ATTACHMENT B
`
`

`

`3746.008PC01/TJS/THN
`
`_ 1 _
`
`REPLACEMENT SHEETS OF AMENDED CLAIMS
`
`I l.
`
`A compound of formula (I):
`
`N H2
`R2 A2J\A
`1d“RWfJ:N/R3
`
`(I),
`
`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, —C14 alkyl,
`
`10
`
`-C14 alkoxy, and ~CN;
`
`n is 1 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 -CM alkyl, -C3_10 cycloalkyl, -CM alkyl-
`
`C3_10 cycloalkyl, -C5.1o aryl, ~C1_4 alkyl—C540 aryl, —(5— to lO—membered)—C1,9 heteroaryl, -C14
`
`15
`
`alkyl—(S— to 10-membered)-C1_9 heteroaryl, -(5- to 10—membered)—C2_9 heterocyclyl, -CM
`
`alkyl-(5- to 10-membered)-C2_9 heterocyclyl, and —C(=O)Ra, wherein said -C1_4'a1kyl, —C3_10
`
`cycloalkyl, —C1.4 alkyl-€3.10
`
`cycloalkyl, —C5_10 aryl, —C1_4 alkyl-C540 aryl, —(5— to 10-
`
`membered)-C1_9 heteroaryl,
`
`-C1_4 alkyl-(S- to lO-membered)—C1.9 heteroaryl,
`
`-(5- to 10-
`
`membered)—C2.9 heterocyclyl and -C1_4 alkyl-(S- to 10-membered)—C2_9 heterocyclyl groups
`
`20
`
`are optionally substituted with 1, 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 1, 2, or 3 halogen atoms, optionally
`
`substituted -C6_1o aryl, optionally substituted —(5— to 10—membered)—C1.9 heteroaryl, —(5— to 10-
`
`membered)-C2,9 heterocyclyl, and optionally substituted —0—(C6_10 aryl),
`
`i
`
`AMENDED SHEET
`
`
`
`{28/16/2018
`
`

`

`rum--. “fit“...
`
`
`EPtinted; 02.71%
`
`,
`, n. ......i,._.._..,,\
`\C-LM-SPAMPCT/IB 2017/058 477 — 26.10.2018'fig9171953477J
`
`3746.008PC01/TJS/THN
`
`_ 2 _
`
`wherein the optional substituents in said optionally substituted —C5.10 aryl and —O-(C(,
`
`10 aryl) are selected from 1, 2, or 3 substituents, which can be the same or different, selected
`
`from the group consisting of halogen, —OH, C14 alkoxycarbonyl, hydroxycarbonyl,
`
`carbamoyl, -N02, -CN, —C1.4 alkyl optionally substituted by one or more halogen atoms, -C1_4
`
`5
`
`alkoxy optionally substituted by one or more halogen atoms and C1_4 hydroxyalkyl groups;
`
`and wherein the optional substituents in said optionally substituted -(5- to 10-
`
`membered)—C1.9 heteroaryl are selected from 1, 2, or 3 substituents, which can be the same or
`
`different, selected from the group consisting of halogen, C14 alkoxycarbonyl, carbamoyl,
`
`-N02, —OH, -C1.4 alkyl optionally substituted by one or more halogen atoms, and —C1.4 alkoxy
`
`- 1O
`
`optionally substituted by one or more halogen atoms; and wherein said -C3_10 cycloalkyl,
`
`15
`
`i
`
`20
`
`25
`
`-C1_4 alkyl-€3-10
`
`cycloalkyl,
`
`-C5-10 aryl, —C14 alkyl-C510 aryl, —(5-
`
`to 10—membered)-Cl.9
`
`alkyl—(S— to lO—membered)—C1.9 heteroaryl, —(5— to 10—membered)—C2_9
`heteroaryl, —C1_4
`heterocyclyl and -C1.4 alkyl-(S- to 10—membered)—C2_9 heterocyclyl is optionally fused to a
`further (second) ring; and
`-
`R2 is selected from the group consisting of hydrogen, —C14 alkyl, and -C:3_5 cycloalkyl,
`wherein said -C14 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
`optionally substituted 5— to 10-membered heterocyclic ring, wherein said 5— to EIO—membered
`heterocyclic ring optionally contains 1, 2, or 3 additional heteroatoms selected from the
`I
`group consisting of N, S, or O, and wherein said 5- to lO-membered heteroicyclic ring is
`
`l
`optionally fused to a phenyl ring;
`Ra is selected from the group consisting of -CM alkyl, -C3-1o cycloalkyl, -C14 alkyl-
`C3.1o cycloalkyl, -C5.10 aryl, -C1_4 alkyl-C610 aryl, -(5— to 10-membered)—C1.9 hejteroaryl, -C14
`alkyl-(S— to 10—membered)—C1_9 heteroaryl, -(5— to lO-membered)—C2_9 heterocytizlyl, and —C1_4
`alkyl—(S- to 10-membered)-C2_9 heterocyclyl, wherein said -C1_4 alkyl, -C3_10 cycloalkyl, -C1_4
`alkyl-€3-10 cycloalkyl, -C5t10 aryl, —C14 alkyl—C540 aryl, —(5- to lO—membered)— 11.9 heteroaryl,
`
`I
`-C1.4 alkyl—(S— to lO—membered)—C1_9 heteroaryl, —(5— to lO—membered)-C2_9 heterocyclyl and
`
`—C1_4 alkyl—(S— to 10—membered)-C2_9 heterocyclyl groups are optionally substituted with l, 2
`
`"2
`
`AMENDED SHEET
`
`Wfléfifil
`
`

