ATTACHMENT C
`
`

`

`US ZOE/6337922 Al
`
`NOV. 7., 2919
`
`co
`
`{6888} A], AZ and A3are each independently seleCted
`
`from the group consi::ting olNA‘llandC (1321) providedthat
`at least one ofA ,A2 or A‘ is N;
`{38891
`eachrx"4 is it dependent selected from the group
`consisting of halogert,t'VL4 alkyl, CL4 alhoxy, and CN;
`
`10890}
`n is 1 012;
`C1 _4
`10891} R is selected from the group consisting ol
`alliyl,
`77777 C,“ cycloalkyl CL __.L alltyl-CL} .10 cycloalkyl,
`77777(IMO aryl, 7CL4 alkyl -C,_ 0 arylC5— to 3lCline1iibe1ed)~
`CL9 heteroaiyl, 77777CL4 allcyl-{5 to lh—znertibered)—CL9 het-
`eroaryl,
`(5-
`to lil—1nenihered)-C?_9 ,,eterC,-cyclyl,
`77777 31.4
`alkyl—(S- to 10-niei’nher1';‘.d)—C2_9 heterocyclyl, and,7C(:O)
`Ra, wherein said ilkyl, cycloalkyl, alkylcycloallryl, aryl,
`alkylaryl, heteroaryl, allazylheteroaiyl, heterocyclyl and alky-
`lheterOCyclyl groups are optionally suhstituted with l, 2 or
`3 substitueuts each it dependently selected from the group
`consisting of halogen, hydroxy, 7CN, 7ORb 7SRb,
`77777NCRb)2, C 1.4 alkyl optitionally substituted with l,.2, or33
`h2Ctl)gen atonis, optionally substituted ?????C( 1721 aryl, option-
`"lly substituted {5— to lO—ineniheredl—C 9lteterodryl, and
`
`-C.‘3-
`to lCl-nien’ihered}-Cz_9 heterocyclyl, and wherein said
`cycloalltyl, al 4'V7lcV7cloallel, aryl, alliylaryl, heteroaryl, alle-
`lheteroaryl, heterocyclyl and alliylheterocyelyl is optionally
`fused to a lurtlier (second) ring; and
`{38921 R2 is hydrogen or C 1.4 2:ll<yl; or
`
`{0893}
`R1 and, 2 2 together with thenitiogen atom to which
`they are attached form an optionally substituted 5-
`to
`lO-filemb'TCd hetei‘ocyclic ring, wherein said heterocyclic
`ring optionally contains l, 2, or 3 additional heteroatorns
`
`selected from the group co
`2.1ng of N, S, or Cl, and
`wherein said heterocyclic ring is optionally fused to phenyl
`ring;
`{11894}
`Ra is selected from the group consisting of 7C1.4
`77777C; 10 Cycloalle, CM alltyl-C_.5_m cyCloallt'7l,
`all<yl,
`77777Ca 10 21rV7l, 27CL4 alkzyl——CO_ 10 aiyl, (5- to l0-nien1bered)-
`C1 _9 heteroaryl, 7CL4 alkyl-(S- to l0men1bered)—CL9 het-
`
`eroaryl, (5- to lO-meinberedlCm heterocyclyl, and
`alkyl-(S— to lCl-rnernberedil—CL9 heterocyelyl, wherein said
`all<yl, cycloalltyl, alkylcycloalltyl, aryl, alltylaryl, heteroaryl,
`2:1l,<yl etero2zryl, hetero-"yelyl and a ll<ylheterocyelyl groups
`are optionally substituted wit-h 1,2 or 3 suhstituents each
`independently selected lroni the group consisting oi‘1halo--
`""21 1 .4
`gen, hydroxy,
`77777CN,
`77777OKb,
`777772R1“ 77777N(l{l~).,
`
`alky'l optionally substituted with 1, 2, or 3 halogen atoms,
`optionally suhstituted (IMO 21rV7l, optionally substituted (5— to
`l0-n1emhered)—CL9 heteroaryl, and (5- to lO-niemberedj-
`(:39 heterocyclyl; and wherein said cycloallryl, alkylcy--
`cloalkyl, aryl, alltylaryl, heteroaryl, allaylheteroaiyl, hetero-
`Cyclyl and allgylhetercmyclylis optionally fused to a further
`(second) ring;
`{0895}
`each Rb is independently hydrogen, 7C L4 alkyl,
`77777€3.10 cycloall<yl, or C5— to lO-meinbered)x-CZ"9 heterocy-
`elV'l, whereinsaid allC‘V'l, eyeloallazyl o1'heterocyelyl group is
