C (at this temperature the solid dissolved) and then stirred for 3 h. The reaction was cooled and the neutralized to pH 6-7. The slurry was filtered via a Büchner funnel under house vacuum, the solid residue was washed with water and then diethyl ether to 50 obtain 5,7-dimethylpyrazolo [1,5-a]pyrimidine-3-carboxylic acid (1.4 g, 7.3 mmol, 57 % yield). LC-MS: rt (min) = 2.61. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.57 (s, 3 H), 2.71 (s, 3 H), 7.10 (s, 1 H), 8.50 (s, 1 H).

Step 2. Synthesis of N-(4-Ethynylphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide (13)

55 [0085]

12 EP 2 649 075 B1

15 [0086] 5,7-Dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (722 mg, 3.78 mmol), 4-ethynylaniline (442 mg, 3.78 mmol), and HATU (1436 mg, 3.78 mmol) were taken up in DMF (10 ml) and then treated with diisopropylethylamine (1.979 ml, 11.33 mmol). The contents stirred at room temperature overnight. The product had precipitated from reaction mixture. The reaction was diluted with water, filtered through a Büchner funnel under house vacuum. The residue was 20 washed with water (X2), then CH 2Cl2, diethyl ether, and air dried to obtain N-(4-ethynylphenyl)-5,7-dimethylpyrazolo[1,5- a]pyrimidine-3-carboxamide (500 mg, 1.72 mmol, 46 % yield). LC-MS: rt (min) = 3.65. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.71 (s, 3 H), 2.77 (s, 3 H), 4.11 (s, 1 H), 7.21 (s, 1 H), 7.49 (d, J=8.6 Hz, 2 H), 7.77 (d, J=8.6 Hz, 2 H), 8.65 (s, 1 H), 10.31 (s, 1 H).

25 EXAMPLE 3. ASSAY PROTOCOL FOR GLUCOCEREBROSIDASE ACTIVITY

[0087] qHTS Assay for Inhibitors and Activators of N370S glucocerebrosidase as a Potential Chaperone Treatment of Gaucher Disease: Primary Screen Confirmation [0088] This is a fluorogenic enzyme assay with 4-methylumbelliferyl-beta-D-glucopyranoside as the substrate and 30 N370S glucocerebrosidase from human spleen homogenate as the enzyme preparation. Upon the hydrolysis of this fluorogenic substrate, the resulting product, 4-methyllumbelliferone, can be excited at 365 nm and emits at 440 nm which can be detected by a standard fluorescence plate reader. Data were normalized to the controls for basal activity (without enzyme)and 100%activity (with enzyme).The AC50values were determined fromconcentration-response data modeled with the standard Hill equation. 35 [0089] Human spleen homogenate is prepared as follows by homogenizing spleen with assay buffer containing 50 mM citric acid (titrated with potassium phosphate to pH 5.0), 100 mM potassium chloride, 10 mM sodium chloride, 1 mM magnesium chloride, 0.01% Tween-20. The protein concentration of the human spleen homogenate is approximated 1.35 ug/ ul. [0090] The assay is performed in 1536 well plates according to the following protocol. (1) 2 ul spleen homogenate (27 40 ug final) is added to each well. (2) 23 nL test compound in DMSO solution is added to each well. The final concentration of compound in the test well is 0.5 nM to 58 uM. (3) 2 ul of substrate (1 mM final) are added to each well. (4) Incubate assay plates at 37 °C for 40 min. (5) Add 2 ul stop solution (1M NaOH and 1M Glycine mixture, pH 10) to each well. (6) Detect the assay plate in a ViewLux plate reader (PerkinElmer) using 365 nm excitation with emission at 440nm.

45 EXAMPLE 4. CHAPERONE ACTIVITY OF N-(4-ETHYNYLPHENYL)-5,7-DIMETHYLPYRAZOLO[1,5-A]PYRIMIDINE- 3-CARBOXAMIDE (NGC00188758-01)

[0091] Chaperone activity of NGC00188758-1 (1 mM and 5 mM), isofagomine (1 mM), and a vehicle control were evaluated in a N370S patient derived fibroblast for chaperone activity. GCase was visualized with red stain (anti GCase 50 R386 antibody), lysosome with green (LAMP), and nucleus with blue (DAPI). An overlay of all stains shows bright yellow color (due to overlap of red and green color) color indicating the presence of GCase in the lysosome. All laser settings were held constant across all of the fields imaged. Both isofagomine and NGC00188758-1 showed significantly increased GCase activity in the lysosome relative to vehicle control.

13 EP 2 649 075 B1

EXAMPLE 5. SELECTIVITY ASSAY: QHTS ASSAY FOR INHIBITORS AND ACTIVATORS OF N370S GLUCOCER- EBROSIDASE AS A POTENTIAL CHAPERONE TREATMENT OF GAUCHER DISEASE: ALPHA-GLUCOSIDASE COUNTERSCREEN

5 [0092] To characterize compound selectivity, selected hits from the primary screen were screened against purified alpha-glucosidase, a related sugar hydrolase. Alpha-glucosidase is responsible for hydrolysis of terminal, non-reducing 1,4-linked alpha-D-glucose residues with release of alpha-D-glucose. This is a fluorogenic enzyme assay using 4- methylumbelliferyl-alpha-D-pyranoside as the substrate and human alpha-glucosidase as the enzyme preparation. Upon the hydrolysis of this fluorogenic substrate, the resulting product, 1.4-methyllumbelliferone, can be excited at 365 nm 10 and emits at 440 nm. Emission is detected by a standard fluorescence plate reader. Data were normalized to the controls for basal activity (without enzyme) and 100% activity (with enzyme). The AC50 values were determined from concentration-response data modeled with the standard Hill equation. [0093] The assay is performed in 1536 well plates according to the following protocol. (1) Add 2 ul/well of human alpha-glucosidase enzyme (4 nM final) in assay buffer (50 mM citric acid (titrated with potassium phosphate to pH 5.0), 15 0.005% Tween-20, pH 5.0) to each well. (2) Add 23 nL compounds in DMSO solution. The final compound titration is 0.7 nM to 77 uM. (3) Add 1 ul of substrate (400 uM final). (4) Incubate at room temperature for 20 min. (5) Add 2 ul stop solution (1M NaOH and 1M Glycine mixture, pH 10) (6) Detect the assay plate in a ViewLux plate reader (PerkinElmer) with Ex=365 nm and Em=440nm.

20 EXAMPLE 6. LYSOSOMAL TRANSLOCATION ASSAY: CHAPERONE ACTIVITY IN GAUCHER FIBROBLASTS AF- TER MULTI-DAY INCUBATION WITH COMPOUND

[0094] This assay quantitates translocated glucocerebrosidase protein in patient-derived fibroblasts following extended compound incubation. The fibroblasts tested in this experiment were homozygous for N370S glucocerebrosidase. 25 [0095] Primary dermal fibroblasts derived from skin biopsies from two previously described N370S/N370S Gaucher patients (Goker-Alpan et al, 2008) and a control were seeded in Lab-Tek 4 chamber slides (Fisher Scientific, Pittsburgh, PA). After compound treatment fibroblasts were fixed in 3% paraformaldehyde. The cells were permeabelized with 0.1 % Triton-X for 10 min. and blocked in PBS containing 0.1% saponin, 100 mM glycine, 0.1% BSA and 2% donkey serum followed by incubation with mouse monoclonal anti-LAMP1 or LAMP-2 (1:100, Developmental Studies Hybridoma bank, 30 University of Iowa, Iowa City, IA) and the rabbit polyclonal anti-GCase R386 antibody (1:500). The cells were washed and incubated with secondary donkey anti-mouse or anti-rabbit antibodies conjugated to ALEXA-488 or ALEXA-555, respectively (Invitrogen, Carlsbad, CA), washed again, and mounted in VectaShield with DAPI (Vector Laboratories, Burlingame, CA). [0096] Cells were imaged with a Zeiss 510 META confocal laser-scanning microscope (Carl Zeiss, Microimaging Inc., 35 Germany) using an Argon (458, 477, 488, 514 nm) 30 mW laser, a HeNe (543 nm) 1 mW laser, and a laser diode (405 nm). Low and high magnification images were acquired using a Plan-Apochromat 20X/0.75 objective and a Plan-Apochro- mat 100x/1.4 oil DIC objective, respectively. Images were taken with the same laser settings and all the images are collapsed z-stacks. Images suggested significant translocation of glucocerebrosidase protein to lysosomes in compound treated fibroblasts relative to untreated fibroblasts. 40 EXAMPLE 8. ADDITIONAL COMPOUNDS

[0097] The following compounds are prepared according to the procedures provided in Examples 1 and 2. Those of skill in the art will recognize that reagents and reaction conditions will need to be varied to achieve the listed compounds. 45 Such variations will be readily apparent to those of skill in the art of organic chemical synthesis. The compounds of the present invention are those falling within the scope of the claims. The other compounds are disclosed as reference. [0098] LCMS retention time data was obtained as follows:

Method 1. Column: Phenomenex Luna C18 (3 micron, 3 x 75 mm). Run time: 8 min. Gradient: 4% to 100% Acetonitrile 50 in water over 7 min. Mobile phase: Acetonitrile (0.025 % TFA), water (0.05 % TFA). Flow rate: 1 mL/min. Temperature: 50 oC. UV wavelength: 220 nm, 254 nm Method 2: detection UV214, Gemini column, Solvent A is water, Solvent B is 90%acetonitrile,10% water; 0.1% AcOH modifier. Gradient initial condition is 100%A with hold time 0.5 min; gradient time is 3 min. Gradient final conc. is 100%B. gradient final hold is 0.5 min. Run time 5 min. Flow ate 1.5 ml/min. 55 Method 3. detection UV220, Phenomenex Luna 2.5 micron C18 100X2.00 mm column, Solvent A is water (0.05% TFA), Solvent B is acetonitrile (0.025% TFA). Gradient initial condition is 95%A, 5%B with hold time 0.1 min; gradient time is 2.1 min. Gradient final conc. is 100%B, 5%A. gradient final hold is 0.5 min. Then another hold for further 0.3 min with 98%A, 2%B. Run time 3 min. Flow ate 0.30 to 0.5 ml/min.

The LCMS retention times are from Method 1 unless indicated otherwise.

