Benzamide amine ARYL ether analogs as inhibitors of the menin-MLL interaction

Abstract

The present disclosure is directed to benzamide amine aryl ether analogs of Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as inhibitors of the interaction of menin with MLL and MLL fusion proteins, pharmaceutical compositions containing the same, and their use in the treatment of cancer and other diseases mediated by the menin-MLL interaction.

Description

[0001] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0002] BENZAMIDE AMINE ARYL ETHER ANALOGS AS INHIBITORS OF THE MENIN- MLL INTERACTION

[0003] RELATED APPLICATIONS

[0004] This application claims priority to U. S. Provisional Application No. 63 / 729,167, filed December 06, 2024, U. S. Provisional Application No. 63 / 763,167, filed February' 25, 2025, and U. S. Provisional Application No, 63 / 914,807, filed November 10, 2025, the entire contents of each of which is incorporated herein by reference,

[0005] BACKGROUND

[0006] The mixed-lineage leukemia (MLL), also known as KMT2A, gene encodes a protein that is a histone methyltransferase that is mutated in clinically and biologically distinctive subsets of acute leukemia. Rearranged mixed lineage leukemia (MLL-r) involves recurrent translocations of the 11 q23 chromosome locus which lead to an aggressive form of acute leukemia with limited therapeutic options. These translocations target the MLL gene creating an oncogenic fusion protein comprising the amino-terminus of MLL fused in frame with more than 60 different fusion protein partners. Menin, a ubiquitously expressed, nuclear protein encoded by the multiple endocrine neoplasia type 1 QMENL) tumor suppressor gene, has a high affinity binding interaction with MLL fusion proteins and is an essential co-factor of oncogenic MLL-r fusion proteins. Disruption of this interaction leads to selective growth inhibition and apoptosis of MLL-r leukemia cells both in vitro and in vivo.

[0007] The interaction between menin and MLL or MLL fusion proteins is an attractive target for therapeutic intervention, and there is a need for novel agents that inhibit the memn-MLL interaction for the treatment of various diseases and conditions, including leukemia, other cancers, and diabetes.

[0008] SUMMARY

[0009] In one aspect, the present disclosure is directed to a compound of Formula I’, Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0010]

[0011] a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0012] denotes a single bond or a double bond, as valency permits;

[0013] Bi, Bj, D, and E are each independently selected from C(RA1)(RA2), -C(RA1)(RA2)-C(RA1)(RA2)-, -C(RA1)(RA2)-O-, -C(RA1)(RA2)-NRA3-, -C(=O)-, -C(RA1)(RA2) C( O) -, and -N=C(NH2)- wherein no more than one of Bi, B2, D, and E is

[0014]

[0015] C(RA1)(RA2) -C(RA1)(RA2)-NRA3-, C(RA1)(RA2) C(=O)-, or -N=C(NH2)-;

[0016] V is N or CRW, wherein RWis H, halo, CN, OH, C1-C4 alkyl, C1-C4 alkoxy, amino, C1-C4 alkyl amino, or C2-C8 dialkylamino;

[0017] X is N or CRX, wherein Rxis absent, H, halo, CN, OH, C1-C4 alkyl, C1-C4 alkoxy, amino, C1-C4 alkyl amino, or C2-C8 dialkylamino;

[0018] each RA1is independently selected from absent, H, halo, C1-C4 alkyl, C1-C4 alkoxy, Ci- C4 haloalkyl, C1-C4 haloalkoxy, amino, C1-C4 alkylamino, C2-Cs dialkylamino, CN, NO2, and OH;

[0019] each RA2is independently selected from H, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, amino, C1-C4 alkylamino, C2-Cs dialkylamino, CN, NO2, and OH;

[0020] each R’3is independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C(O)RZ, and C(O)ORZ, wherein said C1-C4 alkyl is optionally substituted by phenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, CN, NO2, or OH;

[0021] RZis H, C1-C4 alkyl, or phenyl;

[0022] W is N or CH;

[0023] Y is N or CH; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0024] R1is

[0025] (a) -Ci-Cg alkylene-N(R3a’)(R3b’) or -C3-C12 cycloalkylene-N(R’a’)(R'’b’), wherein the Ci-Cg alkylene or C3-C12 cycloalkylene is optionally substituted with one or more R1as;

[0026] each R1asis independently halo, oxo, Ci-Cg alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0027] (b) 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1bs;

[0028] each R1bsis independently halo, oxo, ORja’, Ci-Cg alkyl, Ci-Cg haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(Rja’)(Rjb’), or S(=O)2R3a’; or (c) C3-C12 cycloalkyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C12 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0029] each R1csis independently halo, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, C(:::O)(R3a’), N(R3a’)(R3b’), OR3a\ or S(:==O)2R3a’> wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Cg alkoxy;

[0030] R2is H, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-C10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-Cio aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, or N(R4a’)(R4b’);

[0031] Z is O, CH2, or NH;

[0032] Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl or 6- to 10-membered heteroaryl is optionally substituted with one or more C1-C6 alkyl, halo, OH, CN, or C1-C6 alkoxy;

[0033] X3is H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halo, OR4a, oxo, CN, C(=O)N(R4a)(R4b), or N(R4a)(R4b);

[0034] R3is H, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-C10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, C(O)(R4a), or C(O)O- C(R4a)2-OC(O)(R4a), wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0035] cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R3a; or R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected;

[0036] each R3ais independently halo, OR4a, oxo, C(O)O(R4a), CN, C(=O)N(R4a)(R4b), OC(O)N(R4a)(R4b), S(=O)2R4b’, N(R4a)(R4b), Ci-C6alkyl, C3-C12 cycloalkyl, Ci-C6alkoxy, C6-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C3-C12 cycloalkyl, C6-C10 aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more substituent independently selected from halo, O(R4a’), oxo, CN, C(O)OR4a’, OC(O)N(R4a’)(R4b’), N(R4a’)(R4b’), N(R4a’)C(O)(R4b’), N(R4a’)C(O)O(R4b’), Ci-Ce alkyl that is optionally substituted with O(R4a), and 3- to 12-membered heterocyclyl that is optionally substituted with oxo;

[0037] each R4ais independently H, CN, or C1-C6 alkyl optionally substituted with C6-C10 aryl or N(R4a’)(R4b’);

[0038] each R4bis independently II, S(==O)2R4b’, C(O)()R4b’, C(O)R4b’, C(())NR4a’R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-Ce alkyl, C3-C12 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Ce alkyl is optionally substituted with Ci-Ce alkoxy or C(O)N(R4a’)(R4b’);

[0039] each R3a’ is independently H, Ci-Ce alkyl, Ci-C’e haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0040] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl;

[0041] each R3C’ IS independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl;

[0042] each R4a’ and R4b’ is independently H, Ci-Ce alkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0043] n is 1, 2, or 3.