`2
`optionally substituted by l. Zor 3 ll-torine atorns;
`
`-(5— to l0-men1hered)-CL2,
`{38961 R” is 77777C6 121 a1y7l C-r
`heteroaryl, wherein s2.id aryl or hetero2.ryl group is option-
`ally substituted with l, 2 or 3 suhstituentz: each indepenn
`dently selected from the group consisting of halogen,
`
`hydroxy, CN,
`77777ClRh ????? SRh.
`77777N(Rh)3,
`77777 L4alkyl
`
`, 2, or 3 suhstituents each
`optionally su
`ituted with ‘
`independently selected from the group consisting of h2.lo-
`gen, CN, 70Rb, and rrrrrNCRb)2, optionally substituted
`77777€5.10
`aCV'l, optionally substituted {5— to lClinenibeied}
`C 1—9 heteroaryl and «(5— to lil—inertiber’edl—C32_9 heterocyelyl.
`
`[0897} All puhlications Cited in this specification are
`incorporated herein by relerence While the disclosure has
`been descnhed with reterence to particular embodiments it
`
`will be appreciated that ntodifi.2ation7‘ can be made‘ without
`departing ironi the spirit ol the disclosu .Such inodilica
`tions are intended to f2.ll within the scope.col the appended
`clairns.
`What is claimed is:
`
`l. A compound of formula (I):
`
`NH3
`
`Cl)
`
`1' Mn
`
`I 2
`.1
`A’
`
`N
`
`x
`
`11‘
`
`R‘
`
`N/
`
`ll
`
`or a phamtaeeutic2lly aCeeptahle salt or solyate thereof,
`wherein
`
`A2, or A3
`
`Al, A‘ and A3 are e2.ch independently selected from
`the group consisting of N, CH and C(R“), provided
`that at: least one
`A], A", or A3 is N;
`with the proViso that no more than two 01A],
`is N;
`each R4 is independently selected from the group con-
`sisting of halogen, ?????C 1.4 alkyl, ?????C 1.4 all<oxy, and
`77777 CN,
`11 is 1 012., wherein the alkylene chain can he optionally
`substituted. with one or more 7CL4 allel groups;
`R1 is selected from the group consisting of7CL4 alkyl,
`77777C} 10 cycloallg'yl, ""Ci.4 all<1V7lan_LO cycloalkyl,
`77777C(HO aryl. 27CL.L alkylC,” ayl,
`-(5-
`to
`lO-niembered.—)CL9 hetero2.ryl7CLA all<yl—(5- to
`1C)"rnernbered}-C,. 1.9 heteroaiy l,
`--(5 to ll)--ine1:1-
`hered,‘1—_C2o
`heterocyclyl, 7C1 _4
`alkyl (5-
`to
`
`lO—rneirihered)—C29 heterocyclyl and 7L
`,
`whereinsar
`
`
`alnylai'yl heteroaryl alkylheteroaryl
`l‘cterocyclyl
`
`
`and alkylheterocyclyl groups are optionally substi-
`
`
`’ u e
`’ suns 1tuents eac 1 ln'ependent
`selected from the group consisting of halogen,
`hV7drC'XV’,
`77777CN, 77777OR‘o,
`22222SRh, 77777NCR1“)? 22 31.4
`alnyl optionally substituted withl
`,or 3 halogen
`atoms, optionally substituted CF.10 aryl, optionally
`substituted -(5- to lO-niernbereC -CL9 lieteroaryl,
`
`
`. eioai'yl,a
`
`
`
`
`is optioiiallly fused to 22 liutlier (second)
`SUV‘X‘VC‘ll
`
`
`Ag; and
`R21is selected1min the ::oup consisting of'nyddi'ogen,
`7CLL alkyl, and 7C3_6 cycloalkyl, wherein said
`7CL4 alkylis optionally substituted with 70(C 1»
`4)all{yl optionally substituted with 77777ClCCLA)NllZ,
`
`hydro-X
`7CN, halogen, or 77777N(ijg 01
`R1 and R together with the nitrogen atorn to which
`they are attached fonn an optionally substituted 5— to
`
`lO-rnenibered heterocyclic ring, wherein"
`cyclic ring optionally contains l, '2. or 3 additiona
`hetero-atoms selectcd from the group consisting of N,
`
`