14 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 0.3659 5.784 1.4566 6.094 1.4566 6.434 1.4566 5.519 3- 3- a] a] 15 [1,5- pyrimidine- carboxamide 1.6343 5.823 pyrimidine- a] a] pyrazol o [1,5- [1,5- 20 phenyl) [1,5- dimethylpyrazolo pyrimidine-3- a] 5,7- carboxamide carboxamide [1,5- 3- 3- Name dimethylpyrazolo dimethylpyrazolo carboxamide 25 carboxamide 5,7- 5,7- pyrimidine- pyrimidine- tolylpyrazolo methoxyphenyl)- N-(4-(trifluoromethyl) p- 4- N- 30 fluoro- dimethyl- dimethylphenyl)- ethynylphenyl)- dimethyl- 5,7- N-(3- N-(4- 5,7- N-(3,4-

40 Structure 45

55 Cmpd. # Cmpd. NCGC00188758-01 NCGC00188783-01 NCGC00188787-01 NCGC00188776-01 NCGC00188772-01

15 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 1.8338 6.437 2.0575 6.208 2.0575 5.793 2.0575 7.439 2.2387 2 Method 2.47 a] a] a]

15 [1,5- [1,5- a]pyrimidine- a]pyrimidine- pyrimidine-3- a]

20 methylpyrazolo 5- 5-phenylpyrazolo [1,5- dimethylpyrazolo 5,7- carboxamide carboxamide carboxamide [1,5- dimethylpyrazolo methyl- 3- 3- 3- Name 7- 5,7- carboxamide

25 carboxamide ethylphenyl)- dimethylpyrazolo [1,5- dimethylpyrazolo 3- 5,7- pyrimidine- pyrimidine- pyrimidine- methoxyphenyl)- 4- methylphenyl)- 30 butylcyclohexyl)- 4- chloro- tert- (continued) bromophenyl)- chloro- N-(3- N-(4- 7-(difluoromethyl)-N-(4- N-(4- N-(3- 35

40 Structure 45

55 Cmpd. # Cmpd. MLS000708974-01 NCGC00188782-01 NCGC00188756-01 NCGC00188780-01 NCGC00229708-01

16 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 2.3086 6.745 2.5119 Method3 2.67 2.5119 Method3 2.44 2.5119 Method3 2.71 2.5902 6.328 3- a] 4,5- 15 pyrimidine- a] 7-(difluoromethyl)- methylene- carboxamide 5- carboxamide carboxamide 3- 5-methylene-4,5- 3- 20 3- [1,5- dimethylpyrazolo 5,7- carboxamide yl)- a]pyrimidine- pyrimidine- pyrimidine- 3- cyclopropylidene- Name a] a] ethoxyphenyl)- 5- [1,5- dimethylpyrazolo [1,5-

25 carboxamide [1,5- [1,5- 5,7- inden-5- pyrimidine- 1H- fluorophenyl)- butylphenyl)-7-(difluoromethyl)- 30 dihydro- butylphenyl)- dihydropyrazolo sec- dihydropyrazolo dihydropyrazolo (continued) tert- 4,5- 7-(difluoromethyl)-N-(2- bromo-2- N-(2,3- N-(4- N-(4- N-(4- 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00188764-01 NCGC00182141-01 NCGC00182160-01 NCGC00182179-01 NCGC00187969-01

17 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 3.1623 Method3 2.59 3.1623 Method3 2.58 3.1623 Method3 2.57 3.2609 6.231 3.2609 2 Method 2.34 4,5- 4,5- 4,5- 3- 5-

15 yl)- 4- pyrimidine- a] pyrazol- difluorophenyl)- dimethylphenyl)- carboxamide carboxamide carboxamide carboxamide 7-(difluoromethyl)- 1H- 3- 3- 3- 20 3- pyrimidine- pyrimidine- pyrimidine- pyrimidine- Name fluorobenzyl)- a] a] a] a]

25 carboxamide cyclopropylidene- dimethylpyrazolo [1,5- dimethylpyrazolo [1,5- [1,5- [1,5- [1,5- 5- 5,7- yl)- 7-(difluoromethyl)-N-(2,5- 7-(difluoromethyl)-N-(3,4- 2-

30 phenylpyrazolo dihydropyrazolo dihydropyrazolo dihydropyrazolo ethylphenyl)- (continued) chloropyridin- 7-(difluoromethyl)-N-(1-(4- N-(4- cyclopropylidene- cyclopropylidene- 5- 5- N-(5- 35

40 Structure 45

55 Cmpd. # Cmpd. MLS000662187-01 NCGC00182133-01 NCGC00182171-01 NCGC00182172-01 NCGC00187970-01

18 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 3.6588 6.462 3.9811 Method3 2.64 3.9811 4.1053 6.939 5.0119 2 Method 2.76 3- a] 3- [1,5-

15 inden-5- 1H- pyrimidine- pyrimidine- a] a] dihydropyrazolo carboxamide [1,5- 3- 4,5- dihydro- methylpyrazolo

20 5- carboxamide 3- carboxamide a]pyrimidine- 5-methylene- 3- Name dimethylpyrazolo [1,5- dimethylpyrazolo [1,5- dimethylpyrazolo carboxamide 25 carboxamide 5,7- methyl- 5,7- pyrimidine- 7-(difluoromethyl)- 7- a] 7-(difluoromethyl)-N-(2,3- pyrimidine- [1,5-

30 dihydropyrazolo butylphenyl)- butylcyclohexyl)- 4,5- dichlorophenyl)- (continued) difluorophenyl)- sec- yl)- tert- cyclopropylidene- N-(3,4- N-(4- 5- N-(2,4- N-(4- 35

40 Structure 45

55 Cmpd. # Cmpd. MLS000662237-01 NCGC00229713-01 NCGC00182174-01 NCGC00182166-01 NCGC00188755-01

19 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 6.5064 5.329 6.1783 6.129 5.7988 5.581 5.7988 7.298 3- 3- a]

15 [1,5- pyrimidine- a] carboxamide 6.5064 5.841 a]pyrimidine- pyrimidine- [1,5- a]

20 5-phenylpyrazolo a]pyrimidine-3- carboxamide [1,5- dimethylpyrazolo methyl- 3- Name 7- 5,7- dimethylpyrazolo [1,5- dimethylpyrazolo carboxamide carboxamide 25 carboxamide [1,5- dimethylpyrazolo 3- yl)- 5,7- 5- pyrimidine- tolylpyrazolo m- dioxol- N-

30 butylcyclohexyl)- [d][1,3] tert- fluorophenyl)-5,7- difluorophenyl)- (continued) dimethyl- N-(4- N-(4- 5,7- N-(3,5- N-(benzo 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00188766-01 NCGC00188771-01 NCGC00054856-02 NCGC00229707-01 NCGC00187967-01

20 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 6.5064 7.257 7.0795 Method3 2.72 7.0795 2 Method 2.66 3- 4,5-

15 pyrimidine- phenyl)- a] pyrimidine- a] [1,5- carboxamide

20 3- phenylpyrazolo 5- pyrimidine- Name a] dimethylpyrazolo [1,5- dimethylpyrazolo carboxamide

25 carboxamide 3- methyl- 5,7- 7- 7-(difluoromethyl)-N-(2-(phenylthio)

30 dihydropyrazolo [1,5- dihydropyrazolo dichlorophenyl)- (continued) dichlorophenyl)- cyclopropylidene- N-(3,4- 5- N-(3,4- 35

40 Structure 45

55 Cmpd. # Cmpd. MLS000765493-01 NCGC00229715-01 NCGC00182186-01

21 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 8.1911 7.025 8.1911 5.328 8.9125 Method3 2.37 a] 3- [b][1,4] [1,5- 15 carboxamide carboxamide 8.1911 5.522 pyrimidine- 3- 3- a] dihydrobenzo

20 phenylpyrazolo 5- pyrimidine- pyrimidine- a] a] methyl- carboxamide [1,5- [1,5- 7- 3- Name yl)- [1,5- dimethylpyrazolo

25 carboxamide 5,7- inden-5- pyrimidine- 7-(difluoromethyl)-N-(2,3- phenylpyrazolo dihydropyrazolo 1H- N-

30 4,5- yl)- dihydro- (continued) methoxyphenyl)- dimethyl- cyclopropylidene- N-(4- 5,7- N-(2,3- dioxin-6- 5- 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00229719-01 NCGC00187975-01 NCGC00188768-01 NCGC00182167-01

22 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS 10 Method3 2.50 10 Method3 2.48 10 Method3 2.36

10 AC50 9.1905 6.884 10.3119 5.301 a] 3- a] 4,5- 15 4,5- pyrimidine- a] [1,5- 5-methylene- methylene- carboxamide carboxamide [1,5- dimethylpyrazolo 5- 3- 3-

20 benzoate dihydropyrazolo [1,5- dihydropyrazolo 5,7- 4,5- yl)- carboxamide pyrimidine- pyrimidine- 3- phenylpyrazolo Name a] a] 7- carboxamido) dioxin-6- 7-(difluoromethyl)-

25 carboxamide [1,5- [1,5- methylene- 5- methyl- [1,4][b] pyrimidine- 5- pyrimidine-3- 30 dichlorobenzyl)- dihydropyrazolo dihydropyrazolo (continued) dihydrobenzo 7-(difluoromethyl)-N-(3-ethylphenyl)- ethylphenyl)- N-(2,4- methyl- 2-(7- methyl N-(4- N-(2,3- 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00182142-01 NCGC00229717-01 NCGC00182146-01 NCGC00182165-01 NCGC00188773-01

23 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 11.2202 Method3 2.83 11.5702 6.112 11.2202 Method3 1.75 4,5-

15 pyrimidine- carboxamide 10.3119 5.551 a] 3- methylene- [1,5- 5- 7-(difluoromethyl)- carboxamide carboxamide 3-

20 3- pyrimidine- a] dimethylpyrazolo a]pyrimidine- pyrimidine- Name a] 7-(difluoromethyl)- cyclopropylidene- 5,7- carboxamide 5-

25 [1,5- 3- [1,5- phenyl)- [1,5- dimethylpyrazolo methylphenyl)- 30 5,7- dihydropyrazolo butylcyclohexyl)- dihydropyrazolo (continued) 4,5- tert- fluoro-4- cyclohexyl- N-(4-(diethylamino) N-(4- N-(2- N- 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00187971-01 NCGC00182182-01 NCGC00182154-01 NCGC00188779-01

24 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 12.5893 Method3 2.55 12.5893 Method3 2.60 12.5893 Method3 2.15 12.5893 Method3 2.48 12.5893 Method3 2.39 4,5- yl)- 4,5- 15 2- carboxamide carboxamide carboxamide carboxamide carboxamide methylpyridin- 3- 3- 3- 3-

20 7-(difluoromethyl)-4,5- 7-(difluoromethyl)- 7-(difluoromethyl)-4,5- a]pyrimidine-3- pyrimidine- pyrimidine- pyrimidine- pyrimidine- Name a] a] a] a] 25 [1,5- [1,5- [1,5- cyclopropylidene- 5- cyclopropylidene- cyclopropylidene- 7-(difluoromethyl)-N-(3-(phenylamino)phenyl)- 7-(difluoromethyl)-N-(6- 5- 5-

30 dihydropyrazolo [1,5- dihydropyrazolo dihydropyrazolo dihydropyrazolo dihydropyrazolo dihydropyrazolo [1,5- dihydropyrazolo (continued) cyclohexyl- bromophenyl)- cyclopentyl- 4,5- N- N- N-(2- cyclopropylidene- cyclopropylidene- 5- 5- 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00182188-01 NCGC00182185-01 NCGC00182170-01 NCGC00182139-01 NCGC00182175-01

25 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 12.982 Method3 2.72 12.982 6.914 12.982 6.112 3- 4,5-

15 phenyl)- pyrimidine-3- pyrimidine- a] a] [1,5- carboxamide

20 3- pyrimidine- phenylpyrazolo Name a] 5- dimethylpyrazolo [1,5- dimethylpyrazolo carboxamide 25 carboxamide [1,5- 5,7- methyl- 7-(difluoromethyl)-N-(2-(phenylthio) 7-

30 dihydropyrazolo (continued) dimethylphenyl)- ethylphenyl)- cyclopropylidene- N-(4- N-(2,4- 5- 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00182186-01 NCGC00188778-01 NCGC00229714-01

26 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 14.1254 14.1254 Method3 2.26 14.1254 Method3 2.76 14.1254 Method3 2.35 3-

15 4,5- a]pyrimidine- [1,5- methylene- carboxamide 5- carboxamide carboxamide 5-methylene-4,5- 3- 3- 20 3- phenyl)-7-(trifluoromethyl)-4,5- pyrimidine- pyrimidine- pyrimidine- dihydropyrazolo Name a] a] a] 7-(difluoromethyl)-N-(1,2,3,4- methoxybenzyl)- 4,5-

25 carboxamide 7-(difluoromethyl)- [1,5- [1,5- yl)- N-(2-(phenylthio)

30 chlorobenzyl)- cyclopropylidene- dihydropyrazolo dihydropyrazolo 5- dihydropyrazolo [1,5- dihydropyrazolo (continued) N-(2- 7-(difluoromethyl)-N-(2- cyclopropylidene- tetrahydronaphthalen-1- 5- 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00182162-01 NCGC00182148-01 NCGC00182190-01 NCGC00182176-01