[0044] In one aspect, the present disclosure is directed to a compound of Formula I, Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0045]

[0046] a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0047] W is N or CH;

[0048] Y is N or CH;

[0049] R1is

[0050] (a) -Ci-C6alkylene-N(R3a’)(R3b’) or -C3-C12 cycloalkylene-N(R’a’)(R'’b’), wherein the Ci-Ce alkylene or C3-C12 cycloalkylene is optionally substituted with one or more R1as;

[0051] each R1asis independently halo, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0052] (b) 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1bs;

[0053] each R1bsis independently halo, oxo, ORja’, Ci-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’; or (c) C3-C12 cycloalkyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C12 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0054] each R1csis independently halo, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, C(::::())(R3a’), N(R3a’)(R3b’), OR3a' or S(:==O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Ce alkoxy;

[0055] R2is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-C10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Ce Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0056] alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-Cio aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, or N(R4a’)(R4b’);

[0057] Z is O, CH2, or NH;

[0058] Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl or 6- to 10-membered heteroaryl is optionally substituted with one or more C1-C6 alkyl, halo, OH, CN, or C1-C6 alkoxy;

[0059] X3is H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halo, OR4a, oxo, CN, C(=O)N(R4a)(R4b), or N(R4a)(R4b);

[0060] RJis H, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg- C10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, C(O)(R4a), or C(O)O-C(R4a)2-OC(O)(R4a), wherein the Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, Cg-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R3a; or R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected;

[0061] each R3ais independently halo, OR4a, oxo, C(O)O(R4a), CN, C(===O)N(R4a)(R4b), ()C(O)N(R4a)(R4b), S(==O)2R4b’, N(R4a)(R4b), Ci-Cg alkyl, C3-C12 cycloalkyl, Ci-C6alkoxy, Cg-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the Ci-Cg alkyl, C3-C12 cycloalkyl, Cg-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more substituent independently selected from halo, O(R4a’), oxo, CN, C(O)OR4a’, OC(O)N(R4a’)(R4b), N(R4a’)(R4b’), N(R4a’)C(O)(R4b’), N(R4a’)C(O)O(R4b’), Ci-Cg alkyl that is optionally substituted with O(R4a), and 3- to 12-membered heterocyclyl that is optionally substituted with oxo;

[0062] each R4ais independently H, CN, or Ci-Cg alkyl optionally substituted with Cg-Cio aryl or N(R4a,)(R4b’);

[0063] each R4bis independently H, S(=O)2R4b’, C(O)OR4b’, C(O)R4b’, C(O)NR4a’R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-Cg alkyl, C3-C12 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Cg alkyl is optionally substituted with Ci-Cg alkoxy or C(O)N(R4a’)(R4b’); Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0064] each R3a’ is independently H, Ci-Ce alkyl, Ci-Cg haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Cg alkoxy;

[0065] each R3b’ is independently H, Ci-Ce alkyl, Ci-Cg haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl;

[0066] each R3C’ is independently H, Ci-Cg alkyl, Ci-Cg haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl;

[0067] each R4a’ and R4b’ is independently H, Ci-Cg alkyl, Cs-Cn cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0068] n is 1, 2, or 3.

[0069] In one aspect, the present disclosure is directed to a compound of Formula I-a,

[0070]

[0071] a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0072] W is N or CH;

[0073] Y is N or CH;

[0074] R1is

[0075] (a) -C1-C6 alkylene-N(R3a’)(R3b’) or -C3-C12 cycloalkylene-N(R3a’)(R3b’), wherein the Ci-Ce alkylene or C3-C12 cycloalkylene is optionally substituted with one or more R1as;

[0076] each R1asis independently halo, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, C(::::())(R3a’), N(R3a’)(R3b’), or S(===O)2R3a’;

[0077] (b) 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1bs; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0078] each R,bsis independently halo, oxo, ORja’, Ci-Cg alkyl, Ci-C6 haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’; or (c) C3-C12 cycloalkyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C12 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more Rles;

[0079] each R1csis independently halo, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Cg alkoxy;

[0080] R2is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg- C10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ct-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, or N(R4a’)(R4b’);

[0081] Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl, wherein the 6- to 10- membered aryl or 6- to 10-membered heteroaryl is optionally substituted with one or more C1-C6 alkyl, halo, OH, CN, or C1-C6 alkoxy;

[0082] X3is H or C1-C6alkyl, wherein the Ci-Cg alkyl is optionally substituted with one or more halo, OR4a, oxo, C

[0083]

[0084] CN, C(=O)N(R4a)(R4b), or N(R4a)(R4b);

[0085] R3is H, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-C10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, C(O)(R4a), or C(O)O-C(R4a)2-OC(O)(R4a), wherein the Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R3a; or R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected;

[0086] each R3ais independently halo, OR4a, oxo, C(O)O(R4a), CN, C(=O)N(R4a)(R4b), OC(O)N(R4a)(R4b), S(=O)2R4b’, N(R4a)(R4b), Ci-Cg alkyl, C3-C12 cycloalkyl, Ci-Cg alkoxy, Cg-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the Ci-Cg alkyl, C3-C12 cycloalkyl, Cg-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more substituent independently selected from halo, O(R4a’), oxo, CN, C(O)OR4a’, OC(O)N(R4a’)(R4b’), N(R4a’)(R4b’), N(R4a’)C(O)(R4b’), Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0087] N(R4a’)C(O)O(R4b’), Ci-Ce alkyl that is optionally substituted with O(R4a), and 3- to 12-membered heterocyclyl that is optionally substituted with oxo;

[0088] each R4ais independently H, CN, or Ci-Ce alkyl optionally substituted with Ce-Cio aryl or N(R4a’)(R4b’);

[0089] each R4bis independently H, S(=O)2R4b’, C(O)OR4b’, C(O)R4b’, C(O)NR4a’R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-C6alkyl, C3-C12 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Ce alkyl is optionally substituted with Ci-Ce alkoxy or C(O)N(R4a’)(R4b’);

[0090] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0091] eachR3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-Ci2cycloalkyl, or 3- to 12- membered heterocyclyl;

[0092] each RC’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl;

[0093] each R4a’ and R4b’ is independently H, C1-C6 alkyl, Cs-Ci cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0094] n is 1, 2, or 3.

[0095] In one aspect, the present disclosure is directed to a compound of Formula 1-b,

[0096]

[0097] a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0098] W is N or CH;

[0099] Y is N or CH; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0100] R1is

[0101] (a) -Ci-Cg alkylene-N(R3a’)(R3b’) or -C3-C12 cycloalkylene-N(R’a’)(R'’b’), wherein the Ci-Cg alkylene or C3-C12 cycloalkylene is optionally substituted with one or more R1as;

[0102] each R1asis independently halo, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0103] (b) 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1bs;

[0104] each R1bsis independently halo, oxo, ORja’, Ci-Cg alkyl, Ci-Cg haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(Rja’)(Rjb’), or S(=O)2R3a’; or (c) C3-C12 cycloalkyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C12 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0105] each R1csis independently halo, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, C(::::())(R3a’), N(R3a’)(R3b’), OR3a' or S(==O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Cg alkoxy;

[0106] R2is H, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-C10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-Cio aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, or N(R4a’)(R4b’);

[0107] Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl or 6- to 10-membered heteroaryl is optionally substituted with one or more C1-C6 alkyl, halo, OH, CN, or C1-C6 alkoxy;

[0108] X3is H or C1-C6alkyl, wherein the Ci-Cg alkyl is optionally substituted with one or more halo, OR4a, oxo, C

[0109]

[0110] N, C(=O)N(R4a)(R4b), or N(R4a)(R4b);

[0111] R3is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, C(O)(R4a), or C(O)O-C(R4a)2-OC(O)(R4a), wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl is Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0112] optionally substituted with one or more R3a; or R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected;

[0113] each R3ais independently halo, OR4a, oxo, C(O)O(R4a), CN, C(=O)N(R4a)(R4b), OC(O)N(R4a)(R4b), S(=O)2R4b’, N(R4a)(R4b), Ci-C6alkyl, C3-C12 cycloalkyl, Ci-C6alkoxy, C6-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more substituent independently selected from halo, O(R4a’), oxo, CN, C(O)OR4a’, OC(O)N(R4a’)(R4b’), N(R4a’)(R4b’), N(R4a’)C(O)(R4b’), N(R4a’)C(O)O(R4b’), Ci-C6alkyl that is optionally substituted with O(R4a), and 3- to 12-membered heterocyclyl that is optionally substituted with oxo;

[0114] each R4ais independently H, CN, or C1-C6 alkyl optionally substituted with C6-C10 aryl or N(R4a’)(R4b’);

[0115] each R4bis independently H, S(=O)2R4b'C(O)OR4b’, C(())R4b’, C(O)NR4a’R4b’ C(O)CH2-N(R4a’)(R4b’), Ci-C6alkyl, C3-C12 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Ce alkyl is optionally substituted with Ci-Ce alkoxy or C(O)N(R4a’)(R4b’);

[0116] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R’C’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0117] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl;

[0118] each R3c' is independently H, C1-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl;

[0119] each R4a’ and R4b’ is independently H, Ci-Ce alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0120] n is 1, 2, or 3.