`

`US ZOE/6337922 Al
`
`NOV. 7., Mill)
`
`co ix)
`
`S, or O, "and wherein satdnetCroe/cl
`to ring is option—
`
`6
`ally lused to a phenyl ring;
`’ 11—4
`
`'
`selected {rorn the group consisting or"
`alkyl,
`.2
`cyCloaI ‘
`7774314
`allaszl-C3_10
`
`cydoalhyl,
`LL2 alkal—C6_11C aryl, {5—
`
`to lO-n1embCre21)(I1_9hetero2terl, ?????C14 21-'lCWfl~(‘2- to
`lO—inetnhered‘er heteroain, {5-
`to lO—mein—
`here-zl)--(I9_9 heterocyclyl, and 77777(I144 alkyl-{S— to
`
`lO-me. i .'
`)-C2_9 heterocyClel, w,1ere1n s21]
`..
`
`
`
`
`cydoalhyl, alhych/cloalkyl,
`arWl, alkylaryl,
`het—
`
`
`eroaryl, alltylheteroaryt, heterocyclyl and all<ylhet--
`
`
`erocyclyl groups are optionally substit ited with l, 76
`
`or 3 suhstitnen " each independently selected from
`the group con
`'ng oi l121llogen thdroXW',
`77777(IN,
`
`77777()Rh, ,,,,23Rb6
`trio C1 _4 alkyl optionally
`substituted with l, 2, or 3 halogen atoms, optionally
`substituted 4C610 aryl, optionally s1bstttuted {5-
`
`fCl02lll~2yl1
`
`het—
`Wl: alkylaryl,
`lhleW/Cloalle,
`6
`6,eroaryl alltylheteroaryt, heterocyclyl and all<ylhet--
`’
`ocW'chl is optionally fused to 21 further (second)
`n ’
`
`'1
`l\
`
`aCh Rhis independenth hydroger ~~C1_.alltyl
`m cyCloalCWlf ,or ~(5- to lO-memheredi-C ”9 hetero-
`cychl, wherein said alliyl, cycloalkyl or l1eteroc_jchfl
`
`group is optionally su
`ituted by l, 2 or 3 lluorine
`atoms; and
`3 is selected from the group consisting of WC 21.10 aerl,
`~(‘-
`to
`lO-n1en1beredj-C1_9 heteroaryl, %9C
`
`cycloall<yl, and--(5- to l()- n1eniheetl)--C:_9 het-erocy-
`
`clyl, wherein said
`heterocyclyl groups rC op -ona W suns .
`
`
`2 or 3 suhstituents e21Ch independently sel Cted lrorn
`
`the')group consisting of halogen, hydroxy ifN
`
`
`77777()Rh,
`2,22,311136 22222N(l{h)9,
`,_4alltyl op. onallV
`substituted with l, 2, or?1151-hstituents each indepen-
`denth selected-iron1 theegroup Consisting olhalogen,
`:1 l, WORh, and 77777NtinitZ, optionally substituted
`:C646 athl, optionally substituted —(5— to lO—mein—
`er-ed‘6 -
`'
`to lO-nternl ‘ redi-
`529 heteroCchlyl, 2znd wherein said a.Wf heteroarWl,
`cyCloalltyl, and heterocyclylis optionally fused toa
`further (secondl iinrr.
`2. The compound of claim l,
`or apharn1aceutically acceptable salt or solVate thereof,
`wherein
`
`
`
`A5 are eachn dependently selected fioni
`
`the group consisting of N, (Ill and C0924), provided
`that at least one ol'AJ, A4, or A5 is N;
`1‘
`with the proviso that no more than two ofAJ, A", or A3
`i
`.5 N;
`
`
`:h R4 is independent‘
`elected lron1 the group con-
`ing of halogen, ?????C14 alliyl, ?????C14 allCoXW', and
`
`
`sselected from the group consistingof 2(IL4.alkyl,
`7777715,(I916 CW'Cloalkal. C14 21ll<ylC316. Cchloalkal,
`22222€5.10
`aryl,
`:mCl _4
`allty—lC6 .0 aryl
`{5— to
`lO-mernhered)-(
`_9 heteroaryl, 22222(I14 all<Vl-(5-- to
`lt'l-r‘iCrr‘hCrcdlC19 heteroaryl,
`-(5— to lO-mern-
`heredr-CM heteiochlel,
`
`l (l-inenihered
`
`wherein said
`
`
`alkW'larWl, heterot
`and a
`
`.
`
`
`
`tuted with l, 2 or 3 suhstituCnts eaCh indepenanthf
`selected from the group consisting of halogen,
`hydroxy, WEN, WORh, ?????Shh, 77777N(1111162,,
`?????C 144
`allCW'l optionally substituted with l, 2, or 3 halogen
`atoms, op ionally substituted 2222(I641, aryl, op ionally
`subsituted 45— to lO—meinberedl—C 2 heteroaer
`
`
`
`and 1’5— to lil—n1enibered)iC949 heter‘ocyclyl; and
`
`wherein said cycloalkyl, 21]l<ylc:loall<Wfl,ai fl. alky-
`
`
`
`laryl, l1ete:oaerl alltylheteroaryl, heterocychl and
`rU
`
`2ill<Vlheter21C fclV.
`is
`2tionallf fused to a further
`
`
`,
`_
`\second}ing, and
`
`
`
`2 is hydrogen or 77777C1 4 alkyl; or
`
`R} an r\Ztopether with the nitrogen atom to which
`they are attached-iorni an optionally substituted’i to
`ill—menibered heterocyClic ring,wherei1 1
`.idl1eteo-
`
`
`cyclic ring optionally contains l, 2, or 3 additional
`heteroatonts selecte ‘
`* insisting of N.
`
`
`Ra is selected?
`{a
`
`”””l“12.4
`alkyl"‘«'3.io
`('Vhlodll‘s‘ll
`22222(I940
`alkyl,
`
`
`6_ .0 arylCL4all<Wfl~C6_1021.ryl, —’_5-
`cycloall<yl
`to lO- 1’1":-emhered)--(I19 heteroarWl,
`C1,14121lkvl--(5-to
`lll—m,e111beied)-L .
`heteroaiyl,
`-(5-
`to l0niein—
`
`
`and ,
`I
`
`
`.
`.
`.
`1
`:
`
`
`
`
`
`chloall< fl, aky'cWCloa. l,
`2 l, al’laryl, het-6
`eroaryl, alkylheteroaryl, lieterocyclyl and alkylhet—
`
`
`
`
`
`6 ei‘oCVclVl Jon 5 are e 1tionall'f substituted with l, 26
`
`or 3 suhstituents eaCh independently sel2cted fro 11
`the group consisting of halogen, hydroxy,
`22222CN,
`iORh, iSR‘o,
`
`, i‘CL4 all<yl optionally
`substituted with l, 2, or 3 halogen atoms, optionally
`substituted ????? (I641, 2terl, optionally suhstituted -(5—
`to
`lil-nienibered
`heteroaer
`and —(5-
`to
`
`
`
`lO-nieinhered)-(I29 heteroCWchfl; 1nd wherein said
`
`
`
`
`chcloallCWfl, alkylcycloalliyl, aql, alliylaryl, het-6
`
`
`eroaryl, alkylheteroaryl, heterocyclyl and alkylhet—
`
`
`
`
`6eroCVclVl
`is ontionallv fused to 21 furt 1er (second‘
`ring;
`eacl1 Rh is independently hydrogen 7C1_4 alky117C}
`CWCloallth, or--(56-66to 10--mewhorexfi -C1
`hetero
`
`CyClel, wherein
`.
`
`
`fluorine
`group is optionallW substitutednW l1 2 or 3
`atoms;
`
`R3 is "2&610 aryl or (5— to ':l6(lrnernhered —C1_9 het—
`
`ercarWl, wherein said
`group is
`
`optionally substitute",ubs .ients each
`independently selected from the group consisting of
`halogen, hydroxy, 22222t"N 77777()Kb, 77777SKb, 77777N’“)3.
`77777C21_4all<2yl optionally substituted with l, 2, or 3
`
`.,.1bstituents each independently selected from the
`group consisting of halogen, 4CN, 40%), and,
`?????N(l{h)2, optionally
`substituted ~~C6_1 6
`ar‘ l,
`optionally substituted -(5— to it)rneinhered)C19
`l1ete:oaerl and —(5 to l0meinhered)——C2_9 heteroch
`
`
`
`3, The compound of claim 1 or 2, or a pharmaceutically
`
`acceptable salt or solvate thereo., wherein AJ is N and A2
`and A3 are each independently selected it1n1 the group
`consisting of CH and C(R4).
`
`

