ATTACHMENT A
`
`

`

`3746.008PCOl/TJS/THN
`
`1.
`
`A compound of formula (I):
`
`MARKED-UP CLAIMS
`
`NH2
`
`NHJMk
`
`5
`
`or a pharmaceutically acceptable salt or solvate thereof, wherein
`
`A1, A2, and A3 are each independently selected from the group consisting of N, CH
`
`and C(R4), provided that at least one of A1, A2, or A3 is N,
`
`with the proviso that no more than two of A1, A2, or A3 is N,
`
`each R4 is independently selected from the group consisting of halogen, -C1-4 alkyl,
`
`10
`
`-C1_4 alkoxy, and -CN,
`
`11 is l or 2, wherein the alkylene chain can be optionally substituted with one or more
`
`-C1-4 alkyl groups,
`
`R1 is selected from the group consisting of -C1-4 alkyl, -C3-10 cycloalkyl, -C1-4 alkyl-
`
`C3-10 cycloalkyl, -C6.10 aryl, -C1-4 alkyl-C6-10 aryl, -(5- to lO-membered)-C1-9 heteroaryl, -C1.4
`
`15
`
`alkyl-(S- to lO-membered)—C1.9 heteroaryl, -(5- to lO-membered)-C2.9 heterocyclyl,
`
`alkyl-(S- to lO-membered)-C2.9 heterocyclyl, and —C(=O)Ra, wherein said “C144”alkyl, M
`
`-C1-4
`
`cycloalkyl,
`
`£211.} alkylfiflgmcycloalkyl, £16,}0maryl, £1,4malkylggédnwaryl, 45' R)
`
`memberedleflflheteroaryl, "CH alkylue’Su to lfiumemberedlelng heteroaryl, "(5“ to 10—
`
`if)—
`
`memberedMCifimheterocyclyl and fiflmalkyln‘fi— to lO—membered —Cgug_heterocyclyl groups
`
`
`20
`
`are optionally substituted with l, 2 or 3 substituents each independently selected from the
`
`group
`
`consisting
`
`of
`
`halogen,
`
`hydroxy,
`
`7
`
`-CN
`
`-ORb,
`
`-SRb,
`
`-N(Rb)2,
`
`-C1-4 alkyl optionally substituted with l, 2, or 3 halogen atoms, optionally
`
`substituted -C6-10 aryl, optionally substituted -(5- to lO-membered)-C1.9 heteroaryl, -(5- to 10-
`
`

`

`3746.008PCOl/TJS/THN
`
`
`
`
`from the group consisting of halogen,
`"OH. CE alkoxycarbonyl. hydrexycarbany!,
`
`
`carbamrwl $10,; JCN ~13 1:} aliwl
`
`
`
`alkaxy o itionaily substituted by one or more halo'rcn atoms and C14 h rdroxvalkyl ‘rrou is
`
`
`
`
`and wherein the national substitumis in said nationally substituted 45— to N)—
`
`
`
`memberedlfilfl heteroarvl are selected from 1. 2 or 3 substituents which can he the same or
`
`
`
`
`ditteront selected from the grou; consisting of haloven CM alkoxycarbonyl carbaniovl
`w
`
`
`
`
`N02. w(IE-i 431.4
`
`
`
`
`allng u itionaliv substituted by one or more halogen atoms and {71-4 alkexy
`
`10
`
`7
`o ationallv substituted by one or more halogen atoms
`
`
`
`and wherein said “C3- ji)_CYCloalky1, :5;
`
`:_{;§_:____tg_____1..9.:mmb_e_te§;)_:{;_r_-_g
`
`_4.____a1ky1._—_é1_3_:;_g_____cycloalkyl, in_____aryl, it_____alkylzflsnmwaryl,
`
`
`
`heteroaryl, “Cflmalkylm 5» to 'l0wmcntberedlCt lOwineniheredluCz-9 ”
`
`
`
`heterocyclyl and £1____,_Lalkyl— S
`
`further (second) ring, and
`
`15
`
`R2 is selected from the group consisting of hydrogen, -C1-4 alkyl, and -C3-6 cycloalkyl,
`
`wherein said -C1-4 alkyl is optionally substituted with —O(C1.4)alkyl optionally substituted
`
`with —O(C1-4)NH2, hydroxy, -CN, halogen, or -N(Rb)2, or
`
`R1 and R2 together with the nitrogen atom to which they are attached form an
`
`20
`
`I
`
`I
`
`optionally substituted 5- to lO-membered heterocyclic ring, wherein said 5— to lfJ—inemberod
`heterocyclic ring optionally contains 1, 2, or 3 additional heteroatoms selected from the
`group consisting of N, S, or O, and wherein said in to lilunieinbered heterocyclic ring is
`optionally fused to a phenyl ring,
`
`Ra is selected from the group consisting of -C1-4 alkyl, -C3_10 cycloalkyl, -C1_4 alkyl-
`
`C340 cycloalkyl, -C6.10 aryl, -C1-4 alkyl-C6-10 aryl, -(5- to lO-membered)-C1-9 heteroaryl, -C1.4
`
`25
`
`alkyl-(S- to 10-membered)-C1-9 heteroaryl, -(5- to lO-membered)-C2.9 heterocyclyl, and -C1-4
`
`alkyl-(S- to lO-membered)-C2-9 heterocyclyl, wherein said mfilkyl, Mcycloalkyl, gm
`
`alkylfiw'cycloalkyl, Maryl, ilfl'alkylfiflaryl, ~55— ‘Lo l0~meniberedl~€3 1-9 heteroaryl,
`
`£fi_alkyl“
`
`
`
` Sm to 'EOnnemheredluCflnheteroaryl, "'5" to lfiumembered ~C Ewheterocyclyl and
`
`Lgflwalkyl-{fi to l{Linwithered'3—Cgfgwheterocyclyl groups are optionally substituted with l, 2
`
`