[0121] In one aspect, the present disclosure is directed to a compound of Formula I-c, Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0122]

[0123] a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0124] W is N or CH;

[0125] Y is N or CH;

[0126] R1is

[0127] (a) -Ci-C6alkylene-N(R3a’)(R3b’) or -C3-C12 cycloalkylene-N(Rja’)(R'’b’), wherein the Ci-Ce alkylene or C3-C12 cycloalkylene is optionally substituted with one or more R1as;

[0128] each R1asis independently halo, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0129] (b) 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1bs;

[0130] each R1bsis independently halo, oxo, ORja’, Ci-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’; or (c) C3-C12 cycloalkyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C12 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0131] each R1csis independently halo, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, C(::::())(R3a’), N(R3a’)(R3b’), OR3a' or S(:==O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Ce alkoxy;

[0132] R2is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-C10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Ce Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0133] alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-Cio aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, or N(R4a’)(R4b’);

[0134] Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl or 6- to 10-membered heteroaryl is optionally substituted with one or more Ci-Cg alkyl, halo, OH, CN, or C1-C6 alkoxy;

[0135] X3is H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halo, OR4a, oxo, CN, C(=O)N(R4a)(R4b), or N(R4a)(R4b);

[0136] R3is H, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-C10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, C(O)(R4a), or C(O)O-C(R4a)2-OC(O)(R4a), wherein the Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R3a; or R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected;

[0137] each R3ais independently halo, OR4a, oxo, C(O)O(R4a), CN, C(=O)N(R4a)(R4b), OC(O)N(R4a)(R4b),

[0138]

[0139] C(O)N(R4a)(R4b), S(=O)2R4b' N(R4a)(R4b), C1-C6 alkyl, C3-C12 cycloalkyl, C1-C6 alkoxy, C6-C10 aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the Ci-Cg alkyl, C3-C12 cycloalkyl, Cg-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more substituent independently selected from halo, O(R4a’), oxo, CN, C(O)OR4a’, OC(O)N(R4a’)(R4b’), N(R4a’)(R4b’), N(R4a’)C(O)(R4b’), N(R4a)C(O)O(R4b’), Ci-Cg alkyl that is optionally substituted with O(R4a), and 3- to 12-membered heterocyclyl that is optionally substituted with oxo;

[0140] each R4ais independently H, CN, or Ci-Cg alkyl optionally substituted with Cg-Cio aryl or N(R4a’)(R4b’);

[0141] each R4bis independently H, S(=O)2R4b’, C(O)OR4b’, C(O)R4b’, C(O)NR4a,R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-Cg alkyl, C3-C12 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Cg alkyl is optionally substituted with Ci-Cg alkoxy or C(O)N(R4a’)(R4b’);

[0142] each Rja’ is independently H, Ci-Cg alkyl, Ci-Cg haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Cg alkoxy; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0143] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl;

[0144] each R3c’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl;

[0145] each R4a’ and R4b’ is independently H, Ci-Ce alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0146] n is 1, 2, or 3.

[0147] In one aspect, the present application relates to a pharmaceutical composition comprising a compound of the application, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0148] In one aspect, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the application, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0149] In one aspect, the present application relates to a pharmaceutical composition comprising a compound of the application, and a pharmaceutically acceptable carrier.

[0150] In one aspect, the present application relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the application, and a pharmaceutically acceptable carrier.

[0151] The present disclosure further provides a use of a compound of Formula I’, I, I-a, I-b, or I-c, or a stereoisomer, or a pharmaceutically acceptable salt thereof in a method of treating cancer in a patient in need thereof.

[0152] The present disclosure further provides a compound of Formula I’, I, I-a, I-b, or I-c, or a stereoisomer, or a pharmaceutically acceptable salt thereof for use in a method of treating cancer in a patient in need thereof.

[0153] The present disclosure further provides a compound of Formula F, I, I-a, I-b, or I-c, or a stereoisomer, or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of cancer in a patient in need thereof.

[0154] The present disclosure further provides a method of inhibiting the interaction between menin and MLL comprising contacting the menin and MLL with an effective amount of a compound of Formula F, I, I-a, I-b, or I-c, or a stereoisomer, or a pharmaceutically acceptable salt thereof. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0155] The present disclosure further provides a method of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of Formula I’, I, I-a, I-b, or I-c, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0156] The present disclosure further provides a method of inhibiting the interaction between menin and MLL comprising contacting the menin and MLL with a compound of Formula I’, I, I-a, I-b, or I-c, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0157] The present di sclosure further provides a method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of Formula F, I, I-a, I-b, or I-c, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0158] The present disclosure further provides a method of inhibiting the interaction between menin and MLL comprising contacting the menin and MLL with a compound of Formula I’, I, I-a, I-b, or I-c, or a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0159] The present disclosure further provides a method of inhibiting the interaction between menin and MLL comprising contacting the menin and MLL with a pharmaceutical composition comprising a compound of Formula F, I, I-a, I-b, or I-c, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0160] The present disclosure further provides a method of treating cancer in a patient comprising administering to the patient a compound of Formula I’, I, I-a, I-b, or I-c, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0161] The present disclosure further provides a method of treating cancer in a patient comprising administering to the patient a pharmaceutical composition comprising a compound of Formula F, I, I-a, I-b, or I-c, a stereoisomer, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0162] The present disclosure further provides a pharmaceutical composition comprising a compound of Formula I’, I, I-a, I-b, or I-c, a stereoisomer, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0163] The present disclosure further provides a pharmaceutical composition comprising a salt or crystalline form of a compound of Formula F, I, I-a, I-b, or I-c, and at least one pharmaceutically acceptable carrier. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0164] The present disclosure further provides a compound of Formula I’, I, I-a, I-b, or I-c, wherein the compound is useful for the treatment of cancer and wherein the compound minimizes hERG binding.

[0165] In some embodiments, present disclosure further provides a method of preparing a compound herein according to a scheme of the present disclosure or synthetic description in the Examples.

[0166] In some embodiments, present disclosure further provides an intermediate useful in the preparation of any one of the compounds herein.

[0167] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, illustrative methods and materials are now described. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinaiy skill in the art to which this disclosure belongs.

[0168] DETAILED DESCRIPTION

[0169] In some embodiments, the present disclosure is directed to a compound of Formula I’,

[0170]

[0171] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0172] a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0173] denotes a single bond or a double bond, as valency permits;

[0174] Bi, B2, D, and E are each independently selected from -C(RA1)(RA2)--C(RA1)(R^)-C(RA1)(R-'2)-, -C(RA1)(RA2)-O- -C(RA1)(R-,32)-NR^-, -C(=O)--C(RA1)(RA2)-C(=O)-, and -N=C(NH2)- wherein no more than one of Bi, B2, D, and E is -C(RA1)(R^)~O-, -C(RA1)(RA2)-NR / A?- -C(RA1)(RA2)-C(=O)-, -C(=O)- or -N=C(NH2)-;

[0175] V is N or CRW, wherein Rwis H, halo, CN, OH, C1-C4 alkyl, C1-C4 alkoxy, amino, C1-C4 alkyl amino, or C -C8 dialkylamino;

[0176] X is N or CRX, wherein Rxis absent, H, halo, CN, OH, Cj-C4 alkyl, C1-C4 alkoxy, amino, C1-C4 alkyl amino, or C2-C8 dialkylamino;