`

`US 2019/11337922 Al
`
`Nov. 7., 21119
`
`CO La»)
`
`4. '1he compound of claim 1 or 2 (latpharniaceutically
`accep1ahle sa11, or solvate thereof, wherein AZ is N and AJ
`and A’ 211C each independently selected from the group
`consisting of CH and (X114).
`
`5. the compound of claim 1 01 2,01 21 11l111n11aee ‘1'ca1‘1V'
`aeeeptahlessalt or solvate thereof. Where1n1-“13 is N and L‘x‘
`and AZ are each independently selected from the group
`nsisting of CH and C(R“).
`6. The cotnpou1 21 of Claim 1 or 2, or a phamiaceutically
`acceptable salt or solvate thei‘eol‘. wherein A‘ and A“ are
`‘not11 N and A3 is CH or C(18).
`7.lhe cotnpou1 21 ot Claim 1 or 2, or a phamiaceu '
`
`acceptable salt or solvate thereof, wherein Al and A“
`hoth N and A2 is CH or C(l1&4)
`8. The compo-111.101 claim 1 or 2. or 1 phamiaceutically
`
`acceptable salt or solVate thereof, wherein A12 and A" are
`both N and A" 1s CH or C(Rfi.
`9. The compound of any one of claims 1—8 or a phan’na-
`
`ceutqically acceptahle " ‘lt or s-:lV‘a1e thereol', w111eein 11 is 1
`The compound of any one 01 claims 1-8. or 11
`nl11rni11ccut11y aCeepta‘1lc salt or solV ate the:1eot. wh‘reir
`n ls 2
`
`11 The compound oat"my one of claims 1-10, or a
`p111rn1ace1-t‘ca11y accept'abl salt or sotvate1hereot', wherein
`6-
`R3is ui1substi1uted-C 11 aryl or WCéuJ. aryl suhstit1‘11ed
`W1th 1 or7 substituentts each independently selected 1ron1
`
`the group consisting of halogen. hydroxy. 77777CN. 77777()(CL
`
`4)alkyl. 78(Cb41a1k31.
`_ “'1—4 alkyl)?
`11(C1_4 alkyl‘.
`and ~~C._L alkyl optionally substituted with l, 2, or 3
`substituents each independently selec1ed from the group
`Consisting of halogen,
`77777LVN.
`777770(C]_4)allzy1,
`7777711(Cl_4
`2111ry1)z, and 77777Nl’1((jl_4 allryl).
`12 The compound of any one 01" Claims 1311.211“ 11
`pharni121eutically aCCepta'hle salt or solVate thereof. wherein
`1.1-1
`R" i: l
`
`13 lhe compound of any one of claims 11—11, or a
`pl111ri11.ace1‘111 ,a11_,' acceptable salt or solvate1hereo1'. wherein
`R2 is 4C1_4 alkyl.
`
`14. The compound of an ' one of claims 1—11 or 13 or a
`pharniaceutie.1lly accep1111h1e salt-ozro1V211e thereof. wherein
`R2113 i11etl1yl.
`The compound of any one of Claims 1:14, or 11
`nl11r11111cc111c1a11y aeeeptahle salt or sol‘Jate thereof. wherein
`R s~~C._
`a . 1 or ....1(1.11lkyl-Cbm aryl. wherein said
`
`
`a1'yl or 2.1ky1a1'y: is o1t11ona1ly substituted wlthll. 2 or 3
`
`
`
`
`
`groups eat: 1 1n e11ende11t1yselee1ed from tl e group consist-
`
`ingo1‘ halogen hydroxy ~~CN. 22222r1"?‘13111 11111Nt'RbilZ,
`22222
`.1 _4 alhyl optionally su‘nstitut:d with 1 2,01 3 ha1ogen
`atoms, optionally substituted 22222C1110 2113.1. optionally sub--
`stituted, -(5— to 1O—n1e1nhe1‘ed)-Cl»9 heteroaryl. and, —(5- to
`
`lO-metnh rub—CZ"? heterocyclyl, wherein Rh is as defined
`in claim
`
`The compound of any one of claims 1:15, or 11
`pharniaceutically aCCepta'hle salt or solvate thereof. wherein
`Rh is hydrogen or ~~(Zl_4 alltyl.
`.17. The cotnpou (‘1 C: ‘ any one of claims lx-ll, or a
`pl111ri11.ace1‘111 ,a11_,' acceptable salt or solvate1hereo1'. wherein
`R1 and R2 together wi '11 the nitrogen atom to which they are
`attached form an optionally substituted 5- to ‘1(l--n1embered
`heterocycll10 ring. Whereirrino optionally
`
`
`
`.
`.
`‘ 2 or 3 addi1,
`111111 heteroaton
`“elected from 1he
`
`group eons' 11ngol‘N. S.or().andwl1en
`ring is optionally fused to a phenyl ring.
`
`18.1‘11e Compound ofclaim 17. oraapnar
`acceptable salt or solvate thereof, wherein R'
`together with the nitrogen atom to which they are attache"
`form a 5— or 6-n1e1nhered. ring optionally fused. to
`a phenyl
`1ing.
`
`eutically
`and R"
`
`19.1he compound ot claim 11 VVhiCh1s selected. from the
`group consisting of
`
`
`
`N
`
`\N A
`
`\
`
`/
`
`
`
` \_ Z\ mm-/’
`
`
`
`

`

`US 2019/6337922 A1
`
`NOV. 7., 2019
`
`~cominued
`
`gm
`
`NAN
`
`
`
`[
`
`—c0n[inued
`
`NH;
`
`/ N,
`
`‘31”
`
`/\
`
`N//L\\"N
`
`
`
`
`group consisting of
`
`k k
`N \ N
`/
`
`I
`
`or a pharmaceutically acceptable salt (at salvatc thereof.
`
`20. The compound 0f Claim 1. which is selected from the
`
`CN
`
`NH,
`
`H
`
`\0
`
`>
`
`

`

`US ZOE/6337922 Al
`
`NOV. 7., 2019
`
`co NJ
`
`OMB.
`
`I
`
`\N
`
`N
`
`:
`
`oMc
`
`/ \VAN/
`
`N
`
`—continued
`NHZ
`
`
`
`N\)\
`
`i
`i
`MAE \
`NH2
`A
`NJNN A
`
`A i
`i:
`\j\N‘ NW
`
`CN
`
`I
`N
`
`22. A compound selected. from the " oup consisting
`
`
`
`1H
`
`AV
`
`NH;
`
`‘ AN
`
`or a pharmaceutically acceptable salt or solvate thereof.
`23. A pharn’racentical composition, comprising an etl’ee-
`tive amount of a compound, of any one of claims 1—223 or a
`pharmaceutically acceptable salt or solvate thereof, and at
`least one pharmaceutiuily acceptable excipienti
`24. A met} eat of treating or preventing a lysosomal
`storage disease, comprising administering to a patient
`in
`need thereof an effective amount of a compound oi" timnula
`(I):
`
`(11>
`
`NH;
`
`AZ/l\\‘A3
`I A /R‘
`A‘
`N
`
`
`
`
`'n
`
`or a phartnaceuticaily acceptable salt or solvate thereof,
`wherein
`
`A} A2, and A5 are each independently selected trom the
`group consisting ofN, CH and C(R4), provided that at
`least one of Al, A2, or A3 is N;
`each R4 is independent, selected from the group co
`oi'halogeri, ?????C 1.4 alkyi, ?????C1 _4 alkoxy, and 7
`n
`n is l or A wherein the allgylerie chain can be optionally
`substituted with one or more ?????C14 alkyl groups;
`
`)
`
`3
`
`Br
`
`Oi 1'3
`
`()Me
`
`lMc/vak/ NH
`
`v
`
`NH;
`
`l
`
`N
`
`\t/K
`
`i
`
`/i
`NA)
`NH:
`
`N
`
`E
`
`/:
`NANH,
`NHZ
`
`NA19;
`NH;
`
`@/ I
`N
`
`N \if
`J!\ /E
`\v/ NANH
`
`