`

`3746.008PCOl/TJS/THN
`
`or 3 substituents each independently selected from the group consisting of halogen, hydroxy,
`
`-CN,
`
`-ORb, -SRb, -N(Rb)2, -C1-4 alkyl optionally substituted with l, 2, or 3 halogen atoms,
`
`optionally substituted -C6-10 aryl, optionally substituted -(5- to lO-membered)—C1.9 heteroaryl,
`
`and -(5- to lO-membered)—C2-9 heterocyclyl;
`
`wherein the o itional Substituents in said o1tio11aliv substituted £6.11) 21
`
`
`
`
`
`'3 are seieeted
`
`1710111
`
`,1
`
`1 01 3 wubsutuent» 11117111111 can be the same or different selected 11011; the 010111
`
`
`
`
`substituted by one 1'31 111011—13 halogen 2111311191 and C111 bvdrosvaliogl; and
`
`10
`
`wherein the eational substituents in said mtionallv substituted 35— te lO~men1be1‘ed"—
`
`
`
`substituted by one or more halogen atoms,
`
`15
`
`and wherein said C1A1cycloalkyl, 1~C1AalkylCA11_cycloalkyl, —C1A11a,ryl C11._1alkyl~
`
`
`
`‘5 ~
`
`
`
`heteroaryl, ~ 5 to it)inen1be1ed‘;C 9Aheterocyclyl and 1C1alkyl" '5’? to lOmmen‘ibetedt—CM
`
`
`
`to lilmembeted ~C1.9_"heteroaryl, £1141malkyl~ ~
`
`to l0~membetedt~€ifi
`
`heterocyclyl1s optionally fused to a further (second) ring,
`
`each Rb is independently hydrogen,
`
`-C1-1 alkyl,
`
`-C3_10 cycloalkyl, or -(5- to 10-
`
`20
`
`membered)-C2-9 heterocyclyl, wherein said —C.1_____““1alkyl, C_3__.__1_g_cycloalkyl or ~§S~ to lO~
`
`membered‘gqunheterocyclyl group is optionally substituted by l, 2 or 3 fluorine atoms, and
`
`-(5- to lO-membered)-C1-9
`R3 is selected from the group consisting of -C6-10 aryl,
`heteroaryl, -C3-10 cycloalkyl, and -(5- to lO-membered)—C2.9 heterocyclyl, wherein said 1:516 G
`
`aryl, ~53 te lOunernbered‘yCfluheteroaryl, :CwLAigucycloalkyl, and ~( 5" to lgnl‘ilffiiflbCIGd‘FCAg
`
`25
`
`heterocyclyl groups are optionally substituted with l, 2 or 3 substituents each independently
`
`selected from the group consisting of halogen, hydroxy, -CN, -ORb, -SRb, -N(Rb)2, -C1.
`
`4alkyl optionally substituted with l, 2, or 3 substituents each independently selected from the
`
`group consisting of halogen, -CN, -ORb, and -N(Rb)2, optionally substituted -C6.10 aryl,
`
`

`

`3746.008PCOl/TJS/THN
`
`optionally substituted -(5- to lO-membered)-C1-9 heteroaryl and -(5- to lO-membered)-C2.9
`
`heterocyclyl;
`
`wherein the optimal substituents in said optionally substituted "Ci aryl are selected
`
`from 3
`2; or 3 substitumts winch can he the same or different. selected from the Ui‘OU
`
`5
`
`eonsisting of halogen: “0H (71.4
`
`
`
`
`
`ailmx *car‘hon fl; lwdrox carbon '1; carbamevL mNC‘; “CM. _
`
`
`
`the}; 2
`
`
`
`QM alk’l o tionall" substituted by one or more halogen atoms; «CT-i4 a
`
`:3 3h emails;
`
`
`
`
`
`
`
`
`
`
`
`substituted h ; we or more halooen atoms and C121 h IdE'mvalR’vl vrou vs and
`
`wherein the o tienal substituents in said 0 tionall ' substituted —"5— to lO—nrembered w
`.3
`{21-9 heteroar ii are selected from 1 g. or '3 su‘l’ss‘tititrents which can he the same or different
`
`
`
`
`10
`
`1 5
`
`
`
`selected from the (Iron censistino ofhaloven CM alkomcarbonyl. carhan‘rovl. ~NO; —OH. ~
`
`
`
`1;?1.:r...e.l19:1."emigre1.35::__snhstitrgtéiri..htrzerreer‘._r11.ereuhehégert__eterh_§,___ahri_.rtltgzrrtilrmsfii._a'2t1ti_erzethi
`
`substituted h ' me or more halogen atoms; and
`
`
`
`
`
`
`2.
`
`The compound of claim 1;
`
`or a pharmaceutically acceptable salt or solvate thereof, wherein
`
`20
`
`A1; A2; and A3 are each independently selected from the group consisting of N; CH
`
`and C(R4); provided that at least one of A1; A2; or A3 is N;
`
`with the proviso that no more than two of A1; A2; or A3 is N;
`
`each R4 is independently selected from the group consisting of halogen, -C1-4 alkyl;
`
`-C1-4 alkoxy; and -CN;
`
`25
`
`n is l or 2;
`
`R1 is selected from the group consisting of -C1-4 alkyl; -C3-10 cycloalkyl; -C1-4 alkyl-
`
`C340 cycloalkyl; -C6.10 aryl; -C1-4 alkyl-C6-10 aryl; -(5- to lO-membered)-C1-9 heteroaryl; -C1.4
`
`