[0177] each RA1is independently selected from absent, H, halo, C1-C4 alkyl, C1-C4 alkoxy, Ci-C4 haloalkyl, C1-C4 haloalkoxy, amino, C1-C4 alkylamino, C2-C8 dialkylamino, CN, NO2, and OH;

[0178] eachR^ is independently selected from H, halo, C1-C4 alkyl, C4-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, amino, Ci-C4alkylatnino, C2-C8 dialkylamino, CN, NO2, and OH;

[0179] each RA3is independently selected from H, C1-C4 alkyl, C4-C4 alkoxy, C1-C4 haloalkyl, C(())RZ, and C(O)ORZ, wherein said C1-C4 alkyl is optionally substituted by phenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, CN, NO2, or OH;

[0180] RZis H, C1-C4 alkyl, or phenyl;

[0181] W is N or CH;

[0182] Y is N or CH;

[0183] R1is

[0184] (a) -Ci-Ce alkylene-N(R3a’)(R3b’) or -C3-C12 cycloalkylene-N(R’a’)(R'’b’), wherein the Ci-Ce alkylene or C3-C12 cycloalkylene is optionally substituted with one or more R1as;

[0185] each R1asis independently halo, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0186] (b) 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1bs;

[0187] each R1bsis independently halo, oxo, ORja’, Ci-Ce, alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’; or Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0188] (c) C3-C12 cycloalkyl substituted with one or more 3- to 12-membered heterocyclyl w’hich has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C12 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more Rles;

[0189] each R1csis independently halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Ce alkoxy;

[0190] R2is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cs alkoxy, C3-C12 cycloalkyl, Ce- C10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, Cs-Cn cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, or N(R4a’)(R4b’);

[0191] Z is 0, CH2, or NH;

[0192] Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl, wherein the 6- to 10- membered aryl or 6- to 10-membered heteroaryl is optionally substituted with one or more C1-C6 alkyl, halo, OH, CN, or C1-C6 alkoxy;

[0193] X3is H or C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with one or more halo, OR4a, oxo, CN, C(=O)N(R4a)(R4b), or N(R4a)(R4b);

[0194] R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce- C10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, C(O)(R4a), or C(O)O-C(R4a)2-OC(O)(R4a), wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R3a; or R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected;

[0195] each R3ais independently halo, OR4a, oxo, C(O)O(R4a), CN, C(=O)N(R4a)(R4b), OC(O)N(R4a)(R4b), S(=O)2R4b’, N(R4a)(R4b), Ci-C6alkyl, C3-C12 cycloalkyl, Ci-C6alkoxy, C6-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, w’herein the Ci-Ce alkyl, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more substituent independently selected from halo, O(R4a’), oxo, CN, C(O)OR4a’, OC(O)N(R4a’)(R4b’), N(R4a’)(R4b’), N(R4a’)C(O)(R4b’), Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0196] N(R4a’)C(O)O(R4b’), Ci-Ce alkyl that is optionally substituted with O(R4a), and 3- to 12-membered heterocyclyl that is optionally substituted with oxo;

[0197] each R4ais independently H, CN, or Ci-Ce alkyl optionally substituted with Ce-Cio aryl or N(R4a’)(R4b’);

[0198] each R4bis independently H, S(=O)2R4b’, C(O)OR4b’, C(O)R4b’, C(O)NR4a’R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-C6alkyl, C3-C12 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Ce alkyl is optionally substituted with Ci-Ce alkoxy or C(O)N(R4a’)(R4b’);

[0199] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0200] eachR3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-Ci2cycloalkyl, or 3- to 12- membered heterocyclyl;

[0201] each RC’ is independently II, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl;

[0202] each R4a’ and R4b’ is independently II, C1-C6 alkyl, Cs-Ci cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0203] n is 1, 2, or 3.

[0204] In some embodiments, when X is N in Formular I’, the atom of Z that is directly bonded with X is other than N.

[0205] In some embodiments, when X is N in Formular I’, the atom of Z that is directly bonded with X is other than O.

[0206] In some embodiments, when X is N in Formular I’, the atom of Z that is directly bonded with X is other than C.

[0207] In some embodiments, when is a double bond, X is C.

[0208] In some embodiments, the spiro moiety represented by the below formula: Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0209]

[0210] wherein e and f indicate points of attachment to the remainder of the molecule, is selected from:

[0211]

[0212] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0213]

[0214] In some embodiments, the present di sclosure is directed to a compound of Formula I,

[0215]

[0216] a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0217] W is N or CH;

[0218] Y is N or CH;

[0219] R1is Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0220] (a) -Ci-Cg alkylene-N(Rja^(Rjb’) or -C3-C12 cycloalkylene-N(R3a’)(R3b’), wherein the Ci-Cg alkylene or C3-C12 cycloalkylene is optionally substituted with one or more R1as;

[0221] each R1asis independently halo, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0222] (b) 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1bs;

[0223] each R1bsis independently halo, oxo, OR3a’, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’; or (c) C3-C12 cycloalkyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C12 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more Rics;

[0224] each R1csis independently halo, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, C( O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Cg alkoxy;

[0225] R2is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce- C10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, or N(R4a’)(R4b’);

[0226] Z is O, CH2, or NH;

[0227] Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl or 6- to 10-membered heteroaryl is optionally substituted with one or more C1-C6 alkyl, halo, OH, CN, or C1-C6 alkoxy;

[0228] X3is H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halo, OR4a, oxo, CN, C(=O)N(R4a)(R4b), or N(R4a)(R4b);

[0229] R3is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, C(O)(R4a), or C(O)O-C(R4a)2-OC(O)(R4a), wherein the Ci-Cg alkyl, C2-C6 alkenyl, C2-Cg alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl is Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0230] optionally substituted with one or more R3a; or R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected;

[0231] each R3ais independently halo, OR4a, oxo, C(O)O(R4a), CN, C(=O)N(R4a)(R4b), OC(O)N(R4a)(R4b), S(=O)2R4b’, N(R4a)(R4b), Ci-C6alkyl, C3-C12 cycloalkyl, Ci-C6alkoxy, C6-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more substituent independently selected from halo, O(R4a’), oxo, CN, C(O)OR4a’, OC(O)N(R4a’)(R4b’), N(R4a’)(R4b’), N(R4a’)C(O)(R4b’), N(R4a’)C(O)O(R4b’), Ci-C6alkyl that is optionally substituted with O(R4a), and 3- to 12-membered heterocyclyl that is optionally substituted with oxo;

[0232] each R4ais independently H, CN, or C1-C6 alkyl optionally substituted with C6-C10 aryl or N(R4a’)(R4b’);

[0233] each R4bis independently H, S(=O)2R4b'C(O)OR4b’, C(())R4b’, C(O)NR4a’R4b’ C(O)CH2-N(R4a’)(R4b’), Ci-C6alkyl, C3-C12 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Ce alkyl is optionally substituted with Ci-Ce alkoxy or C(O)N(R4a’)(R4b’);

[0234] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R’C’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0235] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl;

[0236] each R3c' is independently H, C1-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl;

[0237] each R4a’ and R4b’ is independently H, Ci-Ce alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0238] n is 1, 2, or 3.