`

`{Prlnled02/18188/201 8
`
`I CLMSPAMRj/m 2 o 1 7/0 58 4 7 7 _ 25.1020 18'6201-7 5&le
`
`3746.008PC01/TJS/THN
`
`_ 3 _
`
`0r 3 substituents each independently selected 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,
`
`5
`
`wherein the optional substituents in said optionally substituted -C6_10 aryl are selected
`
`from 1, 2, or 3 substituents, which can be the same or different, selected from the group
`
`consisting of halogen, -OH, C1_4 alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, —N02,
`
`—CN, —C1.4 alkyl optionally substituted by one or more halogen atoms, —C1.4 alkoxy optionally
`
`substituted by one or more halogen atoms and CM hydroxyalkyl; and
`
`10
`
`wherein the optional substituents in said optionally substituted -(5- to 10-membered)-
`
`C1_9 heteroaryl are selected from 1, 2, or 3 substituents, which can be the same or different,
`
`selected from the group consisting of halogen, CM alkoxycarbonyl, carbamoyl, —N02, -OH,
`
`—C1.4 alkyl optionally substituted by one or more halogen atoms, and —CM alkoxy optionally
`
`substituted by one or more halogen atoms;
`
`15
`
`and wherein said —C3_m cycloalkyl, -C1_4 alkyl-€3-10 cycloalkyl, -C(,10 aryl, -C14 alkyl—
`
`C540 aryl, —(5— to 10—membered)—C1_9 heteroaryl, —C14 alkyl—(S-
`
`to 10-membered)—C1_9
`
`heteroaryl, —(5— to 10-membered)—C2_9 heterocyclyl and -CM alkyl—(S- to 10-membered)—C2_9
`
`heterocyclyl is optionally fused to a further (second) ring;
`
`each Rb is independently hydrogen, —C14 alkyl, —C3_10 cycloalkyl, or —(5— to 10—
`
`20
`
`membered)—C2_9 heterocyclyl, wherein said -C14 alkyl,
`
`-C3_1o cycloalkyl or -(5— to 10-'
`
`membered)-C2_9 heterocyclyl group is optionally substituted by 1, 2 or 3 fluorine atoms; and
`
`R3 is selected from the group consisting of -C6_10 aryl,
`
`-(5- to 10-membered)—C1,9
`
`heteroaryl, -C3_10 cycloalkyl, and —(5- to lO—membered)—C2_9 heterocyclyl, wherein said -C5, 10
`
`aryl, —(5— t0 lO—membered)-C1_9 heteroaryl, —C3_10 cycloalkyl, and -(S- to lO—membered)—C2.9
`
`25
`
`heterocyclyl groups are optionally substituted with 1, 2 0r 3 substituents each independently
`
`selected from the group consisting of halogen, hydroxy, —CN, -ORb, —SRb,
`
`-N(Rb)2,
`
`-C1_4a1kyl 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 —C6.1o aryl,
`
`_’3‘
`
`AMENDED SHEET
`
`56/16/26118»:
`
`

`

`{PEihiéHi’“b:2f/fi @013“
`
`,..- ._ _ ..... -.....
`_
`.t awn
`H... ...._.. .I b
`arm—v.
`{CULMSPAMfDi‘T/IB 2017/058 477 — 26.10.201815261765845?
`
`3746.008PC01/TJS/THN
`
`_ 4 _
`
`optionally substituted —(5— to 10-membered)-C1_9 heteroaryl and -(5- to 10-membered)-C2_9
`
`heterocyclyl,
`
`wherein the optional substituents in said optionally substituted —C5_m aryl are selected
`
`from 1, 2, or 3 substituents, which can be the same or different, selected from the group
`
`5
`
`consisting of halogen, —OH, C14 alkoxycarbonyl, hydroxycarbonyl, carbamoyl, —N02, —CN,
`
`—C1,4 alkyl optionally substituted by one or more halogen atoms, —C1,4 alkoxy optionally
`
`substituted by one or more halogen atoms and CM hydroxyalkyl groups; and
`
`wherein the optional substituents in said optionally substituted -(5- to 10-membered)-
`
`C1_9 heteroaryl are selected from 1, 2, or 3 substituents, which can be the same or different,
`
`10
`
`selected from the group consisting of halogen, C14 alkoxycarbonyl, carbamoyl, —N02, -OH,
`
`—C1-4 alkyl optionally substituted by one or more halogen atoms, and —C1,4 alkoxy optionally
`
`substituted by one or more halogen atoms; and
`
`wherein said —C5.10 aryl, —(5- to 10-membered)—C]_9 heteroaryl, —C3_10 cycloalkyl, and
`
`-(5- to 1O-membered)—C2_9 heterocyclyl is optionally fused to a further (second) ring;
`
`15
`
`provided that the compound is not:
`
`
`
`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,
`
`—CM alkoxy, and —CN;
`
`25
`
`n is 1 or 2;
`
`R1 is selected from the group; consisting of CM alkyl, —C3_10 cycloalkyl, -CM alkyl-
`
`C3_10 cycloalkyl, -C6_1o aryl, -C1.4 alkyl—€6-10 aryl, —(5- to lO-membered)-C1_9 heteroaryl, -CM
`
`Sh]
`
`AM EN DED S H EET
`
`,
`
`325/1012018‘
`
`