`

`US ZOE/(1337922 A1
`
`NOV. 7., 21119
`
`co
`
`V1711 1, 2, 013 511b511111en15 C3Ch11idepe11de1111V' selected
`from 111C group C1)11515ting (11‘ halogen. WCN, ~~OR11,
`311d 7 1ij2, 0p1i011311V'
`substitu1ec1 4C6 10
`2113/1,
`optionafly 511bs1itu1ed {Sn to 10—:n2111be1ed)—C
`911C1—
`y.
`'
`'
`'
`1121eroCV'C
`
`71. 31111 11e1—
`,
`er-:)0V7C1Vl 15 01111111121157 1'used11) 21 further (5CC11nd) ring.
`25 The method of 0131111 24,where111 111C 1325050111211
`orage dis-C2151:15 Gaucher 5 5.1512351:
`26. 111C 1111211101101(:131111 24 01' 25, wherCinA1
`are N.
`
`,AZ and A"
`
`27. he me1hodofeiaim .754 or 25,W11ereir11he compound
`a<11ni1iiste1ed15 2153011med111 any one (.11 121311115 1-22
`28. 111e1ne1110c10 EJ121111} 2-41 01 25, wherein the compouh-d
`2111.31111151121’121115 5e1CC1.
`12111"f11)111 the group 00115151111g of
`
`. . 2'
`
`0"” I
`25- K
`
`>
`
`\:
`
`2/1
`
`1 \
`
`1 /
`
`
`
`PC 15 5e1e01eC1 from 111C group consisting of WCM 2111(V1,
`
`. Z340 CV'e10'21111y1,
`22211314
`211kV'1--(
`.10 CV/010211kV1,
`4C410 arV'l, 4C94 2111~:V'1—C6_10 31V}, {5— 10 10—11mm—
`bered)CL 9 heteroatyi 77777Cl 4 311971—510 10—mem-
`bC1ed1CJ 9 heteroarV'l, (5— 11) 10111C111be112d)1.7 9 het-
`A
`
`C1'00V'C171, 4C
`alkV‘l— (5-
`to 111-3113111111?er -C,_2_
`11e1er1)0VC1V1. 311d 77777C(:
`:())R3, wherein 531C1311<V ’
`
`0V7C1031ky1, 31ky10yc1031ky,1 31371, 31kV121rV'1,11e1e1'031V a1 ‘11‘C1eroarV1
`
`11e1‘roc ’C1V1 and 3-11
`
`C )11135 2:1C 011110113137 5111151111111211 VV1111 1, 2 01' 3 511b-
`511111131115 e230
`independently selected 110111 1111: group
`C01351511 gof 112110gen, hydroxy, WCN, 222201113, 77777SRb,
`
`77777N(1111):,remCl_421]kV10111101131575111151117311211121/
`:‘
`'
`",
`or 3 11310ge11 21101115, optionafly 511bs11£u1ed ?????CE10 atyi,
`011110113157 55135111111121} —(5- 11) 10-1111211111121’Cd)-C1_9 het-
`,
`, J1
`.,
`s
`
`131031371,
`-(5— 1o
`1J—‘rr1ei1’1bered1—C
`heterocyel
`1)p11-:)11'2111V7 511115ti1u1ee‘.
`.
`2,“ a 71); 31111 wherein
`
`j
`.
`
`qu1Cu 1
`1
`‘roarVI '31le def!)
`
`R" is 5131Come? 110111 the group 00115151ng 01 hydrogen,
`
`11111C. 4 21111121211121
`'2 31le,Where111 53111
`?????C _4 21kV- 15 ()ptio112zl1y 51113:5111111CC1 'W111] WWO(C1_4)
`31kV71
`011111111311V
`511b5111111ed wi1h
`7777701C, _4)1 11:,
`hydroxy, ~~CN, 112110g1211, 01'
`77777N(R1151, or
`R1 and R2 together 17171111 the nitrogen 2110111 10 which they
`are 31121011Cd
`form 311
`1)p11-:)11'2111V7
`511135111111C11
`5
`10
`
`10-111C11111Cred 111211211)CV7C110 111,10 W11ere1255
`1
`521111 1122112111-
`0'7e1i0 ring 0;)11011311V contains 1, 2, or :3 additioned
`C1121'C12110111‘5 select
`from 11
`1)11515tir1gofN, S,
`
`
`or O, and VVherei‘n— 11mg i5 op1ior1a11V
`fused 1021' phenV'E ring:
`2,
`R315 se1e201ed110111 the group 01)11515tir1g o1 WC, _4 3-111.17V1,
`13-10
`CV'01(1311{V71,
`77741-14
`31kV'—C13 19 CV701031kV1,
`\.'2 u
`7777(:0- '(J
`21rV71,~~Cl4211113214764O 211371,"
`15- 1011112111-
`bered}C 911e1e1031Vi, 4C1 _4 2.111321 1’‘1 10 10—11mm—
`
`bC1'ed‘)--("J_9 he1e1031’V71,3(5--11) 1(1-—me111be1ed)-(2_9 1ie1-
`rocV'C1V1, 311d
`4 21116:41-(5- 11) 1(1--1111211113121’C11)-C2.
`11e1e100V7C.1V71, Wheteih 53131311971, CV010131RV'1, 31kV1CV'—
`
`
`
`C11)311<Vl, aryi, 211kV'13rV1, 11C1eroarVul, 211kV111e1e03rV1,
`
`heteroCV'elV'l 211111 a11<y111e1eroeyc1yi groups are op1ior1—
`)
`
`
`
`3 V 511 5111u1e1 W111]
`,
`or
`511 51.1111en15 eac111ie.e-
`pC1111121111V7 5121CC11211 from the group 001151511113; 111112110-
`,1
`gen,
`hV'droxV,
`22222CN,
`2222201111,
`22222SR1),
`22222N(Rb)3,
`1';
`.. _4 31le 1)p11-:)11'2111V7 5u115ti1u1ee‘. with 1,
`or 3
`halogen 3101115,
`0111101131137 substituted. 7C610 31371,
`11.1011311V 511bsti1uted --{5-11-) 10-membered -C _
`1ie1-
`
`(5
`
`my
`(111’
`Sec
`
`:11chV'01(131hV71
`and wherein said CV011131kV'1,
`3111V'1211'V'1, heteroarV/L 311<V7111e1e1031VL 11e1erochEV
`2111CV111C1e100
`‘1 15 0110113117 fused to a furthm
`011d) ring;
`each R11 15independenflyhydrogen, 22222C. 4311(V'1
`‘1711.,
`:{13 10
`VC]
`0V7C11)31kV1,1)1'(5- to 1(11116111be1'12d)1. 911e1C1
`VVherein said
`i
`’
`
`1111ee. 13V
`,
`1.
`1)p11-:)11311V7 51111511
`*3
`11 dry.
`R3 15 5e1e01C11 {10111111e group con5151111g of 22222(
`-(5— 10
`10-111C111bCred:1-Cl_9
`11e1Cr0211V'1,
`22222
`(-3.1 c
`4
`he1er00 7-
`0V7r'1031kV71, 311d {5— [0 1(1—111e111bere111C.”
`
`01V'1,‘.V11e1ei11 531d 211V},
`
`heteroeydyl 13,.maps 3113 03311011a. V 51;.
`5111:111ec1 “71111 1, '2
`or 3 51.113511tue1111‘, C3011 independently 5e1e01C11 from 1hC
`
`group 00115151111g of 112110551211, hV'C11'0XV 22222CN, 2222213R1),
`22222SR1) r~~N(R11)2, 77745142111971 11p11011311V7 5L1b511£u1ed
`
`, 5
`
`