[0239] In some embodiments, the present disclosure is directed to a compound of Formula I-a, Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0240]

[0241] a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0242] W is N or CH;

[0243] Y is N or CH;

[0244] R1is

[0245] (a) -Ci-C6alkylene-N(R3a’)(R3b’) or -C3-C12 cycloalkylene-N(Rja’)(R'’b’), wherein the Ci-Ce alkylene or C3-C12 cycloalkylene is optionally substituted with one or more R1as;

[0246] each R1asis independently halo, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0247] (b) 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1bs;

[0248] each R1bsis independently halo, oxo, ORja’, Ci-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’; or (c) C3-C12 cycloalkyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C12 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0249] each R1csis independently halo, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, C(::::())(R3a’), N(R3a’)(R3b’), OR3a' or S(:==O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Ce alkoxy;

[0250] R2is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-C10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Ce Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0251] alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-Cio aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, or N(R4a’)(R4b’);

[0252] Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl or 6- to 10-membered heteroaryl is optionally substituted with one or more Ci-Cg alkyl, halo, OH, CN, or C1-C6 alkoxy;

[0253] X3is H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halo, OR4a, oxo, CN, C(=O)N(R4a)(R4b), or N(R4a)(R4b);

[0254] R3is H, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-C10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, C(O)(R4a), or C(O)O-C(R4a)2-OC(O)(R4a), wherein the Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R3a; or R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected;

[0255] each R3ais independently halo, OR4a, oxo, C(O)O(R4a), CN, C(=O)N(R4a)(R4b), OC(O)N(R4a)(R4b),

[0256]

[0257] C(O)N(R4a)(R4b), S(=O)2R4b' N(R4a)(R4b), C1-C6 alkyl, C3-C12 cycloalkyl, C1-C6 alkoxy, C6-C10 aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the Ci-Cg alkyl, C3-C12 cycloalkyl, Cg-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more substituent independently selected from halo, O(R4a’), oxo, CN, C(O)OR4a’, OC(O)N(R4a’)(R4b’), N(R4a’)(R4b’), N(R4a’)C(O)(R4b’), N(R4a)C(O)O(R4b’), Ci-Cg alkyl that is optionally substituted with O(R4a), and 3- to 12-membered heterocyclyl that is optionally substituted with oxo;

[0258] each R4ais independently H, CN, or Ci-Cg alkyl optionally substituted with Cg-Cio aryl or N(R4a’)(R4b’);

[0259] each R4bis independently H, S(=O)2R4b’, C(O)OR4b’, C(O)R4b’, C(O)NR4a,R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-Cg alkyl, C3-C12 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Cg alkyl is optionally substituted with Ci-Cg alkoxy or C(O)N(R4a’)(R4b’);

[0260] each Rja’ is independently H, Ci-Cg alkyl, Ci-Cg haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Cg alkoxy; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0261] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl;

[0262] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl;

[0263] each R4a’ and R4b’ is independently H, Ci-Ce alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0264] n is 1, 2, or 3.

[0265] In some embodiments, the present disclosure is directed to a compound of Formula I-a,

[0266]

[0267] a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0268] W is N or CH;

[0269] Y is N or CH;

[0270] R1is

[0271] (a) -C1-C6 alkylene-N(R3a’)(R3b’) or -C3-C12 cycloalkylene-N(Rja’)(Rjb’), wherein the C1-C6 alkylene or C3-C12 cycloalkylene is optionally substituted with one or more R1as;

[0272] each R1asis independently Ci-Ce alkyl;

[0273] (b) 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, w'herein the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1bs;

[0274] each R1bsis independently halo, oxo, OR3a’, Ci-Ce alkyl, Cj-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(:::())(R3a’), N(R3a’)(R31”), or S(::::O)23a’; or (c) C3-C12 cycloalkyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0275] wherein each of the C3-C12 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0276] each R1csis independently halo, Ci-Cg alkyl, or ORja’, wherein the alkyl is optionally substituted by one or more Ci-Cg alkoxy;

[0277] R2is Ci-Cg alkyl;

[0278] Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl;

[0279] X3is H or C1-C6alkyl;

[0280] R3is H, Ci-C6alkyl, C(O)(R4a), or C(O)O-C(R4a)2-OC(O)(R4a), wherein the Ci-C6alkyl is optionally substituted with one or more R3a; or R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected;

[0281] each R3ais independently Ci-Ce alkoxy, Cg-Cio aryl, or 3- to 12-membered heterocyclyl; each R4ais independently H or C1-C6 alkyl optionally substituted with C6-C10 aryl or N(R4a’)(R4b’);

[0282] each R3a’ is independently II, Ci-Cg alkyl, Ci-Cg haloalkyl, C(O)R3c’, or 3- to 12- membered heterocyclyl, wherein the alkyl is optionally substituted with Ci-Cg alkoxy;

[0283] each R3b’ is independently II or Ci-Cg alkyl,;

[0284] each R3C’ IS independently Ci-Cg alkyl;

[0285] each R4aand R4bis independently H; and

[0286] n is 1 or 2.

[0287] In some embodiments, the present disclosure is directed to a compound of Formula I-b,

[0288]

[0289] a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0290] W is N or CH; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0291] Y is N or CH;

[0292] R1is

[0293] (a) -Ci-Cg alkylene-N(R'’a’)(R'’b’) or -C3-C12 cycloalkylene-N(R3a’)(R3b’), wherein the Ci-Cg alkylene or C3-C12 cycloalkylene is optionally substituted with one or more R1as;

[0294] each R1asis independently halo, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0295] (b) 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1bs;

[0296] each R1bsis independently halo, oxo, OR3a’, Ci-Cg alkyl, Ci-Cg haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’; or (c) C3-C12 cycloalkyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C12 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more Rics;

[0297] each R1csis independently halo, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, C(::O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Cg alkoxy;

[0298] R2is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Ce- C10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, or N(R4a’)(R4b’);

[0299] Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl, w’herein the 6- to 10-membered aryl or 6- to 10-membered heteroaryl is optionally substituted with one or more Ci-Cg alkyl, halo, OH, CN, or Ci-Cg alkoxy;

[0300] X3is H or C1-C6alkyl, wherein the Ci-Cg alkyl is optionally substituted with one or more halo, OR4a, oxo, C

[0301]

[0302] N, C(=O)N(R4a)(R4b), or N(R4a)(R4b);

[0303] R3is H, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-C10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, C(O)(R4a), or C(O)O-C(R4a)2-OC(O)(R4a), wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0304] cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R3a; or R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected;

[0305] each R3ais independently halo, OR4a, oxo, C(O)O(R4a), CN, C(=O)N(R4a)(R4b), OC(O)N(R4a)(R4b), S(=O)2R4b’, N(R4a)(R4b), Ci-C6alkyl, C3-C12 cycloalkyl, Ci-C6alkoxy, C6-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C3-C12 cycloalkyl, C6-C10 aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more substituent independently selected from halo, O(R4a’), oxo, CN, C(O)OR4a’, OC(O)N(R4a’)(R4b’), N(R4a’)(R4b’), N(R4a’)C(O)(R4b’), N(R4a’)C(O)O(R4b’), Ci-Ce alkyl that is optionally substituted with O(R4a), and 3- to 12-membered heterocyclyl that is optionally substituted with oxo;

[0306] each R4ais independently H, CN, or C1-C6 alkyl optionally substituted with C6-C10 aryl or N(R4a’)(R4b’);

[0307] each R4bis independently II, S(==O)2R4b’, C(O)()R4b’, C(O)R4b’, C(())NR4a’R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-Ce alkyl, C3-C12 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Ce alkyl is optionally substituted with Ci-Ce alkoxy or C(O)N(R4a’)(R4b’);

[0308] each R3a’ is independently H, Ci-Ce alkyl, Ci-C’e haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0309] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl;

[0310] each R3C’ IS independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl;

[0311] each R4a’ and R4b’ is independently H, Ci-Ce alkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0312] n is 1, 2, or 3.