27 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 15.8489 Method3 2.54 15.8489 Method3 2.40 15.8489 Method3 2.39 15.8489 Method3 2.47 15.8489 Method3 1.78 4,5- a] 4,5- 15 [1,5- 4,5- benzyl)- benzoate dihydropyrazolo 4,5- 5-methylene- carboxamide carboxamide yl)- 3- 3-

20 2- dihydropyrazolo carboxamido) 3- 7-(difluoromethyl)- carboxamide 4,5- 3- carboxamide N-(2-(trifluoromethyl) pyrimidine- pyrimidine- 3- Name a] a] methylpyridin-

25 7-(difluoromethyl)- pyrimidine- [1,5- [1,5- a] methylene- pyrimidine- 5- N-(5- a] methylene- pyrimidme- [1,5- 5- [1,5- methyl-

30 7- methylene- chlorophenethyl)- 5- dihydropyrazolo dihydropyrazolo (continued) methyl 2-(5-cyclopropylidene- hexyl- N- N-(4- dihydropyrazolo methyl- 7-(difluoromethyl)- 7- 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00182132-01 NCGC00182159-01 NCGC00182161-01 NCGC00182197-01 NCGC00182198-01

28 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 20.575 4.637 16.3433 4.266 18.3375 5.639 18.3375 6.590 - 3- 3- 3- 3- 15 pyrimidine- carboxamide 16.3433 5.730 a] pyrimidine- pyrimidine- a] alpyrimidine-

20 [1,5- pyrimidine-3- [1, pyrazolo 5- a] pyrazolo pyrazolo[1,5- a] [1,5- yl) yl) phenyl) Name 3- carboxamide carboxamide carboxamide 25 carboxamide dimethylpyrazolo [1,5- dimethylpyrazolo 5,7- tolylpyrazolo N-(quinolin-2- o- N-(quinolin- N-

30 N-(2-(phenylthio) dimethyl- chlorobenzyl)- (continued) dimethyl- 5,7- 5,7-dimethyl- dimethyl- N-(3- 5,7- 5,7- 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00188762-01 NCGC00188770-01 NCGC00229712-01 NCGC00188763-01 NCGCOO187965-01

29 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 20.575 5.441 25.1189 Method3 2.31 25.9024 6.715 25.9024 6.816 25.9024 5.483 3- 3- 3- 3- 4,5- 15 pyrimidine- pyrimidine- pyrimidine- a] a] pyrimidine- a] methylene- a] [1,5- [1,5- 5- [1,5- carboxamide [1,5-

20 3- pyrimidine- Name dimethylpyrazolo dimethylpyrazolo a] carboxamide carboxamide carboxamide 25 carboxamide dimethylpyrazolo methoxyphenethyl)- 5,7- 5,7- [1,5- 5,7-dimethylpyrazolo 5,7-

30 butylcyclohexyl)- dihydropyrazolo cyanophenyl)- dichlorophenyl)- (continued) dimethoxyphenyl)- tert- N-(4- 7-(difluoromethyl)-N-(2- N-(3,5- N-(2,4- N-(4- 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00188769-01 NCGC00188754-01 NCGC00182147-01 NCGC00188781-01 NCGC00229716-01

30 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 31.6228 Method3 2.08 31.6228 Method3 2.22 32.6092 5.266 31.6228 Method3 2.38 3- a] 4,5- 15 carboxamide 32.6092 5.075 pyrimidine- dihydropyrazolo a] methanone 4,5- 5-methylene- carboxamide yl)

20 3- dihydropyrazolo [1,5- dihydropyrazolo a]pyrimidine-3- carboxamide 4,5- 3- methylene- 5- pyrimidine- Name a] 7-(difluoromethyl)-

25 carboxamide dimethylpyrazolo [1,5- dimethylpyrazolo [1,5- pyrimidine- (4- phenylpiperazin-1- 5- methylene- 5- 5,7- a] yl) 3- [1,5- 7-(difluoromethyl)- 30 5,7- dimethylpyrazolo [1,5- dimethylpyrazolo 5,7- chlorophenethyl)- dihydropyrazolo pyrimidin- acetylphenyl)- (continued) butyl- N-(2- sec- (7-(difluoromethyl)- N-(3- isobutyl- N- N-

40 Structure 45

55 Cmpd. # Cmpd. NCGC00187978-01 NCGC00188785-01 NCGC00182145-01 NCGC00182151-01 NCGC00182152-01

31 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 51.6821 4.723 35.4813 1.59 41.0526 6.364 32.6092 7.407 3- a] a] a] 15 [1,5- [1,5- [1,5- carboxamide 51.6821 5.189 pyrimidine- 3- methanone a] yl) pyrazol o 1- [1,5- 20 dihydropyrazolo 7-phenylpyrazolo pyrimidine- phenyl) a] 4,5- piperazin- carboxamide carboxamide yl) methyl- 3- 3- 2- Name 5- dimethylpyrazolo

25 carboxamide 5,7- 5- methylene- pyrimidine- pyrimidine- (4-(pyridin- N-(3-(trifluoromethyl) yl) 3- dimethylpyrazolo [1,5- ylmethyl)- 30 butylcyclohexyl)- 2- 5,7- tert- dimethyl- (continued) pyrimidin- 5,7- benzyl- N-(4- (7-(difluoromethyl)- N-(furan- N-

40 Structure 45

55 Cmpd. # Cmpd. NCGC00188786-01 NCGC00187976-01 NCGC00188759-01 NCGC00229711-01 NCGC00182144-01

32 EP 2 649 075 B1 5.250 6.585 5 (min.) 1.86 Method 2 Method 1.86 2.36 Method 2 Method 2.36 LCMS ret. time time ret. LCMS 2 2

10 AC50 51.6821 5.530 163.433 163.433 205.750 205.750 3- 3- a] 3- 15 [1,5- pyrimidine- a]pyrimidine- a] 7-(difluoromethyl) a] pyrimidine- a] [1,5- 20 [1,5- carboxamide dimethylpyrazolo 5,7- cyclopropyl- carboxamide 5- 3- Name tolylpyrazolo pyrimidine-3- [1,5- dimethylpyrazolo carboxamide carboxamide 25 carboxamide dimethylpyrazolo p- a] N- 5,7- 5,7- methylphenyl)- pyrimidine- 2- phenyl- hydroxyphenyl)- 7-

30 [1,5- pyrazolo methoxy- acetylphenyl)- (continued) bromo-2- methyl- hydroxyphenyl)- 5- N-(4- N-(4- N-(5- N-(3-

40 Structure 45

55 Cmpd. # Cmpd. MLS000663265-01 MLS000716072-01 NCGC00188774-01 NCGC00188784-01 NCGC00229718-01

33 EP 2 649 075 B1

5 (min.) 2.84 Method3 2.84 2.60 Method3 2.60 2.78 Method3 2.78 2.35 Method3 2.35 LCMS ret. time time ret. LCMS

10 AC50 4,5- 4,5- 4,5- 15 carboxamide carboxamide carboxamide carboxamide 7-(difluoromethyl)- 3- 3- 3- 3-

20 7-(difluoromethyl)-4,5- 7-(difluoromethyl)- 7-(difluoromethyl)- pyrimidine- pyrimidine- pyrimidine- pyrimidine- Name a] a] a] a]

25 dichlorophenyl)- [1,5- [1,5- [1,5- [1,5- cyclopropylidene- cyclopropylidene- cyclopropylidene- 5- 5- N-(2,4-

30 dihydropyrazolo dihydropyrazolo dihydropyrazolo dihydropyrazolo (continued) dicyclohexyl- 5- dicyclohexyl- acetylphenyl)- bromophenyl)- N,N- cyclopropylidene- N-(4- N-(4- 5-

40 Structure 45

55 Cmpd. # Cmpd. NCGC00182126-01 NCGC00182127-01 NCGC00182128-01 NCGC00182129-01

34 EP 2 649 075 B1

5 (min.) 2.25 Method3 2.25 Method3 2.37 2.57 Method3 2.57 1.71 Method3 1.71 LCMS ret. time time ret. LCMS

10 AC50 a] 4,5- [1,5- 15 4,5- yl)- 4- methanone carboxamide dimethoxyphenethyl)- carboxamide carboxamide 3- dihydropyrazolo (1H)-yl) 3- 3- 2

20 7-(difluoromethyl)- a]pyrimidine- pyrimidine- pyrimidine- Name a] a]

25 [1,5- [1,5- [1,5- 7-(difluoromethyl)-N-(pyridin- cyclopropylidene- dihydroisoquinolin- 5- 7-(difluoromethyl)-4,5- 7-(difluoromethyl)-N-(3,4- (3,4- yl)

30 dihydropyrazolo dihydropyrazolo dihydropyrazolo (continued) chlorophenyl)- 4,5- cyclopropylidene- 5- pyrimidin-3- cyclopropylidene- N-(4- cyclopropylidene- (5- 5- 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00182130-01 NCGC00182131-01 NCGC00182134-01 NCGC00182135-01

35 EP 2 649 075 B1

5 (min.) 1.73 Method3 1.73 1.65 Method3 1.65 1.99 Method3 1.99 2.29 Method3 2.29 2.21 Method3 2.21 LCMS ret. time time ret. LCMS

10 AC50 yl) 4- yl)- 4,5- 15 4,5- yl)- pyrazol- 3- 1H- carboxamide 3- methylene- carboxamide carboxamide 5- carboxamide carboxamide 3- methylpiperidin-4- methyl- 3- 3- 20 3- pyrimidine- a] pyrimidine- a]pyrimidine- pyrimidine- pyrimidine- [1,5- Name a] a] a] methoxybenzyl)-

25 [1,5- [1,5- [1,5- 5-methylene-7-(trifluoromethyl)-4,5- 7-(difluoromethyl)-N-(pyridin- 7-(difluoromethyl)-N-(1- 7-(difluoromethyl)-N-((1- dihydropyrazolo 30 4,5- fluorobenzyl)- dihydropyrazolo dihydropyrazolo dihydropyrazolo dihydropyrazolo [1,5- dihydropyrazolo (continued) 4,5- cyclopropylidene- N-(4- 7-(difluoromethyl)-N-(4- 5- cyclopropylidene- methyl)- cyclopropylidene- 5- 5- 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00182136-01 NCGC00182137-01 NCGC00182138-01 NCGC00182140-01 NCGC00182143-01

36 EP 2 649 075 B1

5 (min.) 2.16 Method3 2.16 2.23 Method3 2.23 Method3 2.09 2.24 Method3 2.24 LCMS ret. time time ret. LCMS

10 AC50 4,5- a] 5- [1,5-

15 4,5- carboxamide 3- 5-methylene- methylene- dihydropyrazolo [1,5- dihydropyrazolo carboxamide carboxamide 5- 3- 3- 7-(difluoromethyl)- 20 methanone 4,5- dihydropyrazolo yl) pyrimidine- 1- a] 4,5- carboxamide phenyl)- [1,5- 3- pyrimidine- pyrimidine- Name fluorobenzyl)- a] a] 5-methylene- 25 (piperidin- dimethoxyphenethyl)- yl) [1,5- [1,5- 3- 5 - methylene- 5 - pyrimidine- a] dihydropyrazolo pyrimidin- 30 4,5- 7-(difluoromethyl)- bromo-2-(trifluoromethyl) dihydropyrazolo dihydropyrazolo (continued) 7-(difluoromethyl)-N-(4- N-(4- (7-(difluoromethyl)- benzyl- methylene- 7-(difluoromethyl)-N-(3,4- N- 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00182149-01 NCGC00182150-01 NCGC00182153-01 NCGC00182156-01 NCGC00182155-01

37 EP 2 649 075 B1

5 (min.) 2.34 Method3 2.34 Method3 2.23 2.00 Method3 2.00 Method3 2.39 LCMS ret. time time ret. LCMS