`

`US 2019/6337922 A1
`
`NOV. 7., 2019
`
`O
`
`~cominued
`NH;
`
`—c0n[inued
`NHZ
`A
`
`NIH,
`
`K N/
`
`N AH \i
`
`H
`
`NHZ
`
`Ax,’......
`
`\
`
`1:
`
`’
`
`/J\
`~ \ Y
`\1“ g
`\
`N
`
`,N
`
`171‘
`A T
`
`T
`=
`
`‘
`
`,
`
`.L
`
`CL, 4m
`
`l
`
`/.
`
`NAN
`
` .
`
`29 The method ofclaim 24 or 253 wherein the compound
`administered is whacked from the group consisting 0i"
`
`
`
`
`

`

`US ZOE/6337922 Al
`
`Nov. 7., 21119
`
`
`ll molecule
`3'7. The method of claim 36, wherein the s
`
`c epe‘rone is selected from the group consisting; of isot'ago-
`mine, N—nonyl—l—deoxy11ojiri1nycin (NN-DNJ), amhroxoi,
`and thiglustat.
`38.211 compound as defined in any one of claims 1-22, or
`a pha1'1naeeutic5:1iy acceptable salt or sclvate thereof, fo;V use
`as a medicament.
`
`39. A compound of formula (l), 01 5: p'1151r1naceut1cally
`acceptable s31: or so1V’ate thereof for use 111 ne reatr 1ent or
`prevention ot 'VVsoso1nal storage (:isease, the compound of
`fo11nu1a (I) having the strnetine:
`
`(l)
`
`
`
`Wheiei11
`
`—cont111ued
`
`
`
` .
`
`(:1,
`
`or a pharmaceutically acceptable 55:1::01 sovate thereof.
`
`31}. The inethod of any one of cl'irns 24-29, further
`conipris ng administering :o the patient a: least one other
`
`therapeutyc agent
`.,
`31 lhe method 01 claim 30,Whe1ein the :l1e1'apeu:i'
`
`is an efiective ameun: of an enzyme for ensze replaeeVnent
`therapy.
`32. The method of claim 31, wherein the enzyme is
`finglucocerehrosidase or an analog thereof.
`The method of claiin 32, wherein the enzyme is
`imigluce use
`The method of any one of claims 313-33, wherein the
`therapeutic agent is an effective amount ofa small molecule
`chaperone.
`35. The method of claim 34 wherein :he sniall inolecuie
`chaperone binds compeeitt1vely toV1 enzyme.
`36. The method of claini 34 or 35, wherein the
`1’1101ecnle chaperone is selected from the group consisting of
`
`iniinoa ditcls intinos gars, aminosuoars,
`thiC1henV/lVVlVVco--
`sides, glV'cosidase sulta:51se, g1V'co:yl
`t1ansfer13e, phos-
`phatase, and peptidase inhibitots.
`
` si‘nall
`
`
`
`A , A., and A3 areeacn independently selected from tre
`group consisting; o1 N, C H and C(R). p1oV'ided that at
`1east one of A', Ag, or A3 is N;
`each R4 is independently selected from the group consist-
`ing o1'11a10ger1, ’51.:alkyl 4:. 1_4 alkoxy, and iCN;
`n is l or 2, wherein tre alkylene chain can be optionally
`
`suhstitu:ed With one or more 11111C 74 alkVVl groups;
`.
`R1 is selected fioni the gros-.ip consisting o1 11111C , 4 511kV-,
`453.10 cVeioallngl 4C.
`ath-l-C3_ .6 cycloa1kyl,
`
`
`~1C646 am. 111111314 alkyl
`m airy], "{5- to lt)--1neni--
`he1ed)-C1_9 heteroaryl,
`11
`1.4 alkyl-(S— to lfi-inem—
`herecD—CL9 hetet‘oat'yl, -(5- to ll)—:ner11l'1ered)—C32_9 het—
`
`eroCVV *1 Vi,
`~~C
`-'5- to
`‘1(1--1nemhered -C,,_(.
`
`
`heterocVclyl and 4L: O)R5:, wherein said a1l~:V'1,
`
`
`cyclcalkyl, alkylcycloalkV/l. arV/l, alkV/laryt, heteroaryl,
`
`
`a1erV1hete1'oa1
`heterocvclV1 and allehete1‘oCVVc1Vl
`
`
`
`
`
`groups are optionally substituted with l, 2 or 3 sub—
`stituents ea 11 independently selected from the group
`consisting ofl1a1ogen, hydroxy, 4CN, iORh, isRh,
`
`
`'' mCMalkyl0111101131le substituted with}.2,
`
`or 3 halo ,1
`.ato111s, optionaliy suhsti:nted 11111 T6_ .6. a1 V1.
`:1
`optionahy snhstituted (5- '.o 101V11er1V1hered)(——Cl_9 l1:—
`
`
`eroaryl, ~15
`to
`lO-me1nheredr-Czug heterocyel
`optionally substituted 707(C6 10 a1yi); and wherein
`saidVcycloalkjt. alhylcV/c1oalhyl, atyi, alhylatyi, het—
`lleheterary1, heterocycly1 51nd .Vilkylhetero—
`is otionali V fused to a funher (second) ring; and
`.
`.
`R2 is se1ected from the group consisting o1 hyo'1ogen,
`WC,
`1 alkyl, and 11111(:3 6 cyclealkyh wher.i-n said
`~11C14 alkyl1s optional1V substituted With ""OK:1.\4/
`a1ky1
`optior1al1y
`substituted with
`111110((11_4)Nllz,
`hVVdroxV, 11111(N hat-1g)e,n or 11111N(Rh)2; OV
`R' anth" toget-her With the nitrogen at:1111 to which they
`are attached form an optiona1ly substituted 5— to
`
`lfinmernhered heterVicV/chc ring, wherein~
`1V:11c ring; optionalty contains 1, _, or ’
`(t:itiont.
`
`heteroatoms select
`11 onsisting of N, S,
`
`or 0, and wherein
`11g is optionally
`‘-11,
`fused to a phenyi ring;
`11
`R51 is selected from the ng-up consisting o1 WC 4 511] V
`‘3
`1111113346
`eyelc1alkV'l,
`1114314
`alkyd—(.346 cycloa1hy
`
`
`
` E3.“0any,
`
`‘l
`
`.
`
`