`

`3746.008PCOl/TJS/THN
`
`alkyl-(S- to lO-membered)—C1.9 heteroaryl, -(5- to lO-membered)-C2.9 heterocyclyl,
`
`alkyl-(S- to lO-membered)-C2.9 heterocyclyl, and —C(=O)Ra, wherein said {31.4 alkyl, 4:33-10
`
`"(3.5-10 aryl, "CE alkyluCfl aryl,
`_(5~ to §O~
`
`cycloalkyl, £fl~alkyl£m_cycloalkyl,
`
`-C1-4
`
`nmmhered“—C_1_Tgmheteroaryl, Li;1__._,;;Fualkyl~£‘5~ to 10~memhered—C_1_Tg_uheteroaryl,
`
`
`
`
`~(S— to 10—
`
`memberedlegwheterocyclyl and fiflfialkylu'fiu to lOumembered "Cg-g_heterocyclyl groups
`
`
`are optionally substituted with l, 2 or 3 substituents each independently selected from the
`
`group
`
`consisting
`
`of
`
`halogen,
`
`hydroxy,
`
`-CN,
`
`-ORb,
`
`-SRb,
`
`-N(Rb)2,
`
`-C1-4 alkyl optionally substituted with l, 2, or 3 halogen atoms, optionally
`
`substituted -C6-10 aryl, optionally substituted -(5- to lO-membered)-C1.9 heteroaryl, and -(5-
`
`to lO-membered)—C2-9 heterocyclyl wherein the o tional substituents in said mtionallv
`
`Silb’étlmmd"(:53.:.E51..54.1261..5.1.11.El...5563.3.3....Ql'fli911%}.131’."fiiflzfli’fli’ffifi_____r.(i:__;i_9;___3_§3:13;1_siznhgirszdlzfli.:2..l;1.s:;t§_rgary.'l
`
`7 m...
`M
`are as defined in ciaim l, and wherein said ~Cg-;g_cycloalkyl 431-4 alkyligflcycloalkyl, “Ci
`
`lguaryl, Li;1__._,;;Palkyl;§;(§_._1_g.’_aryl, ~i5~ to lO—memberedlvfjLigflheteroaryl, $1;_._1_4__~alkyl—§5~ to 1(—
`
`memberedhffigheteroaryl, 4’5" to 'E 0~rnembered‘suCEFheterocyclyl and 1Q_4Falkyl_§ 5~ to 10“
`
`memberecl‘:~C;.E_heterocyclyl is optionally fused to a further (second) ring, and
`
`R2 is hydrogen or -C1.4 alkyl, or
`
`R1 and R2 together with the nitrogen atom to which they are attached form an
`
`optionally substituted 5- to lO-membered heterocyclic ring, wherein said 5- to l0~membered
`
`heterocyclic ring optionally contains 1, 2, or 3 additional heteroatoms selected from the
`
`group consisting of N, S, or O, and wherein said 5~ to l{3=~membered heterocyclic ring is
`
`optionally fused to a phenyl ring,
`
`Ra is selected from the group consisting of -C1-4 alkyl, -C3-10 cycloalkyl, -C1-4 alkyl-
`
`C340 cycloalkyl, -C6.10 aryl, -C1-4 alkyl-C6-10 aryl, -(5- to lO-membered)-C1-9 heteroaryl, -C1.4
`
`alkyl-(S- to lO-membered)-C1-9 heteroaryl,- (5- to lO-membered)-C2.9 heterocyclyl, and -C1-4
`
`alkyl-(S- to lO-membered)-C2-9 heterocyclyl, wherein said MHaIkyl, Mcycloalkyl, "—514";
`
`10
`
`15
`
`20
`
`25
`
`alkylMcycloalkyl, Mfiryl, £5”all<yl;§;.g,__1_g~aryl, ~ '5“ to lO—inembered‘sz j“;- heteroaryl,
`
`4:31“; alkyl—
`
`IG—membered ~{I72_9“heterocyclyl and
`
`
`‘S~ to l0~mem'l’seredl—C1.9 heteroaryl, ~5‘
`
`
`
`:fllliualky1ugsw to lDamembered‘zuCflwheterocyclyl groups are optionally substituted with l, 2
`
`or 3 substituents each independently selected from the group consisting of halogen, hydroxy,
`
`

`

`3746.008PCOl/TJS/THN
`
`-CN,
`
`-ORb, -SRb, -N(Rb)2, -Ci-4 alkyl optionally substituted with l, 2, or 3 halogen atoms,
`
`optionally substituted -C6-10 aryl, optionally substituted -(5- to lO-membered)—C1.9 heteroaryl,
`
`to lO-membered)-C2-9 heterocyclyl, wherein the optional substituents in said
`
`and -(5-
`
`o tionally substituted {76-10 arvl and — S~ to lO~memberedI —C 1-9 heteroaryl are as defined in
`
`
`
`
`
`
`heteroaryl, _ S~ to lO~membered3 —Cl.g_heterocyclyl and fififlalkyl— 5- to l0~memberedt 4137-0
`
`heterocyclyl is optionally fused to a further (second) ring,
`
`each Rb is independently hydrogen,
`
`-C1-4 alkyl,
`
`-C3-10 cycloalkyl, or -(5- to 10-
`
`10
`
`membered)-C2-9 heterocyclyl, wherein said ;_C‘;&__4__alkyl, 1941;“cycloalkyl or {S— to 10—
`
`R3 is -C6.10 aryl or -(5- to lO-membered)-C1.9 heteroaryl, wherein said fimaryl or ;
`
`(5— to lO—memberedtvfjt_._9#heteroaryl group is optionally substituted with l, 2 or 3 substituents
`
`each independently selected from the group consisting of halogen, hydroxy, -CN, -ORb, -
`
`15
`
`SRb,
`
`-N(Rb)2,
`
`-C1-4alkyl optionally substituted with l, 2, or
`
`3
`
`substituents each
`
`independently selected from the group consisting of halogen, -CN, -ORb, and -N(Rb)2,
`
`optionally substituted -C6-10 aryl, optionally substituted -(5- to lO-membered)-C1.9 heteroaryl
`
`and -(5-
`
`
`to lO-membered)-C2-9 heterocyclyl. wherein the o tional substituents in said
`
`
`
`mtionallv substituted "Ce—10 and and m 5, to luminentbet‘etlE—C;-9 heteroar ’l are as defined in
`
`
`
`
`claim. 1 .
`
`
`
`3.
`
`The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof,
`
`wherein A1 is N and A2 and A3 are each independently selected from the group consisting of
`
`CH and C(R4).
`
`4.
`
`The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof,
`
`wherein A2 is N and A1 and A3 are each independently selected from the group consisting of
`
`CH and C(R4).
`
`20
`
`25
`
`