10 AC50 a] a] 4,5- [1,5- 15 [1,5- pyrimidine- a] methanone [1,5- methylene- 5- carboxamide carboxamide 5-methylene-4,5- dihydropyrazolo (1H)-yl) 3- 3- 20 2 methanone dihydropyrazolo yl) 4,5- dihydropyrazolo pyrimidine- pyrimidine- Name a] a] 4,5- (indolin-1- dimethoxybenzyl)- 25 carboxamide yl) 3- 7-(difluoromethyl)- methylene- [1,5- 3- dihydroisoquinolin- 5- 7-(difluoromethyl)-4,5- (3,4- methylene- 5- yl) pyrimidin- 30 chlorobenzyl)- dihydropyrazolo methyl- dihydropyrazolo [1,5- dihydropyrazolo (continued) N-(4- pyrimidin-3- (7-(difluoromethyl)- cyclopropylidene- 7-(difluoromethyl)-N-(3,4- allyl-7- (5- N- 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00182157-01 NCGC00182158-01 NCGC00182164-01 NCGC00182163-01 NCGC00182168-01

38 EP 2 649 075 B1

5 (min.) 2.62 Method3 2.62 2.43 Method3 2.43 2.35 Method3 2.35 2.51 Method3 2.51 LCMS ret. time time ret. LCMS

10 AC50 a] 4,5- 4,5- 4,5-

15 methanone difluorophenyl)- carboxamide carboxamide carboxamide 7-(difluoromethyl)- 7-(difluoromethyl)- yl) 3- 3- 3-

20 1- 4,5 - dihydropyrazolo [1,5- dihydropyrazolo - 4,5 pyrimidine- pyrimidine- pyrimidine- Name a] a] a] 25 cyclopropylidene- cyclopropylidene- methylpiperidin- [1,5- [1,5- [1,5- 5- 5- (2- yl)- yl)- yl) 7-(difluoromethyl)-N-(3,4- 7-(difluoromethyl)- 2- 3-

30 dihydropyrazolo dihydropyrazolo dihydropyrazolo pyrimidin-3- (continued) chloropyridin- bromopyridin- cyclopropylidene- cyclopropylidene- 5- N-(2- N-(5- (5- 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00182169-01 NCGC00182173-01 NCGC00182177-01 NCGC00182178-01

39 EP 2 649 075 B1

5 (min.) 2.58 Method3 2.58 2.56 Method3 2.56 2.77 Method3 2.77 2.46 Method3 2.46 LCMS ret. time time ret. LCMS

10 AC50 4,5- 4,5- 4,5- 4,5-

15 yl)- 1- nitrophenyl)- carboxamide carboxamide carboxamide carboxamide 7-(difluoromethyl)- 7-(trifluoromethyl)- 3- 3- 3- 20 3- pyrimidine- pyrimidine- pyrimidine- pyrimidine- Name a] a] a] a] difluorophenyl)- 25 dichlorophenyl)- [1,5- [1,5- [1,5- [1,5- 7-(difluoromethyl)-N-(4- 7-(difluoromethyl)-N-(naphthalen- N-(3,4- N-(3,5-

30 dihydropyrazolo dihydropyrazolo dihydropyrazolo dihydropyrazolo (continued) cyclopropylidene- cyclopropylidene- 5- cyclopropylidene- cyclopropylidene- 5- 5- 5-

40 Structure 45

55 Cmpd. # Cmpd. NCGC00182180-01 NCGC00182181-01 NCGC00182183-01 NCGC00182184-01

40 EP 2 649 075 B1

5 (min.) 2.07 Method3 2.07 2.49 Method3 2.49 2.52 Method3 2.52 LCMS ret. time time ret. LCMS

10 AC50 a] 4,5- 4,5- [1,5- 15 methanone 7-(difluoromethyl)- (2H)-yl) carboxamide fluorophenyl)- 1 carboxamide carboxamide 3- sulfamoylphenyl)- dihydropyrazolo 3- 20 3- a]pyrimidine- pyrimidine- pyrimidine- cyclopropylidene- Name a] a] 5-

25 [1,5- 3,4-dihydroquinolin- [1,5- [1,5- 7-(difluoromethyl)-N-(2- 7-(difluoromethyl)-4,5- 7-(difluoromethyl)-N-(4- methyl- (6- chlorophenyl)- yl)

30 2- dihydropyrazolo 3- dihydropyrazolo dihydropyrazolo (continued) 4,5- bromo- cyclopropylidene- cyclopropylidene- cyclopropylidene- 5- pyrimidin- 5- (5- N-(4- 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00182187-01 NCGC00182189-01 NCGC00182191-01 NCGC00182192-01

41 EP 2 649 075 B1

5 (min.) 2.5 Method3 2.5 1.71 Method3 1.71 2.47 Method3 2.47 2.07 Method3 2.07 LCMS ret. time time ret. LCMS

10 AC50 4,5- 4,5- 15 ethyl)- yl) 4- carboxamide dihydropyrazolo 3- methylene- phenylcarbam oyl) phenylcarbam 4,5- 5- carboxamide carboxamide 3- 20 3- methyl- pyrimidine- carboxamide 7- a] phenethyl- 3- N- pyrimidine- pyrimidine- [1,5- Name a] a] 25 [1,5- [1,5- N-(3-(3-(trifluoromethyl) pyrimidine- chlorophenyl)- methylene- a] 7-(difluoromethyl)-N-(1-(pyridin- 5- [1,5- dihydropyrazolo methyl- 30 methylene- 4,5- 7- 5- dihydropyrazolo dihydropyrazolo acetamido-3- (continued) N-(4- benzyl- phenyl)- methyl- cyclopropylidene- 7- N- 5- 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00182193-01 NCGC00182195-01 NCGC00182194-01 NCGC00182196-01

42 EP 2 649 075 B1 3.717 5 (min.) 2.07 Method3 2.07 1.68 Method3 1.68 LCMS ret. time time ret. LCMS

10 AC50 3-

15 4,5- dihydropyrazolo pyrimidine- dihydropyrazolo a] 4,5- dihydropyrazolo [1,5- dihydropyrazolo methylene- 4,5- carboxamide [1,5- 5- 3- tolyl- 20 4,5- p- carboxamide carboxamide 3- 3- carboxamide methylene- 3- 5- pyrimidine- methylene- Name fluorobenzyl)- a] 5-

25 carboxamide dimethylpyrazolo [1,5- methyl- pyrimidine- pyrimidine- 5,7- 7- a] a] methyl- pyrimidine- 7-(difluoromethyl)-N- 7- a] [1,5- [1,5- yl)- 5- 30 dihydropyrazolo hydroxybutyl)- (continued) hydroxyphenyl)- 7-(difluoromethyl)-N-(2- N-(4- cyclopropylidene- N-(2- 5- N-(isoquinolin- 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00182199-01 NCGC00182200-01 NCGC00182241-01 NCGC00182242-01 NCGC00187966-01

43 EP 2 649 075 B1 5.079 3.843 5.472 3.709 4.655 5 (min.) LCMS ret. time time ret. LCMS

10 AC50 yl)

15 1- carboxamide pyrimidine-3- a] carboxamide (pyrrolidin- 3- nitrophenyl) (4-(4- yl) [1,5- yl)

20 3- 3- a]pyrimidine-3- pyrimidine- methanone a] pyrimidinyl) pyrimidin- a] 1- Name a] [1,5- methanone

25 carboxamide dimethylpyrazolo [1,5- 5,7- piperazin- dimethylpyrazolo [1,5-

30 5,7- trimethylpyrazolo cyanophenyl)- (continued) dimethylpyrazolo 5,7- N, [1,5- (5,7- dimethylpyrazolo (5,7- N-(3- isopropyl- N- 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00187972-01 NCGC00187968-01 NCGC00187973-01 NCGC00187974-01 NCGC00187977-01

44 EP 2 649 075 B1 4.386 2.543 4.759 3.326 4.169 5 (min.) LCMS ret. time time ret. LCMS

10 AC50 yl) 1- 3- a] 3- 15 [1,5- pyrimidine-3- pyrimidine- a] a] pyrimidine- a] pyrazol o methylpiperazin- [1,5-

20 (4- yl) phenyl) 3- carboxamide [1,5- pyrazolo 3- yl) Name [1,5- dimethylpyrazolo 4- pyrimidin- methanone dimethylpyrazolo carboxamide carboxamide 25 carboxamide a] 5,7- [1,5- pyrimidine- N-(pyridin- N-(4-(methylsulfonyl)

30 difluoroethyl)- dimethyl- dimethyl- (continued) acetamidophenyl)- 5,7- acetamidophenyl)- 5,7- dimethylpyrazolo 5,7- N-(2,2- N-(2- (5,7- 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00188757-01 NCGC00188760-01 NCGC00188761-01 NCGC00188765-01 NCGC00187979-01

45 EP 2 649 075 B1 5.239 4.385 5.026 6.165 7.215 5 (min.) LCMS ret. time time ret. LCMS

10 AC50 3- 3- 3-

15 pyrimidine- pyrimidine- a] pyrimidine- a] pyrimidine- pyrimidine- a] a] a] [1,5- [1,5- [1,5- [1,5- [1,5-

20 pyrazolo phenylpyrazolo phenylpyrazolo 7- 7- Name dimethylpyrazolo dimethylpyrazolo carboxamide carboxamide carboxamide carboxamide 25 carboxamide 5,7- 3- 3- 5,7- methyl- methyl- 5- 5- rimethoxyphenyl)

30 N-(3,4,5- (continued) dimethoxyphenyl)- dichlorophenyl)- acetamidophenyl)- methoxyphenyl)- N-(4- N-(3,4- N-(4- 5,7-dimethyl- N-(3,4- 35

40 Structure 45

55 Cmpd. # Cmpd. NCGC00188777-01 NCGC00188775-01 NCGC00229709-01 NCGC00229710-01 NCGC00188767-01

46 EP 2 649 075 B1 7.281 5 (min.) LCMS ret. time time ret. LCMS

10 AC50 a]

15 cyclopenta cyclopenta pyrazolo [e] 6H- 6H- [e] cyclopenta pyrazolo 1,5- pyrazolo 6H- cyclopenta carboxamide 20 carboxamide carboxamide 7,8-dihydro- 6H- 3- 3- phenyl) 7,8-dihydro- dihydro- carboxamide 7,8- 3- carboxamide methyl- 3- phenyl)- 5- Name pyrimidine- pyrimidine- 7,8-dihydro- yl)- pyrimidine-3- methyl- a] 25 a] a] 2- 5- pyrimidine- N-(2-(phenylthio) [1,5- [1,5- a] methyl- pyrimidine- 5- [1,5- 2,4-dien- phenyl- pyrazolo pyrazolo 7- 30 [1,5- pyrazolo [e] [e] N-(4-(trifluoromethyl) dichlorophenyl)- (continued) 4E)-hexa- methyl- ethylphenyl)- 5- methyl- N-(3,4- 5- N-(4- N-((2E, 35

40 Structure 45

55 Cmpd. # Cmpd. CCB2-5-1 NCGC00229720-01 CCB2-6-1 CCB2-7-1 CGB2-8-1

47 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 3- [e] a] [e]

15 [1,5- quinazoline- cyclopenta a] cyclopenta 6H- tetrahydropyrazolo 6H-

20 carboxamide carboxamide dihydro- 6,7,8,9- tetrahydropyrazolo dihydro- carboxamide 7,8- 3- 7,8- 3 -carboxamide phenyl)- 6,7,8,9- Name methyl- pyrimidine-3- pyrimidine-3- 5-

25 carboxamide tetrahydropyrazolo [1,5- tetrahydropyrazolo methyl- a] a] 5- methyl- quinazoline- 5- a] quinazoline- 6,7,8,9- [1,5- tolyl- [1,5- pyrazolo [1,5- pyrazolo

30 p- butylcyclohexyl)- N-(4-(trifluoromethyl) N- ethynylphenyl)- ethylphenyl)- (continued) tert- N-(4- N-(4- methyl- methyl- N-(4- 5- 5- 35

