— 2 —
`
`GARClA COLLAZO el 61].
`
`Application No. 16/474,461
`
`Amendments to the Claims
`
`This listing of claims will replace all prior versions, and listings, of claims in the application.
`
`(Original) A compound of formula (I):
`
`NH2
`
`R2
`I
`
`A2 \A3
`|
`
`n
`
`3
`
`(I),
`
`I H
`
`R1.N‘HJ\A1’J\N/R
`
`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,
`
`-C1-4 alkoxy, and -CN,
`
`11 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 -C1-4 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-membered)—C2-9 heterocyclyl,
`
`-C1-4 alkyl-(S- to 10-membered)—C2-9 heterocyclyl, and —C(=O)Ra, wherein said -C1-4 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-
`
`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,
`
`-CN,
`
`-ORb,
`
`-SRb,
`
`Atty. Dkt. No. 4315.0020001/TJS/THN
`
`

`

`— 3 —
`
`GARClA COLLAZO el 61].
`
`Application No. 16/474,461
`
`-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, -(5- to
`
`10-membered)-C2-9 heterocyclyl, and optionally substituted —O-(C6-10 aryl),
`
`wherein the optional substituents in said optionally substituted -C6-10 aryl and —0-
`
`(C640 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,
`
`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 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, 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 -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-
`
`membered)-C2-9 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,
`
`-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
`
`optionally substituted 5- to 10-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 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-
`
`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-membered)—C2-9 heterocyclyl, and
`
`Atty. Dkt. No. 4315.0020001/TJS/THN
`
`

`

`— 4 —
`
`GARClA COLLAZO el 61].
`
`Application No. 16/474,461
`
`-C1-4 alkyl-(S-
`
`to 10-membered)—C2-9 heterocyclyl, wherein said -C1-4
`
`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-
`
`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, -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 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 C1-4 hydroxyalkyl, 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 -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-membered)-C2-9 heterocyclyl and -C1-4 alkyl-(S- to 10-membered)-C2-9
`
`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 -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 -C6-10 aryl,
`
`-(5- to 10-membered)-C1.9
`
`heteroaryl, -C3-10 cycloalkyl, and -(5- to 10-membered)—C2-9 heterocyclyl, wherein said -C6-10
`
`aryl, -(5- to 10-membered)—C1-9 heteroaryl, -C3-10 cycloalkyl, and -(5- to 10-membered)-C2.9
`
`Atty. Dkt. No. 4315.0020001/TJS/THN
`
`

`

`— 5 —
`
`GARClA COLLAZO el 61].
`
`Application No. 16/474,461
`
`heterocyclyl groups are optionally substituted with 1, 2 or 3 sub stituents each independently
`
`selected from the group consisting of halogen, hydroxy,
`
`-CN,
`
`-ORb,
`
`-SRb,
`
`-N(Rb)2,
`
`-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 -C6-10
`
`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 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, 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 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, 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 -C6-10 aryl, -(5- to 10-membered)-C1-9 heteroaryl, -C3-10 cycloalkyl, and
`
`-(5- to 10-membered)—C2-9 heterocyclyl is optionally fused to a further (second) ring,
`
`provided that the compound is not:
`
`NH2
`
`OfiN/LS N
`\N N’Q
`0
`
`H
`
`.
`
`(Original) The compound of claim 1,
`
`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,
`
`Atty. Dkt. No. 4315.0020001/TJS/THN
`
`

`

`— 6 —
`
`GARClA COLLAZO el 61].
`
`Application No. 16/474,461
`
`each R4 is independently selected from the group consisting of halogen, -C1-4 alkyl,
`
`-C1_4 alkoxy, and -CN,
`
`11 is 1 or 2,
`
`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 10-membered)-C1-9 heteroaryl,
`
`-C1_4 alkyl-(S- to 10-membered)-C1-9 heteroaryl, -(5- to 10-membered)—C2-9 heterocyclyl,
`
`-C1-4 alkyl-(S- to 10-membered)—C2-9 heterocyclyl, and —C(=O)Ra, wherein said -C1-4 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-
`
`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,
`
`-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 the optional substituents in said optionally
`
`substituted -C6-10 aryl and said optionally substituted -(5- to 10-membered)-C1-9 heteroaryl
`
`are as defined in claim 1, and wherein said -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-membered)-C2.9 heterocyclyl and -C1-4 alkyl-(S- to 10-
`
`membered)-C2-9 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 10-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 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-
`
`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-membered)—C2-9 heterocyclyl, and
`
`Atty. Dkt. No. 4315.0020001/TJS/THN
`
`