`

`."............
`.
`r
`iPti.
`
`keg: 65/} {/2151}?
`
`{ELMngKMb‘T/IB 2017/053 477 — 26.10.20 1813203®§—47E!
`_...<_'
`
`3746.008PC01/TJS/THN
`
`_ 5 _
`
`alkyl-(S- to lO-membered)-C1_9 heteroaryl, —(5-
`
`to 10-membered)-C2_9 heterocyclyl,
`
`-C14
`
`alkyl-(S— to 10-membered)—C2.9 heterocyclyl, and —C(=O)Ra, wherein said —CM alkyl, -C3-10
`
`cycloalkyl, ~C1_4 alkyl—C3.10 cycloalkyl, —C6_10 aryl, —C1_4 alkyl~C6_10 aryl, —(5— to 10—
`
`membered)-C1_9 heteroaryl, —C1_4 alkyl—(S— to 10-membered)-C1_9 heteroaryl, -(5- to 10-
`
`5
`
`membered)-C2_9 heterocyclyl and -C14 alkyl—(S— to lO—membered)-C2_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_4 alkyl optionally substituted with 1, 2, or 3 halogen atoms, optionally
`
`substituted -C5.10 aryl, optionally substituted -(5- to 10-membered)-C1_g heteroaryl, and -(5-
`
`10
`
`to 10-membered)-C2.9 heterocyclyl, wherein the optional substituents in said optionally
`
`substituted —C5_10 aryl and said optionally substituted -(5- to 10—membered)-C1_9 heteroaryl
`
`are as defined in claim 1; and wherein said -C3_1o cycloalkyl, —C1_4 alkyl-C3_10 cycloalkyl,
`
`—C5.10 aryl, —C1_4 alkyl—C5_1o aryl, —(5— to 10—membered)—C1~.9 heteroaryl, -C14 alkyl—(S- to 10—
`
`membered)-C1.9 heteroaryl, -(5- to 10—membered)-C2_9 heterocyclyl and -C14 alkyl-(S- to 10-
`
`15
`
`membered)-C2_9 heterocyclyl is optionally fused to a further (second) ring; and ~
`
`R2 is hydrogen or —C14 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 lO-membered
`
`20
`
`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 ring is
`
`optionally fused to a phenyl ring;
`
`Ra is selected from the group consisting of -C1_/4 alkyl, -C3.10 cycloalkyl, —C14 alkyl-
`
`C3_10 cycloalkyl, _—C6_10 aryl, -C1,4 alkyl—Cmo aryl, —(5— to 10—membered)-C1_9 heteroaryl, -C14
`
`alkyl-(S- to 10—membered)—C1_9 heteroaryl,- (5- to 10-membered)-C2.9 heterocyclyl, and CM I
`
`25
`
`alkyl-(S- to 10-membered)—C2.9 heterocyclyl, wherein said -C1_4 alkyl, -C3_10 cycloalkyl, -C1.4
`
`alkyl-C3_10 cycloalkyl, -C5_10 aryl, —CM alkyl-C6.10 aryl, -(5- to 10—membered)-C1_9 heteroaryl,
`
`—C1_4 alkyl—(S- to 10-membered)—C1_9 heteroaryl, -(5- to 10-membered)—C2_9 heterocyclyl and
`
`-C1-4 alkyl-(S- to 10-membered)-C2.9 heterocyclyl groups are optionally substituted with 1, 2
`
`or 3 substituents each independently selected from the group consisting of halogen, hydroxy,
`
`:5-
`
`AMENDED SHEET
`
`a’ééfibléfifg
`
`