40 Structure 45

55 Cmpd. # Cmpd. CGB2-9-1 CGB2-10-1 CGB2-12-1 CGB2-13-1 CGB2-14-1

48 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 3- a] [1,5- a] [1,5-

15 [1,5- pyrimidine- a] phenyl) pyrazolo phenyl) [1,5- tetrahydropyrazolo

20 methylpyrazolo 5- tetrahydropyrazolo carboxamide 6,7,8,9- carboxamide 3- carboxamide tolylpyrazolo carboxamide 3- 3- 6,7,8,9- p- 3- Name N- N-(4-(trifluoromethyl) methyl-

25 carboxamide ethylphenyl)- 5- methyl- pyrimidine- 5- a] methyl- methyl- quinazoline- pyrimidine- quinazoline- 5- 5- a] [1,5-

30 butylcyclohexyl)- (continued) ethynylphenyl)- tert- 7-(difluoromethyl)-N-(4- N-(4- 7-(difluoromethyl)- 7-(difluoromethyl)- N-(4- 35

40 Structure 45

55 Cmpd. # Cmpd. CGB2-19-1 CGB2-17-1 CGB2-18-1 CGB2-20-1 CGB2-16-1

49 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 3- a] a] [1,5- [1,5- 15 [1,5- pyrimidine- a] [1,5- methylpyrazolo [1,5 -a] pyrimidine- 7- methylpyrazolo methylpyrazolo

20 5- 5- pyrazolo pyrazolo carboxamide carboxamide carboxamide phenyl) 3- 3- 3- yl) Name 1- carboxamide

25 carboxamide 5-(difluoromethyl)- 3- ethynylphenyl)- 7-(difluoromethyl)- pyrimidine- pyrimidine- pyrimidine- a] morpholinophenyl) N-(4- 30 N-(4-(piperidin- butylcyclohexyl)- (continued) dichlorophenyl)- tert- dimethyl- dimethyl- 7-(difluoromethyl)-N-(4- N-(3,4- 5,7- N-(4- 5,7- 35

40 Structure 45

55 Cmpd. # Cmpd. CGB2-21-1 CGB2-22-1 CGB2-23-1 CGB2-33-1 CGB2-32-1

50 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 a] a] 15 pyrimidine- [1,5- [1,5- a] pyrimidine-3- a] pyrimidine-3- a]

20 dimethylpyrazolo dimethylpyrazolo 5,7- 5,7- carboxamide carboxamide [1,5- dimethylpyrazolo 3- 3- Name dimethylpyrazolo [1,5- dimethylpyrazolo 5,7- carboxamide carboxamide 25 carboxamide dimethylpyrazolo [1,5- dimethylpyrazolo phenyl)- phenyl)- 5,7- 3- yl)- 4- 5,7- yl)- 4- pyrimidine- pyrimidine-

30 (continued) bromophenyl)- methoxybiphenyl- cyanobiphenyl- N-(4-(dimethylamino) N-(3-(dimethylamino) N-(4- N-(3’- N-(4’- 35

40 Structure 45

55 Cmpd. # Cmpd. CGB2-39-1 CGB2-35-1 CGB2-36-1 CGB2-41-1 CGB2-34-1

51 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 a] a] [1,5- [1,5- 15 pyrimidine- a] pyrimidine-3- a] pyrimidine-3- a]

20 dimethylpyrazolo dimethylpyrazolo 5,7- 5,7- yl)- yl)- carboxamide carboxamide 4- 4- [1,5- dimethylpyrazolo 3- 3- Name dimethylpyrazolo [1,5- dimethylpyrazolo 5,7- carboxamide carboxamide 25 carboxamide 5,7- 3- dimethylpyrazolo [1,5- yl)- biphenyl- biphenyl- 4- yl)- 5,7- 4- pyrimidine- pyrimidine-

30 iodophenyl)- (continued) methoxybiphenyl- cyanobiphenyl- N-(4- N-(4’-(dimethylamino) N-(3’-(dimethylamino) N-(4’- N-(3’- 35

40 Structure 45

55 Cmpd. # Cmpd. CGB2-42-1 CGB2-43-1 CGB2-62-1 CGB2-63-1 CGB2-68-1

52 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50

15 pyrimidine- pyrimidine- a] a] pyrimidine-3- a] pyrimidine-3- a]

20 [1,5- dimethylpyrazolo [1,5- dimethylpyrazolo Name dimethylpyrazolo [1,5- dimethylpyrazolo 5,7- 5,7- carboxamide carboxamide carboxamide 25 carboxamide dimethylpyrazolo [1,5- dimethylpyrazolo 3- 5,7- 3- yl)- yl)- 3- 3- 5,7- yl)- 3-

30 (continued) bromophenyl)- methoxybiphenyl- methoxybiphenyl- cyanobiphenyl- N-(3- N-(4’- N-(3’- N-(4’- 35

40 Structure 45

55 Cmpd. # Cmpd. CGB2-55-1 CGB2-56-1 CGB2-57-1 CGB2-58-1

53 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 a] a] [1,5- [1,5- 15 pyrimidine- pyrimidine-3- a] a] [1,5-

20 dimethylpyrazolo dimethylpyrazolo pyrazolo 5,7- 5,7- yl)- yl)- carboxamide carboxamide phenyl) 3- 3- 3- 3- yl) Name dimethylpyrazolo [1,5- dimethylpyrazolo 5- carboxamide

25 carboxamide 5,7- 3- biphenyl- biphenyl- yl)- 3- pyrimidine- pyrimidine-

30 N-(3-(pyrimidin- (continued) cyanobiphenyl- dimethyl- N-(4’-(dimethylamino) N-(3’-(dimethylamino) 5,7- N-(3’- 35

40 Structure 45

55 Cmpd. # Cmpd. CGB2-59-1 CGB2-60-1 CGB2-61-1 CGB2-67-1

54 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 a]

15 [1,5- pyrazol o pyrazol pyrimidine- a] [1,5- pyrazolo yl) methylpyrazolo methylpyrazolo methylpyrazolo [1,5- 1- 5- pyrazolo 5- yl) yl)- yl)- 1-

20 1- carboxamide carboxamide carboxamide 3- 3- 3- carboxamide carboxamide methylpiperazin- 3- 7-(piperidin-1- 3- Name morpholinopyrazolo 7-(2-morpholinoethylamino) carboxamide 7-(4- 25 7- 3- isobutylpiperazin- isopropylpiperazin- methyl- pyrimidine- pyrimidine- pyrimidine- 5- a] a] a] pyrimidine- methyl- pyrimidine- methyl- methyl- 7-(4- a] 7-(4- 5- 5- [1,5- [1,5- [1,5-

30 ethylphenyl)- (continued) ethylphenyl)- ethylphenyl)- ethylphenyl)- ethylphenyl)-5- ethylphenyl)- N-(4- N-(4- N-(4- N-(4- N-(4- N-(4- 35

40 Structure 45

55 Cmpd. # Cmpd. CGB2-64-1 CGB2-65-1 CGB2-75-1 CGB2-77-1 CGB2-79-1 CGB2-80-1

55 EP 2 649 075 B1

5 (min.) LCMS ret. time time ret. LCMS

10 AC50 5 - - 5

15 methylpyrazolo ethylphenyl)- methylpyrazolo 5- 5- 5,7-dimethylpyrazolo 5,7-dimethylpyrazolo carboxamide yl)-N-(4- 20 3- phenyl)- carboxamide carboxamide carboxamide ethylphenyl)- ethylphenyl)- 3- 3- 3- ynyl) pyrimidine- Name piperazin -1- piperazin a]

25 yl)-N-(4- 1- [1,5- ethyl) pyrimidine- pyrimidine- pyrimidine- a] a] a] [1,5- [1,5- [1,5-

30 methylpyrazolo (continued) dimethylpiperazin- 7-(3,5-dimethylmorpholino)-N-(4- N-(4-(3-(dimethylamino)prop-1- 7-(3,5- 7-(4-(2-(dimethylamino) 35

40 Structure 45

55 Cmpd. # Cmpd. CGB2-81-1 CGB2-82-1 CGB2-83-1 CGB2-70-1

56 EP 2 649 075 B1 from alkyl, 6 -C 1

5 alkyl, acetyl, and acetyl, alkyl, 4 -C 1 haloalkoxy, and 0 with haloalkoxy, 2 alkylamino, alkylamino, mono- or di- -C 6 1

10 -C 1 fluoro, C fluoro, tituents independently chosen independently tituents amino, amino, -CHO, -COOH, C alkoxy; or alkoxy; 4 and (b) below is met: is below (b) and -C haloalkyl, and C haloalkyl, 15 1 2 is methyl and the other is phenyl. is other the and methyl is 7 -C 1 and R and 5 alkanoyl, alkanoyl, mono- or di- C alkyl, and C and alkyl, 6 4

20 -C -C 2 1 alkylsulfonyl, C alkylsulfonyl, 6 alkyl, and Y is phenyl or pyridyl, each of which is unsubstituted or unsubstituted is which of each pyridyl, or phenyl is Y and alkyl, 4 difluoromethyl; is other the and methyl is -C 7 1 -C alkynyl, alkynyl, C 1 6 -C

25 2 and R and 5 haloalkoxy, and with 0 or 1 substituents chosen from Y-Z- where Z is a covalent a is Z where Y-Z- from chosen substituents 1 or 0 with and haloalkoxy, alkylthio, C alkylthio, 2 6 is hydrogen and one of R of one and hydrogen is 6 -C -C 1 1 alkenyl, alkenyl, C 6 -C

30 2 alkyl; 6 -C 3 alkyl, C 6 alkylene, -S-, -O-, -NR-, -C(O)-, - NHC(O)-, or NHC(O)-, - -C(O)-, -NR-, -O-, -S-, alkylene, haloalkyl, and C and haloalkyl, -C 4 2 1 -C -C 1 1

35 C alkylcarboxamide, 6 are both hydrogen. both are 6 alkoxy. -C 4 1 -C 1 are both methyl, or (2) when R when (2) or methyl, both are alkoxy; and alkoxy; and R and 7 4 3 -C 1

40 C alkylsulfonyl, 6 and R and is methyl and the other is phenyl; or one of R of one or phenyl; is other the and methyl is 5 -C 7 1 alkyl, and C and alkyl, 4 -C alkyl, or C or alkyl, 1 alkyl, and Y is phenyl or pyridyl, each of which is unsubstituted or substituted with 1 to 3 substituents independently chosen chosen independently substituents 3 to 1 with substituted or unsubstituted is which of each pyridyl, or phenyl is Y and alkyl, 4 and R and 4 5 -C -C 1 45 1 alkylthio, C alkylthio, alkylamino, mono- or di-C or mono- alkylamino, 6 6 -C -C 1 1 is hydrogen, and R and hydrogen, is 6

50 alkylene, -S-, -O-, -NR-, -C(O)-, -NHC(O)-, or -C(O)NH-, where R is hydrogen or C or hydrogen is R where -C(O)NH-, or -NHC(O)-, -C(O)-, -NR-, -O-, -S-, alkylene, 4 -C 1 is not unsubstituted phenyl, dihydroindenyl, or phenyl substituted with 1 or 2 substituents independently chosen from chloro, from chloro, chosen with independently 1 or 2 substituents or substituted phenyl dihydroindenyl, phenyl, is not unsubstituted is phenyl, naphthyl, tetrahydronaphthyl or dihydroindenyl, each of which is unsubstituted or substituted with one with or more orsubs substituted which each of unsubstituted is dihydroindenyl, or tetrahydronaphthyl naphthyl, phenyl, is is cyclohexyl, substituted with at least one trifluoromethyl, or C or trifluoromethyl, one least at with substituted cyclohexyl, is alkylcarboxamide, C alkylcarboxamide, R of one or methyl; both are 1 1 1 6 7 -C alkanoyl, mono- or di- C di- mono- or alkanoyl, 55 1 6 substituted with 1 to 3 substituents independently chosen from halogen, hydroxyl, cyano, nitro, amino, C amino, nitro, cyano, hydroxyl, halogen, from chosen independently substituents 3 to 1 with substituted N-(4-ethynylphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; (b) R (b) from from halogen, hydroxyl, cyano, nitro, amino, -CHO, -COOH, C C bond, C bond, (a) R (a) is hydrogen or methyl; or hydrogen is hydrogen; is R and C hydroxyl, halogen, hydrogen, is dihydroindenyl, or tetrahydronaphthyl, naphthyl, phenyl is -C 2 3 5 6 1 2 R trifluoromethyl, (1) when R -C(O)NH-, where R is hydrogen or C or hydrogen is R where -C(O)NH-, wherein R wherein A compound or pharmaceutically acceptable salt thereof, wherein the compound is: compound the wherein thereof, salt acceptable pharmaceutically or compound A C R or 1 substituents chosen from Y-Z- where Z is a covalent bond, C bond, covalent a is Z where Y-Z- from chosen 1 substituents or The pharmaceutical composition of claim 1, wherein R wherein 1, claim of composition pharmaceutical The A pharmaceutical composition comprising a compound of the formula the of compound a comprising composition pharmaceutical A (a) conditions of one wherein carrier, acceptable pharmaceutically a with together thereof salt acceptable pharmaceutically or R R which is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, cyano, nitro, The pharmaceutical composition of any one of Claims 1 to 2, wherein 2, to 1 Claims of one any of composition pharmaceutical The R halogen, hydroxyl, cyano, nitro, amino, C amino, nitro, cyano, hydroxyl, halogen, 4. 2. Claims 1. 3.