`

`— 7 —
`
`GARClA COLLAZO el 61].
`
`Application No. 16/474,461
`
`-C1-4 alkyl-(S-
`
`to 10-membered)—C2-9 heterocyclyl, wherein said -C1-4
`
`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-
`
`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, -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 the optional substituents in said optionally substituted -C6-10 aryl and
`
`-(5- to 10-membered)-C1-9 heteroaryl are as defined in claim 1, and wherein said -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-
`
`membered)-C2-9 heterocyclyl and -C1-4 alkyl-(S- to 10-membered)-C2-9 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 -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 -C6-10 aryl or -(5- to 10-membered)—C1-9 heteroaryl, wherein said -C6-10 aryl or
`
`-(5-
`
`to 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,
`
`-CN, -ORb, -SRb, -N(Rb)2, -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 -C6-10 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
`
`claim 1.
`
`(Currently Amended) The compound of claim 1—er—2, or a pharmaceutically acceptable salt
`
`or solvate thereof, wherein A1 is N and A2 and A3 are each independently selected from the
`
`Atty. Dkt. No. 4315.0020001/TJS/THN
`
`

`

`— 8 —
`
`GARClA COLLAZO el 61].
`
`Application No. 16/474,461
`
`group consisting of CH and C(R4); or A2 is N and A1 and A3 are each independently selected
`
`from the
`
`rou
`
`consistin
`
`of CH and C R4' or A3 is N and A1 and A2 are each
`
`independently selected from the group consisting of CH and C1R4); or A1 and A2 are both N
`
`and A3 is CH or C1R4); or A1 and A3 are both N and A2 is CH or C1R4); or A2 and A3 are
`
`both N and A1 is CH or C1R41.
`
`4-8.
`
`(Cancelled)
`
`(Currently Amended)
`
`The compound of—ambene—ef—el-ai-ms—l—S claim 1, or a
`
`pharmaceutically acceptable salt or solvate thereof, wherein n is 1.
`
`(Currently Amended)
`
`The compound of—an—y—ene—efLel-a-i-ms—l—S claim 1, or a
`
`pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
`
`(Currently Amended)
`
`The compound of—amhene—eFel-ai-ms—l—l-G claim 1, or a
`
`pharmaceutically acceptable salt or solvate thereof, wherein R3 is unsubstituted -C6-10 aryl or
`
`-C6-10 aryl substituted with 1 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 1, 2, or 3 substituents each
`
`independently selected from the group consisting of halogen, -CN, -O(C1-4)alkyl, -N(C1-4
`
`alkyl)2, and -NH(C1-4 alkyl).
`
`(Currently Amended)
`
`The compound Offl6—GPGl—fl-l—EH—S—l—l—l— claim 1, or a
`
`pharmaceutically acceptable salt or solvate thereof, wherein R2 is H.
`
`(Currently Amended)
`
`The compound Offl6—GPGl—fl-l—EH—S—l—l—l— claim 1, or a
`
`pharmaceutically acceptable salt or solvate thereof, wherein R2 is -C1-4 alkyl.
`
`(Cancelled)
`
`(Currently Amended)
`
`The compound of—an—y—ene—efLel-a-i-ms—l—H claim 1, or a
`
`pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C6-10 aryl or -C1-4 alkyl-
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`Atty. Dkt. No. 4315.0020001/TJS/THN
`
`

`

`— 9 —
`
`GARClA COLLAZO el 61].
`
`Application No. 16/474,461
`
`C640 aryl, wherein said -C6-10 aryl or -C1-4 alkyl-C6-10 aryl is optionally substituted with 1, 2
`
`or 3 groups 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, wherein Rb is as defined in claim 1,
`
`and wherein the optional substituents in said optionally substituted -C6-10 aryl and -(5- to
`
`10-membered)-C1-9 heteroaryl are as defined in claim 1.
`
`(Currently Amended)
`
`The compound of—an—y—ene—efLel-a-i-ms—l—lé claim 1, or a
`
`pharmaceutically acceptable salt or solvate thereof, wherein Rb is hydrogen or -C1-4 alkyl.
`
`(Currently Amended)
`
`The compound of—an—y—ene—efLel-a-i-ms—l—l—l- claim 1, 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 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 ring is optionally fused to a phenyl ring.
`
`(Cancelled)
`
`(Original) The compound of claim 1, which is selected from the group consisting of
`
`16.
`
`17.
`
`18.
`
`19.
`
`NHz
`N)\N
`
`NH2
`NAN
`
`CV
`
`7
`
`Ni“;
`NH,
`@0446; CUE/AK)
`
`Atty. Dkt. No. 4315.0020001/TJS/THN
`
`