[0313] In some embodiments, the present disclosure is directed to a compound of Formula I-b, Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0314]

[0315] a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0316] W is N or CH;

[0317] Y is N or CH;

[0318] R1is

[0319] (a) -Ci-C6alkylene-N(R3a’)(R3b’) or -C3-C12 cycloalkylene-N(R’a’)(R'’b’), wherein the Ci-Ce alkylene or C3-C12 cycloalkylene is optionally substituted with one or more R1as;

[0320] each R1asis independently C1-C6 alkyl;

[0321] (b) 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1bs;

[0322] each R1bsis independently halo, oxo, ORja’, C1-C6 alkyl, Ci-Cr, haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’; or (c) C3-C12 cycloalkyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C12 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0323] each R1csis independently halo, Ci-C* alkyl, or OR3a’, wherein the alkyl is optionally substituted by one or more Ci-Ce alkoxy;

[0324] R2is C1-C6 alkyl;

[0325] Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl;

[0326] X3is H or Ci-Ce alkyl; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0327] R3is H, Ci-C6alkyl, C(O)(R4a), or C(O)O-C(R4a)2-OC(O)(R4a), wherein the Ci-C6alkyl is optionally substituted with one or more R3a; or R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected;

[0328] each R3ais independently Ci-Ce alkoxy, Cg-Cio aryl, or 3- to 12-membered heterocyclyl; each R4ais independently H or Ci-Ce alkyl optionally substituted with Ce-Cio aryl or N(R4a’)(R4b’);

[0329] each R3a’ is independently H, Cj-Cx alkyl, Ci-Cx haloalkyl, C(O)R3c’, or 3- to 12-membered heterocyclyl, wherein the alkyl is optionally substituted with Ci-Ce alkoxy;

[0330] each R3b’ is independently H or Ci-Cs alkyl,;

[0331] eachR3c’ is independently C1-C6 alkyl;

[0332] each R4a’ and R4b’ is independently H; and

[0333] n is 1 or 2.

[0334] In some embodiments, the present disclosure is directed to a compound of Formula I-c,

[0335]

[0336] a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0337] W i s N or CH;

[0338] Y is N or CH;

[0339] R1is

[0340] (a) -Ci-C6alkylene-N(R3a’)(R3b’) or -C3-C12 cycloalkylene-N(R3a’)(R3b’), wherein the Ci-Ce alkylene or C3-C12 cycloalkylene is optionally substituted with one or more R1as;

[0341] each R1asis independently halo, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, C(::::())(R3a’), N(R3a’)(R3b’), or S(===O)2R3a’; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0342] (b) 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1bs;

[0343] each R1bsis independently halo, oxo, OR3a’, Ci-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’; or (c) C3-C12 cycloalkyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C12 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0344] each R1csis independently halo, oxo, Cj-Cc, alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Cj-Ce alkoxy;

[0345] R2is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, Cs-Cn cycloalkyl, Ce- C10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Cj-Ce alkyl, C2-C.-. alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cw aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, or N(R4a’)(R4b’);

[0346] Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl or 6- to 10-membered heteroaryl is optionally substituted with one or more Ci-Ce alkyl, halo, OH, CN, or Ci-Co alkoxy;

[0347] X3is H or C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with one or more halo, OR4a, oxo, CN, C(=O)N(R4a)(R4b), or N(R4a)(R4b);

[0348] R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cw aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, C(O)(R4a), or C(O)O-C(R4a)2-OC(O)(R4a), wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R3a; or R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected;

[0349] each R3ais independently halo, OR4a, oxo, C(O)O(R4a), CN, C(=O)N(R4a)(R4b), OC(O)N(R4a)(R4b), S(=O)2R4b’, N(R4a)(R4b), Ci-C6alkyl, C3-C12 cycloalkyl, Ci-C6alkoxy, C6-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl, Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0350] C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more substituent independently selected from halo, O(R4a’), oxo, CN, C(O)OR4a’, OC(O)N(R4a’)(R4b’), N(R4a’)(R4b’), N(R4a’)C(O)(R4b’), N(R4a’)C(O)O(R4b’), C1-C6 alkyl that is optionally substituted with O(R4a), and 3- to 12-membered heterocyclyl that is optionally substituted with oxo;

[0351] each R4ais independently H, CN, or Ci-Ce alkyl optionally substituted with Ce-Cio aryl or N(R4a’)(R4b’);

[0352] each R4bis independently H, S(=O)2R4b’, C(O)OR4b’, C(O)R4b’, C(O)NR4a’R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-Cs alkyl, C3-C12 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-C6 alkyl is optionally substituted with C1-C6 alkoxy or C(O)N(R4a’)(R4b’);

[0353] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0354] each R3b’ is independently II, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl;

[0355] each3C’ IS independently H, Cj-Ce alkyl, Cj-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl;

[0356] each R4a’ and R4b’ is independently II, Ci-Ce alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0357] n is 1, 2, or 3.

[0358] In some embodiments, the present disclosure is directed to a compound of Formula I-c,

[0359]

[0360] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0361] a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0362] W is N or CH;

[0363] Y is N or CH;

[0364] R1is

[0365] (a) -Ci-Ce alkylene-N(Rja’)(Rjb’) or -C3-C12 cycloalkylene-N(R3a’)(R3b’), wherein the C1-C6 alkylene or C3-C12 cycloalkylene is optionally substituted with one or more R1as;

[0366] each R1asis independently Cj-Cr, alkyl;

[0367] (b) 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1bs;

[0368] each R1bsis independently halo, oxo, OR3a’, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(==O)(R3a’), N(R3a’)(R3b’), or S(===O)2R3a’; or (c) C3-C12 cycloalkyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C12 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0369] each R1csis independently halo, Ci-CY alkyl, or OR3a’, wherein the alkyl is optionally substituted by one or more Ci-Cg alkoxy;

[0370] R2is Ci-Ce alkyl;

[0371] Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl;

[0372] X3is H or C1-C6alkyl;

[0373] R3is H, Ci-Ce alkyl, C(O)(R4a), or C(O)O-C(R4a)2-OC(O)(R4a), wherein the Ci-Cg alkyl is optionally substituted with one or more R3a; or R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected;

[0374] each R3ais independently Ci-Ce alkoxy, Cs-Cio aryl, or 3- to 12-membered heterocyclyl; each R4ais independently H or Ci-Ce alkyl optionally substituted with Ce-Cio aryl or N(R4a’)(R4b’);

[0375] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, or 3- to 12- membered heterocyclyl, wherein the alkyl is optionally substituted with Ci-Ce alkoxy;

[0376] each R3b’ is independently H or C1-C6 alkyl,;

[0377] each R3C’ is independently C1-C6 alkyl; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0378] each R4a’ and R4b’ is independently H; and

[0379] n is 1 or 2.

[0380] Embodiments

[0381] For any of Formulae I’, I, I-a, I-b, and I-c where applicable, the following embodiments are considered both alone and in conjunction with another where a stable compound is formed.

[0382] In some embodiments, W is N or CH.

[0383] In some embodiments, W is N,

[0384] In some embodiments, W is CH.

[0385] In some embodiments, Y is N or CH.

[0386] In some embodiments, Y is N,

[0387] In some embodiments, Y is CH.