57 EP 2 649 075 B1

N-(4-bromophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; 5,7-dimethyl-N-(2-(phenylthio)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(4-cyanophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(4-tert-butylcyclohexyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; 5 N-(4-tert-butylcyclohexyl)-5-methyl-7-phenylpyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(3-cyanophenyl)- 5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; 5,7-dimethyl-N-(4-(methylsulfonyl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(2-acetamidophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(4-acetamidophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; 10 5-methyl-7-phenyl-N-(2-(phenylthio)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; 7-(difluoromethyl)-5-methyl-N-p-tolylpyrazolo[1,5-a]pyrimidine-3-carboxamide; 7-(difluoromethyl)-N-(4-ethylphenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide; 7-(difluoromethyl)-5-methyl-N-(4-(trifluoromethyl)phenyl) pyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(3,4-dichlorophenyl)-7-(difluoromethyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide; 15 7-(difluoromethyl)-N-(4-ethynylphenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(4-tert-butylcyclohexyl)-5-(difluoromethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(3-(dimethylamino)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(4-(dimethylamino)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(4-bromophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; 20 N-(4’-cyanobiphenyl-4-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(3’-methoxybiphenyl-4-yl)-5,7 -dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(3 ’-cyanobiphenyl-4-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(4’-(dimethylamino)biphenyl-4-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(4’-methoxybiphenyl-4-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; 25 N-(3’-(dimethylamino)biphenyl-4-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(4-iodophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(3-bromophenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(4’-methoxybiphenyl-3 -yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(4’-cyanobiphenyl-3-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; 30 N-(3’-methoxybiphenyl-3-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(4’-(dimethylamino)biphenyl-3-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(3’-(dimethylamino)biphenyl-3-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; 5,7-dimethyl-N-(3-(pyrimidin-5-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; N-(3’-cyanobiphenyl-3-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide; 35 5. The compound of claim 4, wherein the compound is N-(4-ethynylphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3- carboxamide.

6. The pharmaceuticalcomposition of anyone of Claims1-3, or a pharmaceutical composition comprising thecompound 40 of claim 4 or 5 or salt thereof together with a pharmaceutically acceptable carrier; wherein the composition is optionally in the form of an oral dosage form.

7. A compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in treating Gaucher disease in a patient or preventing the symptoms of Gaucher disease in a patient having a GBA gene mutation, wherein Formula 45 (I) is:

55 wherein the ring

58 EP 2 649 075 B1

is a ring system of the formula

10 (i)

in which R5 is an optionally substituted alkylidene group and R 6 and R7 carry the definitions set forth below, or 20 (ii)

in which R5, R6, and R7 carry the definitions set forth below; 30

R1 is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (mono- or bicyclic carbocycle)C0-C4alkyl, or (mono- or bicyclic heterocycle)C0-C4alkyl, each of which R1 is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, cyano, nitro, amino, -CHO, -COOH,1-C C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C2-C6alkanoyl, (mono- or di- 1-C C 6alkylamino)C0-C4alkyl, mono- or di-C1-C6alkylcarboxamide, 35 C1-C6alkylester, C1-C6alkylthio, C1-C6alkylsulfonyl, C1-C2haloalkyl, and C1-C2haloalkoxy, and with 0 or 1 substituents chosen from Y-Z- where Z is a covalent bond, C 1-C4alkylene, C2-C4alkenylene, C2-C4alkynylene,-S-, -O-, -NR-, - C(O)-, -NHC(O)-, or -C(O)NH-, where R is hydrogen or C 1-C4alkyl, and Y is phenyl, pyrimidinyl, 5- or 6-membered heterocycloalkyl, or pyridyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen,

hydroxyl, cyano, nitro, amino, C 1-C4alkyl, C1-C4alkoxy, mono- and di- C 1-C4alkylamino, trifluoromethyl, difluorome- 40 thyl, trifluoromethoxy, and phenyl; R2 is hydrogen, C1-C6alkyl, C3-C7cycloalkyl, or (phenyl)C0-C2alkyl; or R1 and R2 are joined to form a 5- to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatoms chosen from N, O, and S, which 5- to 7-membered heterocycloalkyl ring is optionally fused to a phenyl or pyridyl; which 5- to 7-membered heterocycloalkyl ring is unsubstituted or substituted with one or more substituents independently 45 chosen from halogen, hydroxyl, C1-C2alkyl, and C1-C2alkoxy; R3 is hydrogen or C1-C2alkyl; R5 is halogen, hydroxyl, amino, cyano, vinyl, cyclopropyl, cyclopropylidenyl, C 1-C4alkyl, C1-C4alkoxy, difluoromethyl, trifluoromethyl, or phenyl;

R6 is hydrogen, halogen, hydroxyl, C1-C4alkyl, or C1-C4alkoxy; and 50 R7 is halogen, hydroxyl, amino, cyano, C 1-C4alkyl, C1-C4alkoxy, difluoromethyl, or trifluoromethyl, or R7 is phenyl or a 5- to 7-membered heterocycloalkyl ring having 1 or 2 heteroatoms chosen from N, O, and S, each of which R7 is directly attached via a covalent bond or attached via a C 1-C4 alkyl, C1-C4alkoxy, or C1-C4alkylamino group, and each of which R7 is unsubstituted or substituted with 1 to 3 substituents independently chosen from halogen, hydroxyl, C1-C4alkyl, C1-C4alkoxy, (mono- and di-C1-C2alkylamino)C0-C4alkyl, C1-C2haloalkyl, and 55 C1-C2haloalkoxy; or R6 and R7 are taken together to form a 5- or 6-membered carbocyclic ring with no additional points of unsaturation, which ring is unsubstituted or substituted with 1 to 3 substituents independently chosen from1-C 2 Calkyl and C1-C2alkoxy,

59 EP 2 649 075 B1

wherein R1 is not unsubstituted phenyl, dihydroindenyl, benzo[b] [1,4]dioxolyl, benzo[d] [1,3]dioxol-5-yl, cyclohexyl, pyridyl, or phenyl substituted with 1 or 2 substituents independently chosen from chloro, fluoro,1-C4 alkyl, C C1-C2alkoxy, acetyl, trifluoromethyl, when R6 is hydrogen, R 5 and R7 are both methyl, or when R6 is hydrogen and one R5 and R 7 is methyl and the other is phenyl; and R 1 is not 1-(4-fluorobenzyl)-1H-pyrazol-4-yl when R 6 is hydrogen 5 and one R5 and R7 is methyl and the other is phenyl.

Patentansprüche

10 1. Pharmazeutische Zusammensetzung, umfassend eine Verbindung der Formel

20 oder pharmazeutisch verträgliches Salz davon, zusammen mit einem pharmazeutisch verträglichen Träger, wobei eine der nachstehenden Bedingungen (a) und (b) erfüllt ist:

(a) R1 Phenyl, Naphthyl, Tetrahydronaphthyl oder Dihydroindenyl ist, wobei jedes davon mit einem oder mehreren Substituenten unsubstituiert oder substituiert ist, die unabhängig ausgewählt sind aus Halogen, Hydroxyl, 25 Cyano, Nitro, Amino, -CHO, -COOH, C1-C6-Alkyl, C2-C6-Alkenyl, C2-C6-Alkynyl, C2-C6-Alkanoyl, Mono- oder Di-C1-C6-Alkylamino, Mono- oder Di-C1-C6-Alkylcarboxamid, C1-C6-Alkylthio, C1-C6-Alkylsulfonyl, C1-C2-Ha- loalkyl und C1-C2-Haloalkoxy und mit 0 oder 1 Substituenten, die ausgewählt sind aus Y - Z, wobei Z eine kovalente Bindung, C1-C4-Alkylen, -S-, -O-, -NR-, -C(O)-, - NHC(O)- oder -C(O)NH- ist, wobei R Wasserstoff oder C1-C4-Alkyl ist und Y Phenyl oder Pyridyl ist, wobei jedes davon unsubstituiert oder substituiert ist mit 1 30 bis 3 Substituenten, die unabhängig ausgewählt sind aus Halogen, Hydroxyl, Cyano, Nitro, Amino, C 1-C4-Alkyl und C1-C4-Alkoxy; oder (b) R1 Cyclohexyl ist, das mit wenigstens Trifluormethyl oder C 3-C6-Alkyl substituiert ist;

R2 Wasserstoff oder Methyl ist; 35 R3 Wasserstoff ist; R5 und R7 beide Methyl sind; oder eines von R5 und R7 Methyl ist und das andere Phenyl ist; oder eines von R5 und R7 Methyl ist und das andere Difluormethyl ist; R6 Wasserstoff, Halogen, Hydroxyl, C1-C4-Alkyl oder C1-C4-Alkoxy ist; und wobei R1 nicht unsubstituiertes Phenyl, Dihydroindenyl oder Phenyl ist, das mit 1 oder 2 Substituenten substituiert 40 ist, die unabhängig ausgewählt sind aus Chlor, Fluor, C 1-C4-Alkyl, Acetyl und Trifluormethyl, (1) wenn R 6 Wasserstoff ist und R5 und R7 beide Methyl sind oder (2) wenn R 6 Wasserstoff ist und eines von R 5 und R7 Methyl ist und das andere Phenyl ist.

2. Pharmazeutische Zusammensetzung nach Anspruch 1, wobei R 3 und R6 beide Wasserstoff sind. 45 3. Pharmazeutische Zusammensetzung nach einem der Ansprüche 1 bis 2, wobei R1 Phenyl, Naphthyl, Tetrahydronaphthyl oder Dihydroindenyl ist, das unsubstituiert oder substituiert ist mit einem oder mehreren Substituenten, die unabhängig ausgewählt sind aus

Halogen, Hydroxyl, Cyano, Nitro, Amino, -CHO, -COOH, C1C6-Alkyl, C2-C6-Alkanoyl, Mono- oder Di-C1-C6-Alkyl- 50 amino, Mono- oder Di-C 1-C6-Alkylcarboxamid, C 1-C6-Alkylthio, C1-C6-Alkylsulfonyl, C 1-C2-Haloalkyl und C 1-C2-Ha- loalkoxy und mit 0 oder 1 Substituenten, die ausgewählt sind aus Y - Z, wobei Z eine kovalente Bindung, C 1-C4-Al- kylen, -S-, -O-, -NR-, -C(O)-, -NHC(O)- oder -C(O)NH- ist, wobei R Wasserstoff oder C 1-C4-Alkyl ist und Y Phenyl oder Pyridyl ist, wobei jedes davon unsubstituiert oder substituiert mit 1 bis 3 Substituenten ist, die unabhängig ausgewählt sind aus Halogen, Hydroxyl, Cyano, Nitro, 55 Amino, C1-C4-Alkyl und C1-C4-Alkoxy.