`

`Etlfi'téa? 52/‘171‘72513‘?
`
`{QLMéEAM PET/Is 2017[058 477 — 26.10.2015'3420179fi-8-34fi;
`
`3746.008PC01/TJS/THN
`
`_ 6 _
`
`-CN,
`
`-ORb, —SRb, —N(Rb)2, -C1.4 alkyl optionally substituted with 1, 2, or 3 halogen atoms,
`
`optionally substituted -C6_1o aryl, optionally substituted -(5- to 10-membered)-C1_9 heteroaryl,
`
`and -(5-
`
`to 10-membered)—C2_9 heterocyclyl, wherein the optional substituents in said
`
`optionally substituted £6-10 aryl and -(5— to 10—membered)-C1.9 heteroaryl are as defined in
`
`5
`
`claim 1; and wherein said -C3_10 cycloalkyl,
`
`-C1_4 alkyl-C3.1o cycloalkyl, —C5_10 aryl, —C1.4
`
`alkyl-Cs-lo aryl, -(5- to 10-membered)—C1_9 heteroaryl, —C1_4 alkyl—(S- to lO—membered)-C1_9
`
`heteroaryl, -(5— to 10-membered)-C2_9 heterocyclyl and -C]_4 alkyl-(S- to 10—membered)-C2-9
`
`heterocyclyl is optionally fused to a further (second) ring;
`
`each Rb is independently hydrogen, -C14 alkyl,
`
`-C3_lo cycloalkyl, or -(5- to 10—
`
`10
`
`membered)—C2_g heterocyclyl, wherein said —C1_4 alkyl,
`
`-C3-10 cycloalkyl or —(5-
`
`to 10—
`
`membered)-C2.9 heterocyclyl group is optionally substituted by 1, 2 or.3 fluorine atoms;
`R3 is -C5_10 aryl or -(S- to lO-membered)—C1.9 heteroaryl, wherein said -C6.1o aryl or
`
`-(5— t0 10-membered)-C1_9 heteroaryl group is optionally substituted with 1, 2 or 3
`
`substituents each independently selected from the group consisting of halogen, hydroxy,
`
`15
`
`-CN, -ORb, —SRb, -N(Rb)z, —C1_4alkyl optionally substituted with 1, 2, or 3 substituents each
`
`independently selected from the group consisting of halogen, —CN, -ORb, and -N(Rb)2,
`
`optionally substituted -C5_10 aryl, optionally substituted -(5— to 10-membered)-C1.9 heteroaryl
`
`and -(5— to 10—membered)-C2.9 heterocyclyl, wherein the optional substituents in said
`
`optionally substituted ~C6,10 aryl and -(5- to 10-membered)-C1.9 heteroaryl are as defined in
`
`20
`
`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(R").
`
`25
`
`4.
`
`The compound of claim 1 0r 2, or a pharmaceutically acceptable salt or solvate thereof,
`wherein A2 is N and Al and A3 are each independently selected from the group consisting of
`
`CH and C(R“).
`
`’6‘
`
`AMENDED SHEET
`
`-
`
`F2611 d/ééTé‘i
`
`

`

`ffiiiritiéiiiéé/i “2533‘.
`
`CLMSPAMDJNB 2017,05,; 477 _ 26, logowléédifigéfiii
`
`3746.008PC01/TJS/THN
`
`5.
`
`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(R“).
`
`5
`
`6.
`
`The compound of claim 1 0r 2, or a pharmaceutically acceptable salt or solvate thereof},
`
`wherein A1 and A2 are both N and A3 is CH or C(RA).
`
`7.
`
`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).
`
`10
`
`8.
`
`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(R“).
`
`9.
`
`. The compound of any one of claims [—8, or a pharmaceutically acceptable salt or solvate
`
`15
`
`thereof, wherein n is 1.
`
`10.
`
`The compound of any one of claims l-8, or a pharmaceutically acceptable salt or solvate
`thereof, wherein n is 2.
`i
`
`20
`
`11.
`
`The compound of any one of claims l—lO, or a pharmaceutically acceptable salt or solvate
`thereof, wherein R3 is unsubstituted -C6_10 aryl or -C6_10 aryl substituted gwith 1 or 2
`substituents each independently selected from the group consisting of halogen, hydroxy,
`—CN, —O(C14)alkyl, —S(C1-4)alkyl, —N(C1_4 alkyl)2, —NH(C1_4 alkyl), and —C1i4 alliyl optionally
`substituted with 1, 2, or 3 substituents each independently selected from the group consisting
`I
`
`lll
`
`25
`
`of halogen, —CN, “0(C1-4)alky1, -N(C1_4 alkyl)2, and —NH(C1_4 alkyl).
`
`12.
`
`The compound of any one of claims 1-11, or a phannaceutically acceptable salt or solvate
`
`thereof, wherein R2 is H.
`
`{.7
`
`AMENDED SHEET
`
`5
`
`rigid/2013:
`
`

`

`a
`(an... .__,,s... H “NW. ..
`1Pri”ted: 02/11/201é'
`
`“mm“, W -
`.
`.CLMSPAMijéT/| B 20 1 7/o5 8 4 77 _ 2 6_ 1 0_2 0 1glé2OJ7Q.
`
`3746.008PC01/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_1o aryl or —C14 alkyl-CGm aryl, wherein said -C5_10 aryl or -C14
`
`alkyl-C5-10 aryl is optionally substituted with 1, 2 or 3 groups each independently selected
`
`10
`
`from the group consisting of halogen, hydroxy, -CN, ~0Rb, —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 optional substituents in
`
`said optionally substituted —C5_10 aryl and
`
`-(5- to 10—membered)-C1-9 heteroaryl are as
`
`15
`
`defined 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 CH 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 lO—membered heterocyclic ring, wherein said 5— to 10—
`
`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
`
`{Q
`
`AM ENDED SH EET
`
`Zeifofz‘fi-‘é‘
`
`