`

`— 10 —
`
`GARClA COLLAZO el 61].
`
`Application No. 16/474,461
`
`NH2
`
`0
`
`NH2
`
`I
`
`wrap wrap
`
`QV'MU CUMHCQ
`
`OVUWO @wQMU
`
`2
`
`7
`
`, and
`
`NH2
`
`| \N
`/ N
`H
`
`I
`N
`
`, or a pharmaceutically acceptable salt or solvate thereof.
`
`20.
`
`(Original) The compound of claim 1, which is selected from the group consisting of
`
`I m
`CU ”1‘“
`NMN @NMNQCN
`
`H
`
`H
`
`NH2
`/N
`NH2
`A
`A
`I
`\N @I NI \”
`©Q “I
`NM”
`N
`/ u
`
`/ N
`I
`
`Atty. Dkt. No. 4315.0020001/TJS/THN
`
`

`

`-11-
`
`GARC1A COLLAZO er 61].
`
`Application No. 16/474,461
`
`NH2
`
`NH2
`
`NJ§N
`|
`/O
`NJ§N
`|
`NMN/O/ Q/NMN/O/
`
`H
`
`H
`
`NH2
`
`NH2
`
`/O
`
`N
`H
`
`\0
`
`NH2
`NJ§N
`|
`NMN
`H
`
`CN
`
`7
`
`,
`
`N
`H
`
`7
`
`\0
`
`NH2
`NJ§N
`|
`NMN
`H
`
`,
`
`NH2
`\0
`CN
`)sz
`@I ”5‘“ <1 @I ”1‘”
`
`NMN
`H
`
`7
`
`N
`
`/ N
`H
`
`7
`
`NH2
`0/
`f2 \O
`AQVI M Q Gyw
`NM”
`
`|
`
`N
`
`/
`
`u
`
`0 \
`
`Atty. Dkt. No. 4315.0020001/TJS/THN
`
`

`

`-12-
`
`GARC1A COLLAZO er 61].
`
`Application No. 16/474,461
`
`N
`N
`R N
`N
`@MN/fij ©\/N\MN
`
`H
`
`H
`
`0/
`
`N \N
`
`l“
`|NMN
`H
`
`NH2
`
`NJ\|N
`I
`/O\©/N \
`
`H
`
`N
`
`O/
`
`NH2
`
`\0
`
`NH2
`
`Atty. Dkt. No. 4315.0020001/TJS/THN
`
`

`

`-13-
`
`GARClA COLLAZO er 61].
`
`Application No. 16/474,461
`
`NH2
`
`\0
`
`(jg ”ifij
`N\)\N/
`
`|
`
`” N
`
`H2
`
`NH2
`
`(fig “Ii
`/N
`
`N
`
`m
`
`NH
`
`2
`O
`(fly “W O\
`N\)\N/u
`
`7
`
`7 /
`
`I
`N
`
`\N
`'~/*~
`H
`
`O\
`
`0
`
`CU ”£5 CU ”Q
`
`N
`
`NAN
`H
`
`7
`
`7
`
`N
`
`NAN
`H
`
`NH2
`NHzl
`60 MO“ 60 Ni)
`NAN
`N
`NAN
`H
`H
`
`,and
`
`N
`
`, or a pharrnaceutically
`
`aceptable salt or solvate thereof.
`
`21.
`
`(Original) A compound selected from the group consisting of
`
`OMe
`
`Atty. Dkt. No. 4315.0020001/TJS/THN
`
`