[0388] In some embodiments, R1is

[0389] (a) -Ci-C6alkylene-N(R3a’)(R3b’) or -C3-C12 cycloalkylene-N(R3a’)(R3b’), wherein the Ci-Ce alkylene or C3-C12 cycloalkylene is optionally substituted with one or more R1as;

[0390] each R1asis independently halo, oxo, Cj-Ce alkyl, C1-C6 haloalkyl, C(::O)(R3a’), N(R3a,)(R3b’), or S(=K))2R3a’;

[0391] (b) 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1bs;

[0392] each R1bsis independently halo, oxo, OR3a’, Ci-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a; or (c) C3-C12 cycloalkyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C12 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0393] each R1csis independently halo, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Ce alkoxy; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0394] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0395] each R3b’ is independently H, Ci-Ce alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0396] each R3C’ is independently H, Ci-C6 alkyl, Ci-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0397] In some embodiments, R1is -Ci-Cs alkylene-N(Rja’)(Rjb’) or -C3-C12 cycloalkylene-N(R3a’)(R3b’), wherein the Ci-Ce alkylene or Cs-Cn cycloalkylene is optionally substituted with one or more Rias;

[0398] each R1asis independently halo, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(::::O)2R3a’;

[0399] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c' C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0400] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0401] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0402] In some embodiments, R1is -Ci-Ce alkylene-N(R3a’)(R3b’), wherein the Ci-Ce alkylene is optionally substituted with one or more R1as;

[0403] each R1asis independently halo, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a,)(R3b’), or S(=O)2R3a’;

[0404] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0405] each R3b’ is independently H, Ci-Ce alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0406] each R3e’ is independently H, Ci-Ce alkyl, Ci-Cg haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0407] In some embodiments, R1is -C1-C5 alkylene-N(R3a’)(R3b’), wherein the C1-C5 alkylene is optionally substituted with one or more R,as;

[0408] each R1asis independently halo, oxo, C1-C6alkyl, C1-C6haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0409] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0410] each R3b’ is independently H, C1-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0411] each R3C’ is independently H, Ci-Ce alkyl, Ci-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0412] In some embodiments, R1is -C4-C4 alkylene-N(R3a’)(R3b’), wherein the C1-C4 alkylene is optionally substituted with one or more R1as;

[0413] each R1asis independently halo, oxo, Ci-Ce alkyl, Cj-Ce haloalkyl, C(===O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0414] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R’C’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0415] each R3b’ is independently I I, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0416] each R3C’ is independently H, Ci-Ce alkyl, Ci-Cg haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0417] In some embodiments, R1is -C1-C3 alkylene-N(R3a’)(R3b’), wherein the C1-C3 alkylene is optionally substituted with one or more R1as;

[0418] each R,asis independently halo, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N

[0419]

[0420] (R3a’)(R3b’), or S(=O)2R3a’;

[0421] each R3a’ is independently H, Ci-Ce alkyl, Ci-Cg haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0422] each R3b’ is independently H, Ci-Ce alkyl, Ci-Cr, haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0423] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0424] In some embodiments, R1is -C1-C2 alkylene-N(R3a’)(R3b’), wherein the C1-C2 alkylene is optionally substituted with one or more R1as;

[0425] each R1asis independently halo, oxo, C1-C6alkyl, C1-C6haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0426] each R3a’ is independently H, Ci-Ce alkyl, Ci-Cc, haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0427] each R3b’ is independently H, C1-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0428] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0429] In some embodiments, R1is -CH2-N(R3a’)(R3b’), wherein the -CH2- is optionally substituted with one or more R1as;

[0430] each R1asis independently halo, oxo, Ci-Ce alkyl, Cj-Ce haloalkyl, C(:::O)(R3a’), N(R3a,)(R3b’), or S(=K))2R3a’;

[0431] each R3ais independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0432] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0433] each R3c' is independently H, C1-C6alkyl, C1-C6haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0434] In some embodiments, R1is

[0435]

[0436] -(CH2)2-N(R3a?)(R3b’), wherein the -(CH2)2- is optionally substituted with one or more R1as;

[0437] each R,asis independently halo, oxo, Ci-C6 alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N

[0438]

[0439] (R3a’)(R3b’), or S(=O)2R3a’;

[0440] each R3a’ is independently H, Ci-Ce alkyl, Ci-Cg haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0441] each R3b’ is independently H, Ci-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0442] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0443] In some embodiments, R1is -(CH2)3-N(R3a’)(R3b’), wherein the -(CH2)3- is optionally substituted with one or more R1as;

[0444] each R1asis independently halo, oxo, Ci-C6 alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0445] each R3a’ is independently H, Ci-Ce alkyl, Ci-Cc, haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0446] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0447] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0448] In some embodiments, R1is -(CH2)4-N(R3a’)(R’b’), wherein the -(CIE^- is optionally substituted with one or more R1as;

[0449] each R1asis independently halo, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a,)(R3b’), or S(===O)2R3a’;

[0450] each R3ais independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0451] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0452] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0453] In some embodiments, R1is -(CH2)5-N(R3a’)(R3b’), wherein the -(CH2)s- is optionally substituted with one or more R1as;

[0454] each R1asis independently halo, oxo, C1-C6alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0455] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0456] each R3b’ is independently H, Ci-Ce alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0457] each R3"’ is independently H, Ci-Ce alkyl, Ci-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0458] In some embodiments, R1is -(CH2)6-N(R3a’)(R3b’), wherein the -(CH2)6- is optionally substituted with one or more R1as;

[0459] each R1asis independently halo, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0460] each R3iis independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0461] each R3b’ is independently II, Ci-Ce alkyl, Cj-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0462] each R3C’ is independently II, C1-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0463] In some embodiments, R1is -C3-C12 cycloalkylene-N(R’a’)(R’b’), wherein the C3-C12 cycloalkylene is optionally substituted with one or more R1as;

[0464] each R1asis independently halo, oxo, C1-C6alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0465] each R3a’ is independently H, Ci-Ce alkyl, Ci-Cg haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0466] each R3b’ is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0467] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0468] In some embodiments, R1is -C3-C11 cycloalkylene-N(R3a’)(R3b’), wherein the C3-C11 cycloalkylene is optionally substituted with one or more R1as; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0469] each R1asis independently halo, oxo, C1-C6alkyl, C1-C6haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0470] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0471] each R3b’ is independently H, Ci-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0472] each R3"’ is independently H, Ci-Ce alkyl, Ci-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0473] In some embodiments, R1is -C3-C10 cycloalkylene-N(R3a’)(R3b’), wherein the C3-C10 cycloalkylene is optionally substituted with one or more R1as;

[0474] each R1asis independently halo, oxo, Ci-Ce alkyl, Cj-Ce haloalkyl, C(=::O)(R3a’), N(R3a,)(R3b’), or S(===O)2R3a’;

[0475] each R3iis independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0476] each R3b’ is independently II, Ci-Ce alkyl, Cj-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0477] each R3C’ is independently II, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0478] In some embodiments, R1is -C3-C9 cycloalkylene-N(R3a)(R3b’), wherein the C3-C9 cycloalkylene is optionally substituted with one or more R1as;

[0479] each R,asis independently halo, oxo, Ci-C6 alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N

[0480]

[0481] (R3a’)(R3b’), or S(=O)2R3a’;

[0482] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0483] each R3b’ is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0484] each R3C’ is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0485] In some embodiments, R1is -Cs-Cs cycloalkylene-N(R3a’)(R3b’), wherein the Cs-Cs cycloalkylene is optionally substituted with one or more R,as;

[0486] each R1asis independently halo, oxo, C1-C6alkyl, C1-C6haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0487] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0488] each R3b’ is independently H, Ci-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0489] each R3C’ is independently H, Ci-Ce alkyl, Ci-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0490] In some embodiments, R1is -C3-C7 cycloalkylene-N(R3a’)(R3b’), wherein the C3-C7 cycloalkylene is optionally substituted with one or more R1as;

[0491] each R1asis independently halo, oxo, Ci-Ce alkyl, Cj-Ce haloalkyl, C(=::O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0492] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R’C’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0493] each R3b’ is independently I I, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0494] each R3C’ is independently H, Ci-Ce alkyl, Ci-Cg haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0495] In some embodiments, R1is -C3-C6 cycloalkylene-N(R3a)(R3b’), wherein the C3-G5 cycloalkylene is optionally substituted with one or more R1as;

[0496] each R,asis independently halo, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N

[0497]

[0498] (R3a’)(R3b’), or S(=O)2R3a’;

[0499] each R3a’ is independently H, Ci-Ce alkyl, Ci-Cg haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0500] each R3b’ is independently H, Ci-Ce alkyl, Ci-Cr, haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0501] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0502] In some embodiments, R1is -C3-C5 cycloalkylene-N(R3a’)(R3b’), wherein the C3-C5 cycloalkylene is optionally substituted with one or more R1as;