`

`US ZOE/(1337922 Al
`
`NOV. 7., 21119
`
`
`
`— to 10—~111en1—
`C140 and 44CJ_4 2111131f5.Jo a1'3'1, —
`to 111---men1
`bered}-CJ9 11e1ero11ry1,
`J _, alkV--(5-
`‘1')ere1:1)—CJ49 11131131023131 4'5 to 10-111Cn1bCred)~C29 '11et—
`al11'3'l—K5) 1o 10—111e1n1)ered)-C
`erocyr*1y1, and 441:.
`etercCyclyl, wherein sa1<1 2:111:31, C3'(:1oalkyl, 2:11<y1e3'-
`Cloalkyl,
`a131,
`a11131211'3'1, heteroaryl, a1li3'1hete1o21r3'1,
`heterocve} '1
`11<v1he1eroe @131 groups are o
`21113 subst1tuted w1t11 1 2 or 3 subs‘dtuents
`pen-den[ly selected from theegroup CO1-15151111g of halo-
`gen, hydroxy,
`44444(N 443R
`44444$1111.14\(Rb)9,
`%_ alkyl optiona11y su-1)st1tute<1 with 1. 2, or 3
`111110331311 atoms, opti11na11y:«:11bstitute-:1
`’ _
`'
`
`1) 11111121113 substituted 1* to 111me11ibered1L _
`eroaryl, and —K5— to 10—1ne111he1ed)—"(2.9 11eteroc3'ely1:
`1111 wherein 5121111 C3'C1oalkyl, 2111iy1e3'doalkyl,
`21r3'1,
`3 1kyi21r3'1, 11ete1'oa1'y1, a1kyl11eteroaryl, heterocyc131 and
`1l1y1hete1'ocyc1y1
`01111011211131 fused to a further {see-
`ond) 11113;;
`
`
`
`11111311 44 .J,‘i
`eaChR‘11) 1s indepe11dent13' hydro
`
`' rocycly1,
`cyc1oal1<3,1 o1
`'
`3 group 151
`_
`,
`,
`,
`,
`Whe1e111 521i
`opt10112t113' 1.1111111 otedn'03' l 2 or 3 fiuonne :1to;1ns 21nd
`
`—eon[inued
`N117
`
`A,
`
`IN
`
`
`
`R 15; selected from tne group C(111s1st111g of 77777C6ary1,
`-(5-—
`to
`‘11)'n.1'1bered)1 J9
`11etero2113'L
`11111(13 J0
`Cye102.11131, and (5- to 11'1-1'1C-1‘bCer1—_C'29 heteroCy—
`C13,l w11e1e11'1 sa1C1211'3'1, heteroaryl, C Icloa1ky1, and
`
`
`
`etei'1-Cyclyl groups a1e 011111011111137 substituted with 1, 2
`or 3 substituenis eacn independently selected from the
`
`graupCC
`1110 of ha1oge11, hydroxy, 11111(N, 1111019113,
`
`iSRb 7\W‘{1,9,41r1_4:11'1{yl optiona11y subst1tuted
`wi1h1, 2, or 3 511.11.131.11'11ents each 111depe11dent13' selected
`from, the group consisting oi'halogen, 44444 CN, 44444013111,
`and 7N(Rb)2, optiona11y substituted 4C6 Jo 211'3'1,
`opt1-11na1-13' substituted 1‘1 to 1(1-—1nen1bered)(J_ 9 net-
`«2.9 11eteroe3'c y1
`and. wherein said a1'3.l 11ete1’o2113'1 C3'elo211ky1 21115. 11et-
`‘
`'
`'
`7 fusedt-o 211111111131? sec111d} 11110.
`
`40. The compound for use as (31211111611 in claim 39, wherein
`said use is for the [reaunent or prevention of Gaucher’s
`disease.
`
`41. The compound for use as Claimed 111 01211111 39 or 40,
`wherein the compound, is as (312111111311 1n .1ny one of claims
`1-22.
`
`
`
`
`42.1116 compound for use as claimed in 1312:1111 39 or 411,
`wherein the C-‘mroundse]ectedfror11t11e group (301191511113;
`of
`
`
`
`N112
`
`‘C VN\/"\N//”\JJ/'\\/
`
`//,1.)
`
`<
`
`"Q
`
`

`

`US 2019/6337922 A1
`
`NOV. 7., 2019
`
`~cominued
`
`—c0n[inued
`
`[
`
`[
`
`5
`N
`
`NH2
`
`5%
`E\
`E
`
`43: The“: compound for use as Ciéainaed in ciaim 39 Gr 40,
`
`whereinthe compound is selected from the group consisting
`
`of
`
`:
`
`N
`
`ii
`I \A k i
`N
`{‘1Al/
`
`h
`or a phammceuticafly 2100619131316 salt or soivate thereof.
`
`
`/ N
`
`(A
`I\
`H a
`
`x.
`
`,
`
`