`

`— 14 —
`
`GARClA COLLAZO el 61].
`
`Application No. 16/474,461
`
`H
`
`N
`H
`
`7
`
`OMe
`
`,
`
`NH2
`A
`N. ‘N
`I
`N\)\ /
`N
`
`NH2
`
`7
`
`)sz
`N
`\N
`um
`N
`
`N/
`
`N
`H
`
`OMe,
`
`NH2
`
`CN
`
`H
`
`and
`
`H
`
`, or a pharmaceutically
`
`acceptable salt or solvate thereof.
`
`22.
`
`(Original) A compound selected from the group consisting of
`
`1H2
`N \N a
`|
`NJNAN \ N
`
`H
`
`(10/
`
`and
`
`NH2
`
`NAN
`nu A Q
`N
`M
`
`ora
`
`pharmaceutically acceptable salt or solvate thereof.
`
`23.
`
`24.
`
`(Currently Amended) A pharmaceutical composition, comprising an effective amount of a
`
`compound of—anJyLene—efLGI-ai-ms—l—22 claim 1, or a pharmaceutically acceptable salt or
`
`solvate thereof, and at least one pharmaceutically acceptable excipient.
`
`(Original) 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):
`
`Atty. Dkt. No. 4315.0020001/TJS/THN
`
`

`

`— 15 —
`
`GARClA COLLAZO el 61].
`
`Application No. 16/474,461
`
`NHZ
`
`R2
`I
`
`A2 \A3
`|
`
`n
`
`3
`
`(I),
`
`| H
`
`R1.N\HJ\A1’J\N,R
`
`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,
`
`each R4 is independent selected from the group consisting of halogen, -C1-4 alkyl,
`
`-C1_4 alkoxy, and -CN,
`
`11 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 -C1-4 alkyl, -C3-10 cycloalkyl, -C1-4 alkyl-
`
`C340 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-membered)—C2-9 heterocyclyl,
`
`-C1-4 alkyl-(S- to 10-membered)—C2-9 heterocyclyl, and —C(=O)Ra, wherein said -C1-4 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-
`
`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,
`
`-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, -(5- to
`
`10-membered)-C2-9 heterocyclyl, and optionally substituted —O-(C6-10 aryl),
`
`wherein the optional substituents in said optionally substituted -C6-10 aryl and
`
`—O-(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,
`
`carbamoyl, -N02, -CN,
`
`-C1-4 alkyl optionally substituted by one or more halogen atoms,
`
`Atty. Dkt. No. 4315.0020001/TJS/THN
`
`

`

`— 16 —
`
`GARClA COLLAZO el 61].
`
`Application No. 16/474,461
`
`-C1-4 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, 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 -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-membered)-C2-9 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,
`
`-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
`
`optionally substituted 5- to 10-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 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-
`
`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-membered)—C2-9 heterocyclyl, and
`
`-C1-4 alkyl-(S-
`
`to 10-membered)—C2-9 heterocyclyl, wherein said -C1-4
`
`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-
`
`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, -CN,
`
`-ORb,
`
`-SRb,
`
`-N(Rb)2,
`
`-C1-4 alkyl optionally
`
`substituted with 1, 2, or 3 halogen atoms, optionally substituted -C6-10 aryl, optionally
`
`Atty. Dkt. No. 4315.0020001/TJS/THN
`
`

`

`— 17 —
`
`GARClA COLLAZO el 61].
`
`Application No. 16/474,461
`
`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 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, 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 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, 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 -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-membered)-C2-9 heterocyclyl and -C1-4 alkyl-(S- to 10-membered)-C2-9
`
`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 -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 -C6-10 aryl,
`
`-(5- to 10-membered)-C1.9
`
`heteroaryl, -C3-10 cycloalkyl, and -(5- to 10-membered)—C2-9 heterocyclyl, wherein said -C6-10
`
`aryl, -(5- to 10-membered)—C1-9 heteroaryl, -C3-10 cycloalkyl, and -(5- to 10-membered)-C2.9
`
`heterocyclyl groups are optionally substituted with 1, 2 or 3 sub stituents each independently
`
`selected from the group consisting of halogen, hydroxy,
`
`-CN, -ORb, -SRb, -N(Rb)2,
`
`-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 -C6-10
`
`aryl, optionally substituted -(5- to 10-membered)-C1.9 heteroaryl and -(5- to 10-membered)-
`
`C2-9 heterocyclyl,
`
`Atty. Dkt. No. 4315.0020001/TJS/THN
`
`