4. Verbindung oder pharmazeutisch verträgliches Salz davon, wobei die Verbindung Folgendes ist:

60 EP 2 649 075 B1

N-(4-Ethynylphenyl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; N-(4-Bromphenyl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; 5,7-Dimethyl-N-(2-(phenylthio)phenyl)pyrazol[1,5-a]pyrimidin-3-carboxamid; N-(4-Cyanophenyl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; 5 N-(4-Tert-butylcyclohexyl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; N-(4-Tert-butylcyclohexyl)-5-methyl-7-phenylpyrazol[1,5-a]pyrimidin-3-carboxamid; N-(3-Cyanophenyl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; 5,7-Dimethyl-N-(4-(methylsulfonyl)phenyl)pyrazol[1,5-a]pyrimidin-3-carboxamid; N-(2-Acetamidphenyl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; 10 N-(4-Acetamidphenyl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; 5-Methyl-7-phenyl-N-(2-(phenylthio)phenyl)pyrazol[1,5-a]pyrimidin-3-carboxamid; 7-(Difluormethyl)-5-methyl-N-p-tolylpyrazol[1,5-a]pyrimidin-3-carboxamid; 7-(Difluormethyl)-N-(4-ethylphenyl)-5-methylpyrazol[1,5-a]pyrimidin-3-carboxamid; 7-(Difluormethyl)-5-methyl-N-(4-trifluormethyl)phenyl)pyrazol[1,5-a]pyrimidin-3-carboxamid; 15 N-(3,4-Dichlorphenyl)-7-(difluormethyl)-5-methylpyrazol[1,5-a]pyrimidin-3-carboxamid; 7-(Difluormethyl)-N-(4-ethynylphenyl)-5-methylpyrazol[1,5-a]pyrimidin-3-carboxamid; N-(4-Tert-butylcyclohexyl)-5-(difluormethyl)-7-methylpyrazol[1,5-a]pyrimidin-3-carboxamid; N-(3-(Dimethylamino)phenyl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; N-(4-(Dimethylamino)phenyl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; 20 N-(4-Bromphenyl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; N-(4’-Cyanobiphenyl-4-yl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; N-(3’-Methoxybiphenyl-4-yl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; N-(3’-Cyanobiphenyl-4-yl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; N-(4’-(Dimethylamino)biphenyl-4-yl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; 25 N-(4’-Methoxybiphenyl-4-yl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; N-(3’(Dimethylamino)biphenyl-4-yl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; N-(4-Iodphenyl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; N-(3-Bromphenyl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; N-(4’-Methoxybiphenyl-3-yl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; 30 N-(4’-Cyanobiphenyl-3-yl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; N-(3’-Merthoxybiphenyl-3-yl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; N-(4’-(Dimethylamino)biphenyl-3-yl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; N-(3’-(Dimethylamino)biphenyl-3-yl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid; 5,7-Dimethyl-N-(3-(pyrimidin-5-yl)phenyl)pyrazol[1,5-a]pyrimidin-3-carboxamid; 35 N-(3’-Cyanobiphenyl-3-yl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3-carboxamid.

5. Verbindung nach Anspruch 4, wobei die Verbindung N-(4-Ethynylphenyl)-5,7-dimethylpyrazol[1,5-a]pyrimidin-3- carboxamid.

40 6. Pharmazeutische Zusammensetzung nach einem der Ansprüche 1 - 3 oder Pharmazeutische Zusammensetzung, umfassend die Verbindung nach Anspruch 4 oder 5 oder ein Salz davon, zusammen mit einem pharmazeutischen verträglichen Träger; wobei die Zusammensetzung optional in der Form einer oralen Dosisform besteht.

7. Verbindung von Formel (I) oder ein pharmazeutisch verträgliches Salz davon zur Verwendung bei der Behandlung 45 von Morbus Gaucher in einem Patienten oder zur Verhütung von Symptomen von Morbus Gaucher in einem Pati- enten mit einer GBA-Genmutation, wobei die Formel (I) wie folgt lautet:

55 wobei der Ring

61 EP 2 649 075 B1

ein Ringsystem der Formel

(i) 10

ist, bei der R5 eine optional substituierte Alkylidengruppe ist und R6 und R7 die wie nachfolgend dargelegten Definitionen tragen oder (ii) 20

ist, bei der R5.R6 und R7 die wie nachfolgend dargelegten Definitionen tragen;

R1 C1-C6-Alkyl, C2-C6-Alkenyl, C2-C6-Alkynyl, (mono- oder bicylisches) C0-C4-Alkyl oder (mono- oder bicylisches 30 Heterocylus-) C0-C4-Alkyl ist, wobei jedes R 1 unsubstituiert oder substituiert ist mit einem oder mehreren Substitu- enten, die unabhängig ausgewählt sind aus Halogen, Hydroxyl, Cyano, Nitro, Amino, -CHO, -COOH, C 1-C6-Alkyl, C2-C6-Alkenyl, C 2-C6-Alkynyl,C 1-C6-Alkoxy,C 2-C6-Alkanoyl, (Mono- oder Di-C 1-C6-Alkylamino) C 0-C4-Alkyl, Mono- oder Di-C1-C6-Alkylcarboxamid, C1-C6-Alkylester, C1-C6-Alkylthio, C1-C6-Alkylsulfonyl, C1-C2-Haloalkyl und C1-C2-Haloalkoxy und mit 0 oder 1 Substituenten, die ausgewählt sind aus Y - Z, wobei Z eine kovalente Bindung, 35 C1-C4-Alkylen, C2-C4-Alkenylen, C2-C4-Alkynylen, -S-, -O-, -NR-, -C(O)-, - NHC(O)- oder -C(O)NH- ist, wobei R Wasserstoff oder C1-C4-Alkyl ist und Y Phenyl, Pyrimidinyl, 5- oder 6-gliedriges Heterocycloalkyl oder Pyridyl ist, wobei jedes mit 0 bis 3 Substituenten substituiert ist, die unabhängig ausgewählt sind aus Halogen, Hydroxyl, Cyano,

Nitro, Amino, C 1-C4-Alkyl, C1-C4-Alkoxy, Mono- und Di-C 1-C4-Alkylamino, Trifluormethyl, Difluormethyl, Trifluorme- thoxy und Phenyl; 40 R2 Wasserstoff, C1-C6-Alkyl, C3-C7-Cycloalkyl oder (Phenyl) C0-C2-Alkyl ist; oder R1 und R2 miteinander verbunden sind, um einen 5- bis 7-gliedrigen Heterocycloalkylring mit 0 oder 1 zusätzlichem Heteroatomen zu bilden, die ausgewählt sind aus N, O und S, welcher 5- bis 7-gliedrige Heterocycloalkylring optional an Phenyl oder Pyridyl kondensiert ist; welcher 5- bis 7-gliedrige Heterocycloalkylring unsubstituiert oder substituiert

ist mit einem oder mehreren Substituenten, die unabhängig ausgewählt sind aus Halogen, Hydroxyl, C1-C2-Alkyl 45 und C1-C2-Alkoxy; R3 Wasserstoff oder C1-C2-Alkyl ist; R5 Halogen, Hydroxyl, Amino, Cyano, Vinyl, Cyclopropyl, Cyclopropylidenyl, C 1-C4-Alkyl, C1C4-Alkoxy, Difluorme- thyl, Trifluormethyl oder Phenyl ist;

R6 Wasserstoff, Halogen, Hydroxyl, C1-C4-Alkyl oder C1-C4-Alkoxy ist; und 50 R7 Halogen, Hydroxyl, Amino, Cyano, C1-C4-Alkyl, C1-C4-Alkoxy, Difluormethyl oder Trifluormethyl ist oder R7 Phenyl oder ein 5- bis 7-gliedriger Heterocycloalkylring mit 1 oder 2 Heteroatomen ist, die ausgewählt sind aus N, O und S, wobei jedes von 7R über eine kovalente Bindung oder über eine C1-C4-Alkyl-, C1C4-Alkoxy- oder C1-C4-Alkylaminogruppe direkt verbunden ist und wobei jedes von R 7 unsubstituiert oder substituiert ist mit 1 bis 3 Substituenten, die unabhängig ausgewählt sind aus Halogen, Hydroxyl, C 1-C4-Alkyl, C1-C4-Alkoxy, (Mono- und Di- 55 C1-C2-Alkylamino) C0-C4-Alkyl, C1-C2-Haloalkyl und C1-C2-Haloalkoxy, oder R6 und R7 zusammen genommen sind, um einen 5- oder 6-gliedrigen carbocyclischen Ring ohne zusätzliche Sät- tigungspunkte zu bilden, welcher Ring unsubstituiert oder substituiert ist mit 1 bis 3 Substituenten, die unabhängig ausgewählt sind aus C1-C2-Alkyl und C1-C2-Alkoxy,

62 EP 2 649 075 B1

wobei R1 nicht unsubstituiertes Phenyl, Dihydroindenyl, Benz[b][1,4]dioxolyl, Benz[d][1,3]dioxol-5-yl, Cyclohexyl, Pyridyl oder Phenyl ist, substituiert mit 1 oder 2 Substituenten, die unabhängig ausgewählt sind aus Chlor, Fluor, C1-C4-Alkyl, C1-C2-Alkoxy, Acetyl, Trifluormethyl, wenn R 6 Wasserstoff ist, R 5 und R7 beide Methyl sind oder wenn R6 Wasserstoff ist und eines von R5 und R7 Methyl ist und das andere Phenyl ist; und R1 nicht 1-(4-Fluorbenzyl)- 5 1H-pyrazol-4-yl ist, wenn R6 Wasserstoff ist und eines von R 5 und R7 Methyl ist und das andere Phenyl ist.

Revendications

10 1. Composition pharmaceutique comprenant un composé de la formule

ou un de ses sels pharmaceutiquement acceptables conjointement avec un support pharmaceutiquement acceptable, 25 où l’une des conditions (a) et (b) ci-dessous est satisfaite :

(a) R1 représente un groupe phényle, naphtyle, tétrahydronaphtyle ou dihydroindényle, chacun étant non subs- titué ou substitué par un ou plusieurs substituant(s) indépendamment choisi(s) parmi un atome d’halogène, des groupes hydroxyle, cyano, nitro, amino, -CHO, -COOH, alkyle en C 1 à C6, alcényle en C2 à C6, alcynyle en C2 30 à C6, alcanoyle en C2 à C6, mono- ou dialkylamino en C1 à C6, mono- ou dialkylcarboxamide en C1 à C6, alkylthio en C1 à C6, alkylsulfonyle en C1 à C6, halogénoalkyle en C1 et C2 et halogénoalcoxy en C1 et C2, et avec 0 ou 1 substituant choisi parmi Y-Z- où Z représente une liaison covalente, un groupe alkylène en C1 à C4, -S-, -O-, -NR-, -C(O)-, - NHC(O)- ou -C(O)NH-, où R représente un atome d’hydrogène ou un groupe alkyle en C1 à C4, et Y représente un groupe phényle ou pyridyle, chacun étant non substitué ou substitué par 1 à 3 35 substituant(s) indépendamment choisi(s) parmi un atome d’halogène, des groupes hydroxyle, cyano, nitro, amino, alkyle en C1 à C4 et alcoxy en C1 à C4 ; ou (b) R 1 représente un groupe cyclohexyle, substitué par au moins un groupe trifluorométhyle ou alkyle en C 3 à C 6 ;

R2 représente un atome d’hydrogène ou un groupe méthyle ; 40 R3 représente un atome d’hydrogène ; R5 et R7 représentent tous deux un groupe méthyle ; ou l’un de R5 et R7 représente un groupe méthyle et l’autre représente un groupe phényle ; ou l’un de R5 et R7 représente un groupe méthyle et l’autre représente un groupe difluorométhyle ;

R6 représente un atome d’hydrogène, un atome d’halogène, un groupe hydroxyle, alkyle en C1 à C4 ou alcoxy en 45 C1 à C4; et où R1 ne représente pas un groupe phényle non substitué, dihydroindényle ou phényle substitué par 1 ou 2 substituant(s) indépendamment choisi(s) parmi des groupes chloro, fluoro, alkyle en C 1 à C 4, acétyle, et trifluorométhyle, (1) lorsque R6 représente un atome d’hydrogène, et R5 et R7 représentent tous deux un groupe méthyle, ou (2) lorsque R6 représente un atome d’hydrogène et l’un de R 5 et R 7 représente un groupe méthyle et l’autre représente 50 un groupe phényle.