`

`éF’li—ntéczili'fliéiill/3,2765{éi
`
`{CLMé‘l’PAMbgT/m 20177058 477 _ 26_10_2013;lém2§1i€iéég77‘
`
`3746.008PCO l/TJSITHN
`
`_ 9 _
`
`19.
`
`The compound of claim 1, which is selected from the group consisting of
`
`NH2
`
`NAN
`
`NH
`
`0/
`
`NH
`
`kaufij ”Mn
`
`5
`
`NH2
`
`““2
`
`m W a“ m ~31 to‘
`
`,
`
`I
`
`'
`
`
`
`, or a pharmaceutically acceptable salt or solvate thereof.
`
`10
`
`20.
`
`The compound of claim 1, which is selected from the group consisting of
`
`’9‘
`
`AM EN DED SHEET
`
`2650/261an
`
`

`

`Printed 02/11/2618
`
`C:SPAMDWB 2017/0523 477 25 102018132017058477
`
`3746.008PC01/TJS/I‘HN
`
`-10-
`
`
`
`{iii
`
`.
`
`AMENDED SHEET
`
`267367503?
`
`

`

`PrihiéfiOéi/fléfié?
`
`tcEM§PAMBT/IB 20171053 477- 26.10.2018'32017058477’
`
`3746.008PC01/TJS/THN
`
`_ 11 -
`
`NH2
`0»mm
`
`\0
`
`
`
`."3
`
`AMENDED SHEET
`
`‘26/16/Edfs
`
`

`

`,,.._. ._.__2 __
`
`Pnnted Q2/1112018
`
`CLMSPAMPT/IB 2017/058 477 26.10.2018'82017058477‘
`
`3746.008PC01
`
`ITJS/THN
`
`-12_
`
`’1‘
`NH2
`N
`.
`/ |
`A
`N \N / _
`5— “a
`7 it" '
`I
`$
`Em,«L\,»N\/JL\%‘\fi/[\; I
`"
`5
`
`‘%3
`
`NH2
`NAN“
`I
`I
`' 'NM
`
`H
`
`‘
`
`NH2
`
`_
`INJj._
`-
`QINJN/ N"0 /| Qi/N‘jwf I :
`H/(S l\
`H
`
`a
`
`5
`
`NH2
`
`V,
`QV'VENZ '/ ‘
`
`. x
`
`H
`
`,oxt
`
`5
`
`,71
`
`7‘
`
`47 l
`’NvflfigkN
`I.
`QM”
`”Au ‘*
`
`x
`
`-~
`
`.
`
`NH2
`
`~
`
`H
`
`‘
`
`NH2
`
`.
`
`1:1
`
`N112
`
`Q"Q 031£qu
`
`, and
`
`, or a pharmaceptically
`
`aceptable salt or solvate thereof
`
`21.
`
`A compound selected from the group consisting of
`
`1i:I willUN
`(3
`ki/qu/Cj @jvk
`
`1O
`
`O
`
`U
`
`AMENDED SHEET
`
`tan/1215332
`
`{
`
`
`

`

` _. me.
`'__"2'711/2o18
`
`
`new M”4.“. .t, m.“
`CLMSPAMDT/IB 2017,05,, 477_ 26 10.2018IBZO170584771
`
`3746.008PC01/TJS/THN
`
`_ 13 _
`
`NH2
`
`.\/'lI NJ§N
`
`NH2
`
`Br Q/ll‘
`
`NJ§N O “ OMe
`
`
`.VJJLZ‘JK,QQOVUMJ Q
`
`NH2
`
`
`
`’
`
`
`
`491:1,Q .VU\
`Q}. . Joli}:'ZuQ .VUNJQ
`
`
`5
`
`acceptable salt or solvate thereof.
`
`22.
`
`A compound selected from the group consisting of
`
`QVVKNJQ mm H
`or 1 / =.
`
`N
`N/
`
`_ \N ~
`
`-
`
`,or a pharrnaceutically
`
`, or a
`
`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
`
`‘
`
`15
`
`pharmaceutically acceptable excipient.
`
`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 (1):
`
`dc?
`
`AMENDED SHEET
`
`287%?2‘61’3‘3
`
`