`

`— 18 —
`
`GARClA COLLAZO el 61].
`
`Application No. 16/474,461
`
`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, 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 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, 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 -C6-10 aryl, -(5- to 10-membered)—C1-9 heteroaryl, -C3-10 cycloalkyl, and
`
`-(5- to 10-membered)—C2-9 heterocyclyl is optionally fused to a further (second) ring.
`
`(Original) The method of claim 24, wherein the lysosomal storage disease is Gaucher’s
`
`disease.
`
`(Currently Amended) The method of claim 246146, wherein A1, A2 and A3 are N.
`
`(Currently Amended) The method of claim 24—er—26, wherein no more than two of A1 A2
`
`or A3 is N in the compound administered
`
`
`
`(Currently Amended) The method of claim 24—er—25, wherein the compound administered is
`
`selected from the group consisting of
`
`NH2
`
`25.
`
`26.
`
`27.
`
`28.
`
`N2\N
`
`“1 ngaéfijflmvkmga
`
`f2
`
`ACki/NNNO
`
`H
`
`MNNNO fiflNN/ifl
`
`H
`
`Atty. Dkt. No. 4315.0020001/TJS/THN
`
`

`

`-19-
`
`GARClA COLLAZO er 61].
`
`Application No. 16/474,461
`
`, and
`
`NH
`
`NH
`
`2 N|
`
`U Qle
`
`7
`
`NH
`
`or a pharrnaceutically acceptable salt or solvate thereof.
`
`29.
`
`(Original) 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
`
`Atty. Dkt. No. 4315.0020001/TJS/THN
`
`

`

`— 20 —
`
`GARClA COLLAZO el 61].
`
`Application No. 16/474,461
`
`N \N
`N/fi
`K/NJ A
`
`N mm
`
`0|, or a pharmaceutically
`
`7
`
`GAR \AN MAE: and
`
`N
`
`N \N
`' A
`
`N
`
`acceptable salt or solvate thereof.
`
`(Currently Amended) The method of—anyLene—eflel-ai-msélw claim 24, further comprising
`
`administering to the patient at least one other therapeutic agent.
`
`(Original) The method of claim 30, wherein the therapeutic agent is an effective amount of
`
`an enzyme for enzyme replacement therapy.
`
`(Original) The method of claim 31, wherein the enzyme is B-glucocerebrosidase or an
`
`analog thereof.
`
`(Cancelled)
`
`(Currently Amended) The method of—anybene—efLel-ai-ms—30—33 claim 30, wherein the
`
`therapeutic agent is an effective amount of a small molecule chaperone.
`
`30.
`
`31.
`
`32.
`
`33.
`
`34.
`
`35-50.
`
`(Cancelled)
`
`51.
`
`(Original) A method of treating or preventing a disease or disorder selected from the group
`
`consisting of Parkinson’s disease, Lewy body disease, dementia, multiple system atrophy,
`
`epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, major depression, polycystic
`
`kidney disease,
`
`type 2 diabetes, open angle glaucoma, multiple sclerosis, and multiple
`
`myeloma, comprising administering to a patient in need thereof an effective amount of a
`
`compound of formula (I):
`
`Atty. Dkt. No. 4315.0020001/TJS/THN
`
`

`

`— 21 —
`
`GARClA COLLAZO el 61].
`
`Application No. 16/474,461
`
`NHZ
`
`R2
`I
`
`A2 \A3
`|
`
`n
`
`3
`
`(I),
`
`| H
`
`R1.N\HJ\A1’J\N,R
`
`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,
`
`each R4 is independent selected from the group consisting of halogen, -C1-4 alkyl,
`
`-C1_4 alkoxy, and -CN,
`
`11 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 -C1-4 alkyl, -C3-10 cycloalkyl, -C1-4 alkyl-
`
`C340 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-membered)—C2-9 heterocyclyl,
`
`-C1-4 alkyl-(S- to 10-membered)—C2-9 heterocyclyl, and —C(=O)Ra, wherein said -C1-4 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-
`
`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,
`
`-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, -(5- to
`
`10-membered)-C2-9 heterocyclyl, and optionally substituted —O-(C6-10 aryl),
`
`wherein the optional substituents in said optionally substituted -C6-10 aryl and —0-
`
`(C640 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,
`
`carbamoyl, -N02, -CN,
`
`-C1-4 alkyl optionally substituted by one or more halogen atoms,
`
`Atty. Dkt. No. 4315.0020001/TJS/THN
`
`

`

`— 22 —
`
`GARClA COLLAZO el 61].
`
`Application No. 16/474,461
`
`-C1-4 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, 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 -C3-10 cycloalkyl, -C1-4 alkyl-C3-10 cycloalkyl, -C6-10 aryl, -C1-4 alkyl-
`
`C640 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 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(