`

`3746.008PCOl/TJS/THN
`
`The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof,
`
`wherein A3 is N and A1 and A2 are each independently selected from the group consisting of
`
`CH and C(R4).
`
`The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof,
`
`wherein A1 and A2 are both N and A3 is CH or C(R4).
`
`The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof,
`
`wherein A1 and A3 are both N and A2 is CH or C(R4).
`
`The compound of claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof,
`
`wherein A2 and A3 are both N and A1 is CH or C(R4).
`
`The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate
`
`thereof, wherein n is l.
`
`10
`
`15
`
`10.
`
`The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate
`
`thereof, wherein n is 2.
`
`20
`
`ll.
`
`The compound of any one of claims 1-10, or a pharmaceutically acceptable salt or solvate
`
`thereof, wherein R3 is unsubstituted -C6.10 aryl or -C6-10 aryl substituted with l or 2
`
`substituents each independently selected from the group consisting of halogen, hydroxy,
`
`-CN, -O(C1-4)alkyl, -S(C1.4)alkyl, -N(C1-4 alkyl)2, -NH(C1-4 alkyl), and -C1-4 alkyl optionally
`
`substituted with l, 2, or 3 substituents each independently selected from the group consisting
`
`25
`
`of halogen, -CN, -O(C1.4)alkyl, -N(C1-4 alkyl)2, and -NH(C1_4 alkyl).
`
`12.
`
`The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate
`
`thereof, wherein R2 is H.
`
`

`

`3746.008PCOl/TJS/THN
`
`_ 8 _
`
`13.
`
`The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate
`
`thereof, wherein R2 is -C1_4 alkyl.
`
`14.
`
`The compound of any one of claims 1-11 or 13, or a pharmaceutically acceptable salt or
`
`5
`
`solvate thereof, wherein R2 is methyl.
`
`15.
`
`The compound of any one of claims 1-14, or a pharmaceutically acceptable salt or solvate
`
`thereof, wherein R1 is -C6-10 aryl or -C1-4 alkyl-C640 aryl, wherein said figfigfiryl or Lgfi
`
`alkylu{?5-m aryl is optionally substituted with 1, 2 or 3 groups each independently selected
`
`10
`
`from the group consisting of halogen, hydroxy, -CN, -ORb, -SRb, -N(Rb)2,
`
`-C1.4 alkyl
`
`optionally substituted with 1, 2, or 3 halogen atoms, optionally substituted -C6.10 aryl,
`
`optionally substituted -(5- to 10-membered)—C1.9 heteroaryl, and -(5- to 10-membered)-C2-9
`
`
`
`heterocyclyl, wherein Rb is as defined in claim 1. and wherein the o ationai substituents in
`
`said onionaliv substituted w
`
`
`
`
`
`CL“; agrl and
`
`"(Sn to iO~memberedé—Cfl heteroawl are as
`
`15
`
`defimd in claim 1.
`
`16.
`
`The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or solvate
`
`thereof, wherein Rb is hydrogen or -C1_4 alkyl.
`
`20
`
`17.
`
`The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate
`
`thereof, wherein R1 and R2 together with the nitrogen atom to which they are attached form
`
`an optionally substituted 5- to 10-membered heterocyclic ring, wherein said 5» to 19-
`
`membered heterocyclic ring optionally contains 1, 2, or 3 additional heteroatoms selected
`
`from the group consisting of N, S, or O, and wherein said 5— to 10~membered heterocyclic
`
`25
`
`ring is optionally fused to a phenyl ring.
`
`18.
`
`The compound of claim 17, or a pharmaceutically acceptable salt or solvate thereof, wherein
`
`R1 and R2 together with the nitrogen atom to which they are attached form a 5- or 6-
`
`membered ring optionally fused to a phenyl ring.
`
`30
`
`

`

`3746.008PCOl/TJS/THN
`
`19.
`
`The compound of claim 1, which is selected from the group consisting of
`
`N3;
`
`N3;
`
`7
`
`\ cwdnrl
`nod330
`@3330 @33*de
`
`Q/J'NOQVNJENKT
`
`NH2
`
`WU
`
`j
`
`H2”
`
`
`er and
`
`cacao
`
`, or a pharmaceutically acceptable salt or solvate thereof.
`
`10
`
`20.
`
`The compound of claim 1, which is selected from the group consisting of
`
`

`

`3746.008PC01/TJS/THN
`
`_ 10 _
`
`NH2
`
`NH2
`
`/ N
`
`|
`jNI
`EN:55;<3W3NN<3
`
`7
`
`<3NN5<3<33NN5<3
`
`NH2
`
`\0
`
`CN
`
`NH
`
`\0
`
`/O
`
`NJ§N
`I
`NMN
`H
`
`NJ§N
`I
`NM
`
`NJ§N
`
`NH2
`
`[NMN
`
`H
`
`0/
`
`©\/N NNJN—LN
`
`NH2
`
`NM”
`
`\0
`
`\
`
`NH2
`
`NH2
`
`NJ§N
`NkN
`QVNMMKEW @333”
`
`o
`
`

`

`3746.008PC01/TJS/THN
`
`_ 11 _
`
`CfiCgCfiC
`
`NH2
`OMe
`NH2
`CUC CECN
`
`0/
`
`:Uwmm CCC
`
`NH
`
`CwCC{ENCC::C
`
`W211:
`
`