`

`'434‘54'44142452711:724:55
`
`.¢._M_S.PAM§3>;T,.B 2017/0523 477 _ 26_ 10.20187l3121b1"'7;65$4i7i
`
`3746.008PC01/TJS/THN
`
`_ 14 _
`
`[\in
`A2J§A3
`2
`R1-""~[.4}/lkal’J\N/R3
`ill
`
`n
`
`(I),
`
`or a pharmaceutically acceptable salt or solvate thereof, wherein
`
`Al, A2, and A3 are each independently selected from the group consisting of N, CH
`
`5
`
`and C(R“), 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,
`
`-C14 alkoxy, and -CN;
`
`11 is 1 or 2, wherein the alkylene chain can be optionally substituted with one or more
`—C14 alkyl groups;
`‘
`
`10
`
`R1 is selected from the group consisting of -C1_4 alkyl, -C3_10 cycloalkyl, —C1,4 alkyl-
`
`€3-10 cycloalkyl, -C6_10 aryl, —C1_4 alkyl-C6_1g aryl, -(5- to 10-membered)—C1_g heteroaryl, -C14
`
`alkyl-(S— to 10—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 -CM alkyl, (33.10
`
`cycloalkyl,
`
`-C14 alkyl—C3.1o cycloalkyl,
`
`-C5.10 aryl, —CM alkyl-C5.10 aryl,
`
`-(5-
`
`to 10-
`
`15
`
`membered)-C1_g heteroaryl,
`
`-C1.4 alkyl—(S— to 10-membered)—C1_9 heteroaryl, —(5— to 10—
`
`membered)—C2-9 heterocyclyl and -CM alkyl-(S- to lO-membered)-C2-g heterocyclyl groups
`
`are Optionally substituted with l, 2 or 3 substituents each independently selected from the
`
`group
`
`consisting
`
`of
`
`halogen,
`
`hydroxy,
`
`-CN,
`
`-0Rb,
`
`-SRb,
`
`—N(Rb)2, —C1_4 alkyl optionally substituted with 1, 2, or 3 halogen atoms, optionally
`
`20
`
`substituted —C5r10 aryl, optionally substituted -(5— to lO-rnembered)—C,_9 heteroaryl, —(5~ to 10-
`
`membered)-C2-9 heterocyclyl, and optionally substituted —O-(C6.m aryl),
`
`wherein the optional substituents in said optionally substituted —C5_10 aryl and
`
`—O—(C6.m aryl) are selected from 1, 2, or 3 substituents, which can be the same or different,
`
`selected from the group consisting of halogen, -OH, C14 alkoxycarbonyl, hydroxycarbonyl,
`
`25
`
`carbamoyl, —N02,'-CN, —C1.4 alkyl optionally substituted by one or more halogen atoms, -C1.4
`
`5—H4
`
`AMENDED—WET
`
`»
`
`26/10/2018
`
`

`

`... ...-im.
`l. ,.
`QPrintedE' ':(,')‘27_1“1/:Etiifs,i
`
`.
`.. ' ...”
`ELM-IS—P’i-rfifi‘T/IB 2017/058 4-77 — 26.10.201813‘2bi-7u05éi???
`
`3746.008PC01/TJS/THN
`
`_ 15 _
`
`alkoxy optionally substituted by one or more halogen atoms and C14 hydroxyalkyl groups;
`
`and
`
`wherein the optional substituents in said optionally substituted -(5- to lO—membered}
`
`C14) heteroaryl are selected from 1, 2, or 3 substituents, which can be the same or different,
`
`5
`
`selected from the group consisting of halogen, C1-4 alkoxycarbonyl, carbamoyl, -N02, -OH,
`
`—C14 alkyl optionally substituted by one or more halogen atoms, and -C1_4 alkoxy optionally
`
`substituted by one or more halogen atoms;
`
`and wherein said -C3_ 10 cycloalkyl, —C1.4 alkyl—C3_m cycloalkyl, —C6-1o aryl, —C1_4 alkyl-
`
`€5.10
`
`aryl, —(5— to 10—membered)-C1.9 heteroaryl, —C1_4
`
`alkyl—(S— to lO—membered)—C1_9
`
`10
`
`heteroaryl, -(5- to 10—membered)-C2_9 heterocyclyl and -C1_4 alkyl-(S— to lO-membered)—C2_9
`
`15
`
`20
`
`heterocyclyl is optionally fused to a further (second) ring; and
`
`R2 is selected from the group consisting of hydrogen, -C14 alkyl, and -C3_5 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
`
`optionally substituted 5- to lO—membered heterocyclic ring, wherein said 5— to IO—mernbered
`
`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 lO-membered heterocyclic ring is
`
`optionally fused to a phenyl ring;
`Ra is selected from the group Consisting of —C1_4 alkyl, -C3.1u cycloalkyl, —C14 alkyl-
`
`C340 cycloalkyl, -C5,10 aryl, —C1_4 alkyl—Cmo aryl, -(5- to 10-membered)—C1,9 heteroaryl, —C14
`
`alkyl-(S- to 10—membered)-C1_9 heteroaryl, -(5— to 10-membered)—C2_9 heterocyclyl, and —C14
`
`alkyl-(S- to lO-membered)-C2_9 heterocyclyl, wherein said _-C1_4 alkyl, -C3_10 cycloalkyl, —C1_4
`
`alkyl—C3_10 cycloalkyl, -C6_10 aryl, -C14 alkyl—C6_ 10 aryl, -(5— to 10-membered)—C1.9 heteroaryl,
`
`25
`
`CM alkyl-(S- to 10-membered)—C1.9 heteroaryl, -(5- to 10—membered)-C2.9 heterocyclyl and
`
`-C1.4 alkyl-(S- to lO—membered)-C2.9 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_4 alkyl optionally substituted with l, 2, or 3 halogen atoms,
`
`15
`
`'
`
`AMENDED SHEET
`
`{$215555}
`
`