`

`US ZOE/$37922 Al
`
`Nov. 7., 21119
`
`—continued
`NY.
`
`and
`
`>11
`
`1
`
`211ly acce ,tahle'::21l1 or so-11Iate tltereol’.
`or a pharmaceut
`4-1. Use of a cornpound ol forrnula (I), or a pharmaceu-
`tically acceptable salt or solV'ate thereof, 1'01 the 1nanuf21cture
`of a medicament
`for the treatment 01 prevention of a
`lysosonial storage disease,
`the Compound of lorniula (l)
`having the structure:
`
`(11
`
`NH)
`
`z/l‘\A3
`' A R3
`N
`12:” MN”
`l/H
`
`wherein
`\
`x
`1
`‘
`’?
`A’, A", and A” are each independently selected iron": the
`
`group consistu 1,211N,CH and CQR4), provided that: at
`, .
`1e21s1 one of A A2 or A’ is N;
`
`each R is independenselectedlrornth2g oup consisting
`of halogen, 7(31.4 alliyl, 41.14 alkoxy, and 4CN;
`11 is l or 2, wherein the alhylene chain can ‘ e optionally
`substituted with one or more 4C“, alkyl groups;
`R1 is selected lioni 1 egroup consisting of 77777(‘14 alkyl,
`~~C3_wCycloalkyl, WCL4 21ll<yl-C3_ 121 C‘Icloalkyl
`
`2 10 aryl, WCJA 2ilkyl-Cfi_1,j aryl, —Q5— to lO—mem-
`ered)CJ 3 heteroaryl,
`77777CL4 alk‘Il Q5— to lO-rnern-
`bored}C_.3 heteroaryl, (5-1to lO—me1nhered)—C33 het-
`
`
`
`. _
`:-1o ll)-—1nernhe1ed)--: _
`
`
`
`heterocyclyl, and ?????CQ22222())Ra, wherein said alkyl
`
`
`
`0"c1‘alkyIl,alliylcycloalkyl.a1yl.all\V'l1rvl hete1oary1
`
`
`alky‘iheteroaryl, het-erocycly‘1 a
`a1ly1heterocyc‘ly'l
`
`
`
`groups 21.e optionally substituted With l, ‘2 or 3 sub-
`stituents each independently selected from the group
`consisting of halogen, hy2'r011.y, 77777CN. 77777t)Rb 77777SRb
`?????NQRh)3, WCL4 alkyl optiona1ly substituted With l, 2
`or 3 halogen atoms, optionally snhstituted 77777C, 211 aryl,
`optionally substituted -Q5— to lO-nicmhcred)-Cl,9 het-
`' l,
`T
`'
`to
`.
`1(1—111ernhered—C
`heteroCIclVl,
`
`optionally suhstituted 77777C)?????QCw .0 ary’l); and wherein
`said cycloalkyl, alkylc 'c1‘alkyIl, 21ryl, alkylaryl, het-
`roaryl, alkylheteroary‘i, heterocycly‘i and
`cyclyl1soptionally fused. to 21 further (second.)r111g; and
`
`alhylhetero-
`
`R" is seelected 1rorn the group consisting of hydrogen,
`~~C.1_4 alkyl, and ?????C34, cycloallry'l,
`‘1' .:.re111 said
`?????CL4 alky1 is optionally substituted with "7770(1114)
`
`alkyl
`optionally
`substituted with
`777770Q(11_4)Nllz,
`Rhy-zlroxy, 77777CN, halogen, or 77777NQRh)34; or
`and R2 tog Ither With the nitrogen atom to which they
`are attached form an optionally substituted 5,
`to
`ltl—mernhered heterocyclic ring wherein-
`Cyclic ring optionally contain.
`1, 2, or 3 additional
`11e1eroaton1s selected from the group consisting ofN, S,
`or O, and wherein”ring is optionally
`
`f11se6. to '21 phenyl ring;
`
`
`Rais selected from the group consisting of WCL4 alkV'1,
`?????€32.10
`cyCloalk‘Il, 2,2514 alhyl—C3_m Cycloallg 1,
`4C310 a1y1. %1_4 alkyd-Cg10 aryl, {5- to lG-nicni-
`hered)- C. _.3 heteroiry‘i,
`77777L 1.4 alkylx-Q5m t
`ll)-—1neni-—
`hered)-C 3 heteeroaryl, —Q5- to l0—n‘eP1hered)-C2 het—
`erocy1yl,a
`T
`'
`'
`
`
`eloalkyl, a1y1.
`
`
`
`I
`aliqy'la;,hetero21ryl, alkyll‘etero.yl,
`heterocv V'l an‘
`‘ky‘iheterocyI
`
`
`
`
` ‘i
`”ally su ,. .‘
`pendently seieC1e‘6. irorn the group consisting of halo—
`
`gen, hydroxy,
`77777C ()Rh,
`77777SRh Nt‘Rh)?
`4C_4 all(V'l optionally sn-hstituted With
`, 2, or 3
`halogen atoms, optional1y substituted 77777Cm0 ary‘i,
`optionally suhstitnted -Q5— to 11)1112111beredZ1-C _ het—
`eroar‘l, and —Q5— to lO—rnenihe1'ed‘1—C23 heterocycly;
`and wherein said cycloalkyl, 21lky'lcyc1oalkyl,
`21.
`.
`rocycly‘l and
`alkylaryl, heteroaryl, alkylheteroaryl, hete
`
`alkylheterocyclyl is optionally lused to 21,11112her Qsec--
`
`each Rh is independently hydrogen 2,2,2: 1, 4 alloyl, ?????€3.10,
`
`
`cycloalkyl or-J5 to 10-menihered '
`
`
`R“ is selected110111 the group con '
`
`het-eroaryl
`2,
`«(5— 1o
`lO-1neriihered)—C _9
`cychalkyl, and (5- to lO-n123rnhere2i)(,39 heterocy—
`
`heterocyclyl groups are opti
`tially substituted with
`2
`or 3 suhstituents each independe ,tly selected from the
`group consistino of halogen, hydroxy, WCN, MORE),
`
`77777SRh, ~~NQRh>2 WCL 42ill<yl optional1y su
`ituted
`With-1. 2, or3 substi uents eachindependently selected
`from the group consisting ol halogen ~~(ZN, mOlRh
`and 77777N(thg, optionall‘I substituted 77777C.» m 211'y'.,
`otionally substituted - 5, to lfi—znernhered —C
`~ he.—
`and--Q5- to 1()--rnemhered)-C.3_(3 heterocyely‘i,
`
`21nd Wheren aid 21ry