`

`

`

`3746.008PCOl/TJS/THN
`
`Cuddly outflow
`dlfip (Judi/Eh
`(JVUKNNENQ QVUKWKP
`(Joli;0 Cum;QM
`
`,a-rmand
`
`pharmaceutically acceptable salt or solvate thereof.
`
`22.
`
`A compound selected from the group consisting of
`
`@wiNxNJ3 mmldm
`
`NH2
`NJ§N
`
`,ora
`
`10
`
`pharmaceutically acceptable salt or solvate thereof.
`
`23.
`
`A pharmaceutical composition, comprising an effective amount of a compound of any one of
`
`claims 1-22, or a pharmaceutically acceptable salt or solvate thereof, and at least one
`
`pharmaceutically acceptable excipient.
`
`15
`
`24.
`
`A method of treating or preventing a lysosomal storage disease, comprising administering to
`
`a patient in need thereof an effective amount of a compound of formula (I):
`
`

`

`3746.008PCOl/TJS/THN
`
`_ 14 _
`
`NH2
`A2J§A3
`2
`R1-|J\|‘HJLAAN’R3
`
`”
`
`(I),
`
`IH
`
`or a pharmaceutically acceptable salt or solvate thereof, wherein
`
`A1, A2, and A3 are each independently selected from the group consisting of N, CH
`
`5
`
`and C(R4), provided that at least one of A1, A2, or A3 is N,
`
`each R4 is independent selected from the group consisting of halogen, -C1-4 alkyl,
`
`10
`
`15
`
`20
`
`-C1_4 alkoxy, and -CN,
`
`11 is l or 2, wherein the alkylene chain can be optionally substituted with one or more
`
`-C1-4 alkyl groups,
`
`R1 is selected from the group consisting of -C1-4 alkyl, -C3-10 cycloalkyl, -C1-4 alkyl-
`
`C340 cycloalkyl, -C6.10 aryl, -C1-4 alkyl-C6-10 aryl, -(5- to lO-membered)-C1-9 heteroaryl, -C1.4
`
`alkyl-(S- to lO-membered)—C1.9 heteroaryl, -(5- to lO-membered)-C2.9 heterocyclyl,
`
`-C1-4
`
`alkyl-(S- to lO-membered)-C2.9 heterocyclyl, and —C(=O)Ra, wherein said 12%;}alkyl, 2.941“
`
`cycloalkyl, Malkylgflchcloalkyl, fimmaryl, 331“”alkyliflmaryl,
`
`memberedMCngheteroaryl, 431-4 alkyln’S— to lO—membered‘sz 1-9 heteroaryl, {5— to 1‘0,—
`{pr
`
`~45— to it)—
`
`
`
`3~ to l{Linembered'3—Cgtg_heterocyclyl groupsmembered)~C_2__._9_mheterocyclyl and filflmalkyl—
`
`are optionally substituted with l, 2 or 3 substituents each independently selected from the
`
`group
`
`consisting
`
`of
`
`halogen,
`
`hydroxy,
`
`-CN,
`
`-ORb,
`
`-SRb,
`
`-N(Rb)2,
`
`-C1-4 alkyl optionally substituted with l, 2, or 3 halogen atoms, optionally
`
`substituted -C6-10 aryl, optionally substituted -(5- to lO-membered)-C1.9 heteroaryl, -(5- to 10-
`
`membered)-C2-9 heterocyclyl, and optionally substituted —O-(C6.10 aryl),
`
`wherein the o tional substituents; in said o3tionaliv
`
`
`
`
`
`substituted ngum and and ~04"ng
`
`
`
`are selected i’mm l. ’2. 01‘ 3 substituents which can be the same or different. selected
`
`
`frail“;
`
`
`
`{31.4 alkox‘v'earbonyi
`the amt:
`eonsistiniy of halogen mOH,
`hydromicarbom’l.
`
`
`
`25
`
`
`
`c-trbamovl 4N0: JCN 431,4. 31le o tionallv substituted by one or more halogen atoms
`
`
`
`~C in;
`
`

`

`3746.008PCOl/TJS/THN
`
`_ 15 _
`
`alkoxv o tionall ' substituted by one or more halogen atoms and C14 hydromialk ’l
`
`
`
`
`
`and
`
`
`wherein the optional su'lz‘stituents in said optionally substituted "(5“ to lfiunrembered}
`
`g;1:? heter
`
`
`
`
`nary} are selected from '1 2 or 3 substituents which can he the same or different
`
`
`
`
`consisting of halogen 0,4 alkoxvcarbcnvl. carbamo
`'3, are; "on, _
`
`
`
`
`
`
`£153 alkyl o tionallv substituted by one or more halrwen atoms and {71,4 alkoxz mtionallv
`; one or more haloaen atoms7
`
`
`
`
`
`
`selected from the
`
`sub sti tuted b
`
`and wherein said €3-13 cycloalkyl, —Cl-4_alkylnC3u;0_cycloalkyl, £131”aryl, —Cl,4_alkyl;
`
`{35-10 aryl,
`
`~65»— to lU~memberedlwiiflmheteroaryl,
`
`
`
`~€231-4“_alkyl—("5— to lb—membered {71,9
`
`
`
`10
`
`
`
` heteroaryl, 4'5" to lO~n1einbered "C2-g_heterocyclyl and fimalkylw’fi— to lO—meinbered 433.9
`
`heterocyclyl is optionally fused to a further (second) ring, and
`
`R2 is selected from the group consisting of hydrogen, -C1-4 alkyl, and -C3-6 cycloalkyl,
`
`wherein said -C1-4 alkyl is optionally substituted with —O(C1.4)alkyl optionally substituted
`
`with —O(C1-4)NH2, hydroxy, -CN, halogen, or -N(Rb)2, or
`
`15
`
`I
`
`I
`
`R1 and R2 together with the nitrogen atom to which they are attached form an
`optionally substituted 5- to lO-membered heterocyclic ring, wherein said 5~ to lilmembered
`heterocyclic ring optionally contains 1, 2, or 3 additional heteroatoms selected from the
`group consisting of N, S, or O, and wherein said 5— to l0~membered heterocyclic ring is
`optionally fused to a phenyl ring,
`
`20
`
`Ra is selected from the group consisting of -C1-4 alkyl, -C3-10 cycloalkyl, -C1-4 alkyl-
`
`C3-10 cycloalkyl, -C6.10 aryl, -C1-4 alkyl-C640 aryl, -(5- to lO-membered)-C1-9 heteroaryl, -C1.4
`
`alkyl-(S- to lO-membered)-C1-9 heteroaryl, -(5- to lO-membered)-C2.9 heterocyclyl, and -C1-4
`
`alkyl-(S- to lO-membered)-C2-9 heterocyclyl, wherein said £14”alkyl, Mpycloalkyl, :QM
`
`alkyllgflpycloalkyl, flwuaryl, fiflualkyllgflfiryl, — 5— to lfimnienibered"—Ci_.2_heteroaryl,
`
`25
`
`
`5- to l{I=—meml_>ered ~{I71-9“heteroaryl, JS~ to l0~memberedé~€w heterocyclyl and
`
`filwalkyla‘
`
`
`
`£41m;alkylwg’S— to lQuinembered‘rCflheterocyclyl groups are optionally substituted with l, 2
`
`or 3 substituents each independently selected from the group consisting of halogen, hydroxy,
`
`-CN,
`
`-ORb, -SRb, -N(Rb)2, -C1-4 alkyl optionally substituted with l, 2, or 3 halogen atoms,
`
`