`

`Printed02/1i/2018
`
`CLMSPAMDvT/lg 2017/053 477 _ 26102018'32017
`
`3746.008PC01/TJS/THN
`
`_ 16 -
`
`optionally substituted -C5_10 aryl, optionally substituted —(5- to lO-membered)-C1.9 heteroaryl,
`
`and -(5— to 10-membered)—C2.9 heterocyclyl,
`
`wherein the optional substituents in said optionally substituted €6.10 aryl are selected
`
`from 1, 2, or 3 substituents, which can be the same or different, selected from the group
`
`5
`
`consisting of halogen, -OH, C14 alkoxycarbonyl, hydroxycarbonyl, carbamoyl, -N02, -CN,
`
`-C1.4 alkyl optionally substituted by one or more halogen atoms, -C14 alkoxy optionally
`substituted by one or more halogen atoms and CM hydroxyalkyl groups; and
`
`wherein the optional substituents in said optionally substituted —(5- to 10-mernbered)—
`
`C[.9 heteroaryl are selected from 1, 2, or 3 substituents, which can be the same or different,
`
`10
`
`selected from the group consisting of halogen, CM alkoxycarbonyl, carbamoyl, -N02, —OHs
`
`-Cl_4 alkyl optionally substituted by one or more halogen atoms, and -C1.4 alkoxy optionally
`
`substituted by one or more halogen atoms;
`
`and wherein said —C3_]o cycloalkyl, -C1_4 alkyl—€3.10 cycloalkyl, €6.10 aryl, -CM alkyl—
`
`C5_10 aryl, —(5— to lO—rnembered)-C1.9 heteroaryl, —C3_4 alkyl—(S-
`
`to lO—membered)-C1,9
`
`15
`
`heteroaryl, —(5— to lO—mernbered)—C2_9 heterocyclyl and -CM alkyl-(S- to lO-membered)-C2_9
`
`heterocyclyl is optionally fused to a further (second) ring;
`
`each Rb is independently hydrogen, -CM alkyl,
`-C3_1o cycloalkyl, or —(5-
`to 10-
`mernbered)—C2.9 heterocyclyl, wherein said -C1_4 alkyl, —C3-10 cycloalkyl or ~(5— to 10-
`membered)-C2_9 heterocyclyl group is optionally substituted by 1, 2 or 3 fluorine atoms; and
`R3 is selected from the group consisting of -C(,_10 aryl,
`-(5- to 10-membered)-Ci.9
`
`20
`
`heteroaryl, -C3-m cycloalkyl, and -(5- to 10—mernbered)—C2_9 heterocyclyl, wherein said ~Csro
`
`aryl, —(5— to 10—membered)—C1.9 heteroaryl, -C3.,10 cycloalkyl, and —(5- to 10—membered)—C2_9
`
`heterocyclyl groups are optionally substituted with l, 2 or 3 substituents each independently
`selected from the group consisting of halogen, hydroxy,
`—CN, -0Rb, —SRb, —N(Rb)2,
`
`25
`
`—C1_4a1kyl optionally substituted with 1, 2, or 3 substituents each independently selected from
`
`the group consisting of halogen, -CN, -ORb, and -N(Rb)2, optionally substituted -C5.10 aryl,
`
`optionally substituted -(5- to lO-membered)—C1_9 heteroaryl and -(5— to 10—membered)-C2,9
`
`heterocyclyl,
`
`

`

`,_., .. w.“«.4.
`
`Iw-A‘mwM
`
`has.a. .‘M a...”.....~__.._
`
`3746.008PC01/TJS/THN
`
`_ 17 _
`
`wherein the optionalsubstituents in said optionally substituted —C5_10 aryl are selected
`
`from 1, 2, or 3 substituents, which can be the same or different, selected from the group
`
`consisting of halogen, -OH, C14 alkoxycarbonyl, hydroxycarbonyl, carbarnoyl, -N02, —CN,
`
`—C1-4 alkyl optionally substituted by one or more halogen atoms, —C1_4 alkoxy optionally
`
`5
`
`substituted by one or more halogen atoms and CM hydroxyalkyl groups; and
`
`wherein the optional substituents in said optionally substituted —(5— to 10—membered)—
`
`C1-9 heteroaryl are selected from 1, 2, or 3 substituents, which can be the same or different,
`
`selected from the group consisting of halogen, C1_4 alkoxycarbonyl, carbamoyl, -N02, -OH,
`-C1_4 alkyl optionally substituted by one or more halogen atoms, and —C1_4 alkoxy optionally
`
`substituted by one or more halogen atoms, and
`wherein said -C5,m aryl, —(5- to 107membered)-C1.9 heteroaryl, -C3.10 cycloalkyl, and
`
`—(5- to 10—membered)—C2,9 heterocyclyl is optionally fused to a further (second) ring.
`
`25.
`
`26.
`
`27.
`
`28.
`
`The method of Claim 24, wherein the lysosomal storage disease is Gaucher’s disease
`i
`E
`The method of claim 24 or 25, wherein A], A2 and A3 are N.
`a
`.
`The method of claim 24 or 25, wherein the compound administered is as claimed in any one
`of claims 1-22.
`!
`g
`The method of claim 24 or 25, wherein the compound administered is seletjited from the
`
`1O
`
`15
`
`20
`
`group consisting of
`
`@VWNO widowU
`
`“2
`
`magiKT Chill?3 Girl,
`
`
`
`{17;
`
`.
`
`AMENDED SHEET
`
`{26?1‘0/2,Dig
`
`