2. Composition pharmaceutique de la revendication 1, dans laquelle R 3 et R6 représentent tous deux un atome d’hy- drogène.

55 3. Composition pharmaceutique de l’une quelconque des revendications 1 et 2, dans laquelle R 1 représente un groupe phényle, naphtyle, tétrahydronaphtyle ou dihydroindényle, qui est non substitué ou substitué par un ou plusieurs substituant(s) indépendamment choisi(s) parmi un atome d’halogène, des groupes hydroxyle, cyano, nitro, amino,

-CHO, -COOH, alkyle en C1 à C6, alcanoyle en C2 à C6, mono- ou dialkylamino en C1 à C6, mono- ou dialkylcar-

63 EP 2 649 075 B1

boxamide en C1 à C6, alkylthio en C 1 à C6, alkylsulfonyle en C1 à C6, halogénoalkyle en C 1 et C 2 et halogénoalcoxy en C1 et C2, et avec 0 ou 1 substituant choisi parmi Y-Z- où Z représente une liaison covalente, un groupe alkylène en C1 à C4, -S-, -O-, -NR-, -C(O)-, -NHC(O)- ou -C(O)NH-, où R représente un atome d’hydrogène ou un groupe alkyle en C1 à C4, et Y représente un groupe phényle ou pyridyle, chacun étant non substitué ou substitué par 1 à 5 3 substituant(s) indépendamment choisi(s) parmi un atome d’halogène, des groupes hydroxyle, cyano, nitro, amino,

alkyle en C1 à C4 et alcoxy en C1 à C4.

4. Composé ou un de ses sels pharmaceutiquement acceptables, dans lequel le composé est :

10 le N-(4-éthynylphényl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(4-bromophényl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le 5,7-diméthyl-N-(2-(phénylthio)phényl)pyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(4-cyanophényl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(4-tert-butylcyclohexyl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; 15 le N-(4-tert-butylcyclohexyl)-5-méthyl-7-phénylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(3-cyanophényl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le 5,7-diméthyl-N-(4-(méthylsulfonyl)phényl)pyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(2-acétamidophényl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(4-acétamidophényl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; 20 le 5-méthyl-7-phényl-N-(2-(phénylthio)phényl)pyrazolo[1,5-a]pyrimidine-3-carboxamide ; le 7-(difluorométhyl)-5-méthyl-N-p-tolylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le 7-(difluorométhyl)-N-(4-éthylphényl)-5-méthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le 7-(difluorométhyl)-5-méthyl-N-(4-(trifluorométhyl)phényl)pyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(3,4-dichlorophényl)-7-(difluorométhyl)-5-méthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; 25 le 7-(difluorométhyl)-N-(4-éthynylphényl)-5-méthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(4-tert-butylcyclohexyl)-5-(difluorométhyl)-7-méthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(3-(diméthylamino)phényl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(4-(diméthylamino)phényl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(4-bromophényl)-5,7-diméthylpyrazolo[1,5-a]pyrimidme-3-carboxamide ; 30 le N-(4’-cyanobiphényl-4-yl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(3’-méthoxybiphényl-4-yl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(3’-cyanobiphényl-4-yl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(4’-(diméthylamino)biphényl-4-yl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(4’-méthoxybiphényl-4-yl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; 35 le N-(3’-(diméthylamino)biphényl-4-yl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(4-iodophényl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(3-bromophényl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(4’-méthoxybiphényl-3-yl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(4’-cyanobiphényl-3-yl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; 40 le N-(3’-méthoxybiphényl-3-yl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(4’-(diméthylamino)biphényl-3-yl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(3’-(diméthylamino)biphényl-3-yl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide ; le 5,7-diméthyl-N-(3-(pyrimidine-5-yl)phényl)pyrazolo[1,5-a]pyrimidine-3-carboxamide ; le N-(3’-cyanobiphényl-3-yl)-5,7-diméthylpyrazolo[1,5-a]pyrimidine-3-carboxamide. 45 5. Composé de la revendication 4, dans lequel le composé est le N-(4-éthynylphényl)-5,7-diméthylpyrazolo[1,5-a] pyrimidine-3-carboxamide.

6. Composition pharmaceutique de l’une quelconque des revendications 1 à 3, ou composition pharmaceutique com- 50 prenant le composé de la revendication 4 ou 5 ou un de ses sels conjointement avec un support pharmaceutiquement acceptable, où la composition se présente facultativement sous une forme galénique orale.

7. Composé de la Formule (I) ou un de ses sels pharmaceutiquement acceptables pour une utilisation dans le traitement de la maladie de Gaucher chez un patient ou la prévention des symptômes de la maladie de Gaucher chez un 55 patient présentant une mutation du gène GBA, où la Formule (I) est :

64 EP 2 649 075 B1

où le noyau

est un système cyclique de la formule 25 (i)

où R5 représente un groupe alkylidène facultativement substitué et R6 et R7 sont conformes aux définitions énoncées ci-dessous, ou (ii) 40

50 où R5, R6 et R7 sont conformes aux définitions énoncées ci-dessous ;

R1 représente un groupe alkyle en C1 à C6, alcényle en C2 à C6, alcynyle en C2 à C6, (carbocycle mono- ou bicyclique)alkyle en C0 à C4 ou (hétérocycle mono- ou bicyclique)alkyle en C 0 à C4, chaque R1 étant non substitué ou substitué par un ou plusieurs substituant(s) indépendamment choisi(s) parmi un atome d’halogène, des groupes 55 hydroxyle, cyano, nitro, amino, -CHO, -COOH, alkyle en C 1 à C6, alcényle en C2 à C6, alcynyle en C2 à C6, alcoxy en C 1 à C 6, alcanoyle en C 2 à C 6, (mono- ou dialkylamino en C 1 à C 6)alkyle en C 0 à C 4, mono- ou dialkylcarboxamide en C1 à C6, alkylester en C1 à C6, alkylthio en C1 à C6, alkylsulfonyle en C1 à C6, halogénoalkyle en C1 et C2 et halogénoalcoxy en C 1 et C2, et avec 0 ou 1 substituant choisi parmi Y-Z- où Z représente une liaison covalente, un

65 EP 2 649 075 B1

groupe alkylène en C 1 à C4, -S-, -O-, -NR-, -C(O)-, - NHC(O)- ou -C(O)NH-, où R représente un atome d’hydrogène ou un groupe alkyle en C1 à C4, et Y représente un groupe phényle, pyrimidinyle, hétérocycloalkyle pentagonal ou hexagonal ou pyridyle, chacun étant substitué par 0 à 3 substituants indépendamment choisis parmi un atome d’halogène, des groupes hydroxyle, cyano, nitro, amino, alkyle en C 1 à C 4, alcoxy en C 1 à C 4, mono- et dialkylamino 5 en C1 à C4, trifluorométhyle, difluorométhyle, trifluorométhoxy et phényle ; R2 représente un atome d’hydrogène, un groupe alkyle en C 1 à C6, cycloalkyle en C 3 à C7, ou (phényl)alkyle en C 0 à C2; ou R1 et R2 sont réunis pour former un noyau hétérocycloalkyle pentagonal à heptagonal ayant 0 ou 1 hétéroatome supplémentaire choisi parmi des atomes N, O et S, lequel noyau hétérocycloalkyle pentagonal à heptagonal est 10 facultativement condensé à un phényle ou un pyridyle ; lequel noyau hétérocycloalkyle pentagonal à heptagonal est non substitué ou substitué par un ou plusieurs substituant(s) indépendamment choisi(s) parmi un atome d’halogè-

ne, des groupes hydroxyle, alkyle en C 1 et C2 et alcoxy en C1 et C2; R3 représente un atome d’hydrogène ou un groupe alkyle en C 1 et C2; R5 représente un atome d’halogène, un groupe hydroxyle, amino, cyano, vinyle, cyclopropyle, cyclopropylidényle, 15 alkyle en C1 à C4, alcoxy en C1 à C4, difluorométhyle, trifluorométhyle ou phényle ; R6 représente un atome d’hydrogène, un atome d’halogène, un groupe hydroxyle, alkyle en C1 à C4 ou alcoxy en C1 à C4; et R7 représente un atome d’halogène, un groupe hydroxyle, amino, cyano, alkyle en 1C à C4, alcoxy en C1 à C4, difluorométhyle ou trifluorométhyle, ou 20 R7 représente un groupe phényle ou un noyau hétérocycloalkyle pentagonal à heptagonal ayant 1 ou 2 hétéroato- me(s) choisi(s) parmi des atomes N, O et S, chaque R 7 étant directement lié par une liaison covalente ou lié par un groupe alkyle en C 1 à C 4, alcoxy en C 1 à C 4 ou alkylamino en C 1 à C 4, et chaque R 7 étant non substitué ou substitué par 1 à 3 substituant(s) indépendamment choisi(s) parmi un atome d’halogène, des groupes hydroxyle, alkyle en

C1 à C4, alcoxy en C1 à C4, (mono- et dialkylamino en C1 et C2)alkyle en C0 à C4, halogénoalkyle en C1 et C2, et 25 halogénoalcoxy en C1 et C2; ou R6 et R 7 sont pris ensemble pour former un noyau carbocyclique pentagonal ou hexagonal sans points d’insaturation additionnels, lequel noyau est non substitué ou substitué par 1 à 3 substituant(s) indépendamment choisi(s) parmi des groupes alkyle en C1 et C2 et alcoxy en C1 et C2, où R1 ne représente pas un groupe phényle non substitué, dihydroindényle, benzo[b][1,4]dioxolyle, benzo[d][1,3] 30 dioxol-5-yle, cyclohexyle, pyridyle ou phényle substitué par 1 ou 2 substituant(s) indépendamment choisi(s) parmi

des groupes chloro, fluoro, alkyle en C1 à C4, alcoxy en C1 et C2, acétyle, trifluorométhyle, lorsque R6 représente un atome d’hydrogène, R5 et R7 représentent tous deux un groupe méthyle, ou lorsque R6 représente un atome d’hydrogène et l’un de R 5 et R7 représente un groupe méthyle et l’autre représente un groupe phényle ; et R 1 n’est pas le 1-(4-fluorobenzyl)-1H-pyrazol-4-yle lorsque R 6 représenteun atome d’hydrogène et l’unde R 5et R 7 représente 35 un groupe méthyle et l’autre représente un groupe phényle.

66 EP 2 649 075 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• WO 2009152083 A1 [0004] • WO 2008134035 A [0082]

Non-patent literature cited in the description

• S. P. PARKER. Dictionary of Chemical Terms. Mc- • Remington’s Pharmaceutical Sciences. Mack Pub- Graw-Hill Book Company, 1984 [0054] lishing Company, 1985, 1418 [0057] • ELIEL, E. ; WILEN, S. Stereochemistry of Organic • HUPPATZ, J. L. Aust. J. Chem., 1985, vol. 38, Compounds. John Wiley & Sons, Inc, 1994 [0054] 221-230 [0082]