`

`3746.008PCOl/TJS/THN
`
`_ 16 _
`
`optionally substituted -C6-10 aryl, optionally substituted -(5- to lO-membered)—C1-9 heteroaryl,
`
`and -(5- to lO-membered)—C2-9 heterocyclyl,
`
`wherein the optional substituents in said optionally substituted "Ci aryl are selected
`
`from l
`2- or 3 substituents wl'iich can be the same or different. selected from the ”1'01:
`
`5
`
`consisting of halogen: “0H {71.4
`
`
`
`
`
`
`ailmx carbon fl, hydrox carbon '1, carbamovi, mNC‘; “CM. _
`
`Elm}; 2 o ail onally
`
`
`
`
`{Cl-4 alk l o tionall' substituted by one or 11mm halogen atoms- ~C-:-4 a
`
`10
`
`
`
`(7-4511 aryl,
`
`{Sn to lOumeinberedhCL-gwheteroaryl, ui-.71-4;alkylu(15u to l0"membered {.77
`
`15
`
`heteroaryl, 4'5" to l0~nieinbered "CL-gfieterocyclyl and Lgflfilkylw’fi— to lO—membered mCifi-
`
`heterocyclyl is optionally fused to a further (second) ring,
`
`each Rb is independently hydrogen,
`
`-C1-4 alkyl,
`
`-C3-10 cycloalkyl, or -(5- to 10-
`
`membered)-C2-9 heterocyclyl, wherein said ~32-4a,lkyl {.73.1.3mcycloalkyl or 45— to ll)—
`
`memberedMCfiheterocyclyl group is optionally substituted by l, 2 or 3 fluorine atoms; and
`
`20
`
`R3 is selected from the group consisting of -C6-10 aryl,
`
`-(5- to lO-membered)-C1-9
`
`heteroaryl, -C3-10 cycloalkyl, and -(5- to lO-membered)—C2-9 heterocyclyl, wherein said M
`
`
`aryl, — 5— to l0~mem.bered3—C 19_,heteroaryl “(3,. 4c.cy,cloalkyl and — 5~ to lfirmernlmred“{72-9
`
`heterocyclyl groups are optionally substituted with l, 2 or 3 substituents each independently
`
`selected from the group consisting of halogen, hydroxy,
`
`-CN, -ORb, -SRb, -N(Rb)2, -C1-
`
`25
`
`4alkyl optionally substituted with l, 2, or 3 substituents each independently selected from the
`
`group consisting of halogen, -CN, -ORb, and -N(Rb)2, optionally substituted -C6-10 aryl,
`
`optionally substituted -(5- to lO-membered)-C1-9 heteroaryl and -(5- to lO-membered)-C2-9
`
`heterocyclyl,
`
`

`

`3746.008PCOl/TJS/THN
`
`_ 17 _
`
`wherein the mtional substituents in said 0 itionallv substituted 4344,44,» awl are selected
`
`
`
`
`
`from 1. 2 or 3 substituents which can he the same or different selected from the ‘
`
`
`consisting of halogen 43H C 4 4 alkoxyearbonvl hydroxyearbonyl caibamoyl "NO; {N u
`
`ll mtionalii substituted by one or more haltwen atoms
`44 alkox’” o tionailv
`
`
`
`£21.44 alk
`"C
`
`5
`
`s
`
`1 0
`
`1 5
`
`20
`
`
`
`5~ to lfiumemberedfiilm heterocyclyl is optionally fused to a further (second) ring.
`
`
`
`25.
`
`The method of claim 24, wherein the lysosomal storage disease is Gaucher’s disease.
`
`26.
`
`The method of claim 24 or 25, wherein A1, A2 and A3 are N.
`
`27.
`
`The method of claim 24 or 25, wherein the compound administered is as claimed in any one
`
`of claims 1-22.
`
`28.
`
`The method of claim 24 or 25, wherein the compound administered is selected from the
`
`group consisting of
`
`«Mpg {fied;W
`
`H2
`
`NAN
`
`m'l“ \NkN/Q/
`
`O
`
`//
`
`NAN
`
`'I“\)\\N' N/Q/ @VlN/AN
`
`