`

`IFIIIIIIIEIIFIIEMIZQB-
`
`b'EM'é'EAM'PCT/IB 2017 /058 477- 26 10.2018'32017058477‘
`
`3746.008PC01/TJS/THN
`
`_ 18 _
`
`NH2
`NH2
`K/ijim’ihla“.I §$mkri
`Q 3'32
`“IL/Mimi“;
`
`\
`
`H
`
`1H2
`
`«'IKK/err/k Lurk G
`
`N \N
`
`OJL/fi Ni:
`ONJMXH«(:I
`NH2
`
`'
`
`JJ
`
`QIJAN'H'INWU @IJININ00“
`
`
`
`or a pharmaceutically acceptable salt or solvate thereof.
`
`29.
`
`A method of treating or preventing a lysosomal storage disease, comprising administering to ,
`
`a patient in need thereof an effective amount of a compound
`
`selected from the group
`
`consisting of
`
`NH2
`
`NH2
`
`NH2
`
`F AAVANAJCI QVIVANANO QwNA'NANJQ
`" WW giIX'NANOFChit/ANS;
` /'
`
`,
`
`NH2
`
`A
`
`NHZ
`
`1O
`
`“VII/NiN0
`6
`.
`
`a
`
`“A”
`OI‘ANJWQC<1WIJASNANKT
`
`9’
`““2
`NH2
`:1
`1H:
`CO.QVNJrNiNgNWA)WNW Lug;
`
`we]
`
`1' '8
`
`AM EN DED SH EET
`
`EEG/1' 0/2018
`
`

`

`gfifififéfiffiz'fjfi[263a
`
`xCLMflDAMpeT/IB 2017/0523 477 - 26102018519261 7058;???
`
`3746.008PC01/TJS/THN
`
`E j’ ‘N
`
`N \N
`
`N
`
`N \N
`
`and
`
`,
`
`“1/ 0', or a pharmaceutically
`
`acceptable salt or solvate thereof.
`
`30.
`
`The method of any one of claims 24—29, further comprising administering to the patient at
`
`'
`
`5
`
`least one other therapeutic agent.
`
`31.
`
`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 31, wherein the enzyme is B-glucocerebrosidase or an analog thereof.
`
`33.
`
`The method of claim 32, wherein the enzyme is imigluoerase.
`
`34.
`
`The method of any one of claims 30-33, wherein the therapeutic agent is an effective amount
`
`15
`
`of a small molecule chaperone.
`
`35-.
`
`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.
`
`37.
`
`The method of claim 36, wherein the small molecule chaperone is selected from the group
`
`25
`
`consisting of isofagomine, N—nonyl-1-deoxynojirimycin (NN—DNJ), ambroxol, and mi glustat.
`
`38.
`
`A compound as defined in any one of claims 1-22, or a pharmaceutically acceptable salt or
`
`solvate thereof, for use as a medicament.
`
`1‘9
`
`AMENDED SHEET
`
`26/107201§
`
`

`

`Printed 02/11/2018
`
`CLMSPAMDTAB 2017,05,; 477_ 25 1020181132017058477
`
`3746.008PC01/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§A
`
`2
`
`EHJLAIE»:
`
`)5
`
`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
`
`-C14 alkyl groups;
`
`R1 is selected from the group consisting of —C1_4 alkyl, —C3_10 cycloalkyl, -C1_4 alkyl-
`
`€3.10 cycloalkyl, -C6_10 aryl, —C1_4 alkyl—C540 aryl, -(5- to lO-membered)—C1_9 heteroaryl, —C14
`
`alkyl-(S- to 10-membered)-C1_9 heteroaryl, —(5— to 10—membered)—C2_9 heterocyclyl, —C1.4
`
`15
`
`alkyl—(5— to 10—membered)-C2_9 heterocyclyl, and —C(=O)Ra, wherein said —C14 alkyl, -C3_10
`
`cycloalkyl,
`
`-C1_4 alkyl-€3.10
`
`cycloalkyl,
`
`-C6_1o aryl,
`
`-C1.4 alkyl-€6.10
`
`aryl,
`
`-(5-
`
`to 10—
`
`membered)-C1_9 heteroaryl, —C1_4 alkyl-(S— to 10—membered)—C1-§ heteroaryl, —(5— to 10—
`
`membered)—C2-9 heterocyclyl and —C14 alkyl-(S- to 10-membered)-C2_9 heterocyclyl groups
`are optionally substituted with 1, 2 or 3 substituents each independently selected féom the
`
`20
`
`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 -C