`

`3746.008PC01/TJS/THN
`
`_ 18 _
`
`NH2
`
`0
`
`N \N
`
`ONJN/ANU
`
`/\o N
`
`\N
`
`NJNAN
`
`or a pharmaceutically acceptable salt or solvate thereof.
`
`H
`
`and
`
`H
`
`29.
`
`
`A method of treatinv 01 11evmtmv a 1 sosomai stora re disease com arisinx administering to
`
`
`
` 21 alien? in need thereof an effective amount of a com mund '7 '
`
`
`
` ‘ selected from the group consisting of
`
`(DVNJNJNO CJVNJNAMO QVNNJfHNAN
`
`10
`
`N/
`
`“%N*N
`
`NH2
`
`EANJNAO €5ng F
`
`

`

`3746.008PCOl/TJS/THN
`
`-19-
`
`F
`
`gm *
`N
`I AN
`“ W H“©
`
`7
`
`Qt fl
`“ ”U
`
`N
`
`acceptable salt or solvate thereof.
`
`C', or a pharmaceutically
`
`30.
`
`31.
`
`The method of any one of claims 24-29, further comprising administering to the patient at
`
`least one other therapeutic agent.
`
`The method of claim 30, wherein the therapeutic agent is an effective amount of an enzyme
`
`for enzyme replacement therapy.
`
`10
`
`32.
`
`The method of claim 3 1, wherein the enzyme is B-glucocerebrosidase or an analog thereof.
`
`33.
`
`34.
`
`35.
`
`15
`
`The method of claim 32, wherein the enzyme is imiglucerase.
`
`The method of any one of claims 30-33, wherein the therapeutic agent is an effective amount
`
`of a small molecule chaperone.
`
`The method of claim 34, wherein the small molecule chaperone binds competitively to an
`
`enzyme.
`
`20
`
`36.
`
`The method of claims 34 or 35, wherein the small molecule chaperone is selected from the
`
`group
`
`consisting of
`
`iminoalditols,
`
`iminosugars,
`
`aminosugars,
`
`thiophenylglycosides,
`
`glycosidase, sulfatase, glycosyl transferase, phosphatase, and peptidase inhibitors.
`
`25
`
`37.
`
`38.
`
`The method of claim 36, wherein the small molecule chaperone is selected from the group
`
`consisting of isofagomine, N—nonyl-l-deoxynojirimycin (NN—DNJ), ambroxol, and miglustat.
`
`A compound as defined in any one of claims 1-22, or a pharmaceutically acceptable salt or
`
`solvate thereof, for use as a medicament.
`
`

`

`3746.008PCOl/TJS/THN
`
`_ 20 _
`
`39.
`
`A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use
`
`in the treatment or prevention of lysosomal storage disease, the compound of formula (I)
`
`having the structure:
`
`NH2
`A2J§A3
`2
`Rl'rl|\HJLAAN’R3
`
`n
`
`(I),
`
`|H
`
`5
`
`wherein
`
`A1, A2, and A3 are each independently selected from the group consisting of N, CH
`
`and C(R4), provided that at least one of A1, A2, or A3 is N,
`
`each R4 is independently selected from the group consisting of halogen, -C1-4 alkyl,
`
`-C1-4 alkoxy, and -CN,
`
`10
`
`n is l or 2, wherein the alkylene chain can be optionally substituted with one or more
`
`-C1_4 alkyl groups,
`
`R1 is selected from the group consisting of -C1-4 alkyl, -C3-10 cycloalkyl, -C1-4 alkyl-
`
`C3-10 cycloalkyl, -C6.10 aryl, -C1-4 alkyl-C6-10 aryl, -(5- to lO-membered)-C1-9 heteroaryl, -C1.4
`
`alkyl-(S- to lO-membered)—C1.9 heteroaryl, -(5- to lO-membered)-C2.9 heterocyclyl,
`
`-C1-4
`
`15
`
`alkyl-(S- to lO-membered)-C2.9 heterocyclyl, and —C(=O)Ra, wherein said mfilkyl, fifl
`
`cycloalkyl,
`
`:____;__}_\_._;gmalky1£3£lngYClOalky1,
`
`fléfigwaryl,
`
`flirgwalkylfififigmaryl,
`
`—§ 5~ t0 lO~
`
`memberedéuij1-9__heteroaryl,
`
`Sm to ldmemberedle heteroaryl, ~{5u to lO~
`lgflmalkylu
`
`
`
`
`— re lO—membered ~13
`
`
`
`
`membered“ ~C ;_:_g_heterocyclyl and it:1_._g_._alkylv(5
`
`are optionally substituted with l, 2 or 3 substituents each independently selected from the
`
`20
`
`group
`
`consisting
`
`of
`
`halogen,
`
`hydroxy,
`
`-CN
`
`,
`
`-ORb,
`
`-SRb,
`
`-N(Rb)2,
`
`-C1-4 alkyl optionally substituted with l, 2, or 3 halogen atoms, optionally
`
`substituted -C6-10 aryl, optionally substituted -(5- to lO-membered)-C1.9 heteroaryl, -(5- to 10-
`
`membered)-C2-9 heterocyclyl, 313d“optionally substituted —O-(C6.10 aryl)a
`
`
`
`wherein the mtional substituents in said 0 tienall ’ substituted —C 6-10 arvl and —0~ C6-
`
`
`
`25
`
`1:) EL
`
`3 l? are selected from 3
`
`
`:2. er 3 substituents which ear: be the same 01' different. selected
`
`
`
`

`

`3746.008PCOl/TJS/THN
`
`_ 21 _
`
`
`
`~OH, CM alkox‘v'carbonvl
`consisting of halogen
`hydromicarbonyl.
`
`
`from the Urou
`
`
`
`
`
`carbamrwl
`éNfix {TN} “CM. alk Il o tional
`iv substituted by one or more haloven atoms. 4:31.;
`
`
`
`
`ailioxy optionally substituted by one or more halogen atoms and CE hydroxyallwl groups;
`
`and
`
`
`
`wherein the o itional substituents in said 0 itionally substituted ~{5u to 'lOunemheredlu
`
`
`
`Q1532 heteroaryl are selected from.
`1
`12. or 3 substituents which can be the same. or different,
`
`
`selected from the won a consistin ‘1 of halooen {I714 alkoxvcai‘bonvL carbamoyl 4N0; {FE-i. ~
`
`
`
`3; 1-4 alkvl ojtionallv substituted b ' one or more halogen atoms. and 431-4 alliox ' o tionally
`
`
`
`
`
`
`substituted by one or more halogen atoms, and
`
`10
`
`7
`.......
`,...
`wherein said ~C5_m_cycloalkyl, —C1-4walkylnC3_;70 cycloalkyl, {imam ~C 1-4 alkylfi‘éw.
`
`_;_:;»_.....ary1,
`
`:(fz:_____te._____i.‘elfiflfilfll?§f.'iiél}:§_1:9 heteroaryl,
`
`i0
`
`10—r'riernbere<fi~fii.q
`
`
`
`heteroaryl, _ 5~ to §O~inemberedl
`
` “figheterocyclyl and finalkylu
`
`
`
`£2,114,_____alky1~é5~
`
`
`'5‘ to lOwinemheredluCz-9
`
`heterocyclyl is optionally fused to a further (second) ring, and
`
`R2 is selected from the group consisting of hydrogen, -C1-4 alkyl, and -C3-6 cycloalkyl,
`
`15
`
`wherein said -C1-4 alkyl is optionally substituted with —O(C1.4)alkyl optionally substituted
`
`with —O(C1-4)NH2, hydroxy, -CN, halogen, or -N(Rb)2, or
`
`I
`
`20 I
`
`R1 and R2 together with the nitrogen atom to which they are attached form an
`optionally substituted 5- to lO-membered heterocyclic ring, wherein said 5- to l0~membered
`heterocyclic ring optionally contains 1, 2, or 3 additional heteroatoms selected from the
`group consisting of N, S, or O, and wherein said 5~ to lil~memhered heterocyclic ring is
`optionally fused to a phenyl ring,
`
`Ra is selected from the group consisting of -C1-4 alkyl, -C3-10 cycloalkyl, -C1-4 alkyl-
`
`C340 cycloalkyl, -C6.10 aryl, -C1-4 alkyl-C6-10 aryl, -(5- to lO-membered)-C1-9 heteroaryl, -C1.4
`
`alkyl-(S- to lO-membered)-C1-9 heteroaryl, -(5- to lO-membered)-C2.9 heterocyclyl, and -C1-4
`
`25
`
`alkyl-(S- to lO-membered)-C2-9 heterocyclyl, wherein said MHaIkyl, Mcycloalkyl, "—514";
`
`alkylMcycloalkyl, Mfiryl, £5”all<yl;§;.g,__1_g~aryl, ~ '5“ to lO—membered‘hC M- heteroaryl,
`
`4:31“; alkyl—
`
`l{}—membered ~{I72_9“heterocyclyl and
`
`
`‘S~ to lCamemberedl—C1.9 heteroaryl, ~5‘
`
`
`
`:fllliualky1ugsw to lDaniembered‘zuCflwheterocyclyl groups are optionally substituted with l, 2
`
`or 3 substituents each independently selected from the group consisting of halogen, hydroxy,
`
`

`

`3746.008PCOl/TJS/THN
`
`_ 22 _
`
`-CN,
`
`-ORb, -SRb, -N(Rb)2, -Ci-4 alkyl optionally substituted with l, 2, or 3 halogen atoms,
`
`optionally substituted -C6-10 aryl, optionally substituted -(5- to lO-membered)—C1.9 heteroaryl,
`
`5
`
`and -(5- to lO-membered)—C2-9 heterocyclyl,
`
`wherein the e tional substituents in said 0 tionally substituted £164.; aer are selected
`’“i
`
`from l 2. er 3 substituents which can he the same at different, selected train the grout
`
`
`eot'tsistin, ot‘l'taloaen 43H CM ailimc'cat'ljonvl hydt'oxcalmed eai'baituwi NO; «{YN ~
`
`liwl o ttionaliv substituted hi
`
`
`
`
`one or more haltfleu atoms, {71-4 ailgoxw eulonailv
`
`
`
`
`
`substituted by une or more halogen atoms and CM
`
`
`
`
`
`
`h ’droxyalkyl
`
`
`
`PIOU is and
`
`
`wherein the mtional substituents in said mtionallv substituted ~’5~ to l0~memhetedl~
`
`
`
`
`
`10
`
`m
`(71-9 heteteawi are selected from i
`1-? or 3 substituents which can be the same. or different,
`
`setsetstittstii_.ttts..stsitn.s2:211.sistisgstltisl tissu,__§5i_:_4,.alisgétyssittsssi i_estttsttissl,__:_TL‘_\_T_Q.;,..:QE:1,__:
`
`Q14 ailwi e tiouallv substituted h I one or mere halogen atoms. and 4311-4 ailiox * ontionailv
`
`
`
`
`
`7
`substituted by one or it'toi'e halo en atoms and
`
`
`
`7 m...
`,—
`wherein said wC3.4;,»“cycloalkyl, "€1-4nalkyluC340 cycloalkyl, fifiaryl 431,4 alkyligé:
`
`15
`
`iguaryl, 45" to 'iGrinenibetedlnCifimheteroaryl,
`‘t
`
`heteroaryl, _ S~ to lCunemheted’—(_,rl.2mheterocyclyl and flinalkyl— 5- to l0~membetedl~ CA2
`
`;_t;“:__.3_wall<yl—'5w to lO—ineinbered‘szLg
`
`
`
`heterocyclyl is optionally fused to a further (second) ring,
`
`each Rb is independently hydrogen,
`
`-C1-4 alkyl,
`
`-C3-10 cycloalkyl, or -(5- to 10-
`
`membered)-C2-9 heterocyclyl, wherein said flatmaIkyl, 1941;“cycloalkyl or {S— to ll)—
`
`20
`
`niemberedi~C_2__._9__heterocyclyl group is optionally substituted by l, 2 or 3 fluorine atoms, and
`
`R