[0503] each R1asis independently halo, oxo, C1-C6alkyl, C1-C6haloalkyl, C(=O)(R3a’), N

[0504]

[0505] (R3a’)(R3b’), or S(=O)2R3a’;

[0506] each R3a’ is independently H, Ci-Ce alkyl, Ci-Cc, haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0507] each R311’ is independently H, C1-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0508] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0509] In some embodiments, R1is -C3-C4 cycloalkylene-N(R3a’)(R3b’), wherein the C3-C4 cycloalkylene is optionally substituted with one or more R1as;

[0510] each R1asis independently halo, oxo, Ci-Ce alkyl, Cj-Ce haloalkyl, C(:::O)(R3a’), N(R3a,)(R3b’), or S(=K))2R3a’;

[0511] each R3ais independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0512] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0513] each R3c' is independently H, C1-C6alkyl, C1-C6haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0514] In some embodiments, R1is -C3 cycloalkylene-N(R3a’)(R3b’), wherein the -C3 cycloalkylene- is optionally substituted with one or more R1as;

[0515] each R,asis independently halo, oxo, Ci-C6 alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N

[0516]

[0517] (R3a’)(R3b’), or S(=O)2R3a’;

[0518] each R3a’ is independently H, Ci-Ce alkyl, Ci-Cg haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0519] each R3b’ is independently H, Ci-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0520] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0521] In some embodiments, R1is -C4 cycloalkylene-N(R3a’)(Rjb’), wherein the -C4 cycloalkylene- is optionally substituted with one or more R1as;

[0522] each R1asis independently halo, oxo, Ci-C6 alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0523] each R3a’ is independently H, Ci-Ce alkyl, Ci-Cc, haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0524] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0525] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0526] In some embodiments, R1is -C5 cycloalkylene-N(R3a’)(R3b’), wherein the -C5 cycloalkylene- is optionally substituted with one or more R1as;

[0527] each R1asis independently halo, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a,)(R3b’), or S(===O)2R3a’;

[0528] each R3ais independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0529] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0530] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0531] In some embodiments, R1is -Ce cycloalkylene-N(R3a’)(R3b’), wherein the -C cycloalkylene- is optionally substituted with one or more R1as;

[0532] each R1asis independently halo, oxo, C1-C6alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0533] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0534] each R3b’ is independently H, Ci-Ce alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0535] each R3"’ is independently H, Ci-Ce alkyl, Ci-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0536] In some embodiments, R1is -C7 cycloalkylene-N(R3a’)(R3b’), wherein the -C7 cycloalkylene- is optionally substituted with one or more R1as;

[0537] each R1asis independently halo, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0538] each R3iis independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0539] each R3b’ is independently II, Ci-Ce alkyl, Cj-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0540] each R3C’ is independently II, C1-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0541] In some embodiments, R1is -Cs cycloalkylene-N(R’a’)(R31”), wherein the -Cg cycloalkylene- is optionally substituted with one or more R1as;

[0542] each R1asis independently halo, oxo, C1-C6alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0543] each R3a’ is independently H, Ci-Ce alkyl, Ci-Cg haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0544] each R3b’ is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0545] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0546] In some embodiments, R1is -C9 cycloalkylene-N(R3a’)(Rjb’), wherein the -C9 cycloalkylene- is optionally substituted with one or more R1as; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0547] each R1asis independently halo, oxo, C1-C6alkyl, C1-C6haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0548] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0549] each R3b’ is independently H, Ci-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0550] each R3"’ is independently H, Ci-Ce alkyl, Ci-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0551] In some embodiments, R1is -C10 cycloalkylene-N(R3a’)(R3b’), wherein the -C10 cycloalkylene- is optionally substituted with one or more R1as;

[0552] each R1asis independently halo, oxo, Ci-Ce alkyl, Cj-Ce haloalkyl, C(=::O)(R3a’), N(R3a,)(R3b’), or S(===O)2R3a’;

[0553] each R3iis independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0554] each R3b’ is independently II, Ci-Ce alkyl, Cj-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0555] each R3C’ is independently II, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0556] In some embodiments, R1is -Cn cycloalkylene-N(R3a’)(R3b’), wherein the -C11 cycloalkylene- is optionally substituted with one or more R1as;

[0557] each R,asis independently halo, oxo, Ci-C6 alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N

[0558]

[0559] (R3a’)(R3b’), or S(=O)2R3a’;

[0560] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0561] each R3b’ is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0562] each R3C’ is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0563] In some embodiments, R1is -C12 cycloalkylene-N(R3a’)(R3b’), wherein the -C12 cycloalkylene- is optionally substituted with one or more R1as;

[0564] each R1asis independently halo, oxo, C1-C6alkyl, C1-C6haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0565] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0566] each R3b’ is independently H, Ci-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0567] each R3C’ is independently H, Ci-Ce alkyl, Ci-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0568] In some embodiments, R1is 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 12- membered heterocyclyl is optionally substituted with one or more R1bs;

[0569] each R1bsis independently halo, oxo, OR3a’, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(::::O)(R3a’), N(R3a’)(R3b’), or S(===O)2R3a’;

[0570] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c' C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0571] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0572] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0573] In some embodiments, R1is 3- to 11 -membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 11-membered heterocyclyl is optionally substituted with one or more R,bs;

[0574] each R1bsis independently halo, oxo, ORja’, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0575] each R3a’ is independently H, Ci-Ce alkyl, Ci-Cg haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0576] each R3b’ is independently H, Ci-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0577] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0578] In some embodiments, R1is 3- to 10-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 10-membered heterocyclyl is optionally substituted with one or more R1bs;

[0579] each R1bsis independently halo, oxo, ORja’, Ci-Ce alkyl, Cj-Cc, haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0580] each R3a’ is independently H, Ci-Ce alkyl, Ci-C6 haloalkyl, C(O)RJC’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0581] each R3b’ is independently I I, Ci-Ce alkyl, Cj-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0582] each R3C’ is independently II, C1-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0583] In some embodiments, R1is 3- to 9-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 9-membered heterocyclyl is optionally substituted with one or more R1bs;

[0584] each R1bsis independently halo, oxo, OR3a’, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0585] each R3ais independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0586] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0587] each R3C’ is independently H, Ci-Ce alkyl, Ci-Cg haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0588] In some embodiments, R1is 3- to 8-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 8-membered heterocyclyl is optionally substituted with one or more R1bs; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0589] each R1bsis independently halo, oxo, OR3a’, Ci-Ce alkyl, Ci-C6 haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0590] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0591] each R3b’ is independently H, Ci-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0592] each R3"’ is independently H, Ci-Ce alkyl, Ci-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0593] In some embodiments, R1is 3- to 7-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 7-membered heterocyclyl is optionally substituted with one or more R1bs;

[0594] each R1bsis independently halo, oxo, OR3a’, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(::::O)(R3a’), N(R3a’)(R3b’), or S(===O)2R3a’;

[0595] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c' C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0596] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0597] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0598] In some embodiments, R1is 3- to 6-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 6-membered heterocyclyl is optionally substituted with one or more R1bs;

[0599] each R1bsis independently halo, oxo, ORja’, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0600] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0601] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0602] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0603] In some embodiments, R1is 3- to 5-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 5-membered heterocyclyl is optionally substituted with one or more R1bs;

[0604] each R1bsis independently halo, oxo, ORja’, Ci-Ce alkyl, Cj-Cc, haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0605] each R3a’ is independently H, Ci-Ce alkyl, Ci-C6 haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0606] each R3b’ is independently H, Ci-Ce alkyl, Cj-Cc, haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0607] each R3C’ is independently II, C1-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0608] In some embodiments, R1is 3- to 4-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 4-membered heterocyclyl is optionally substituted with one or more R1bs;

[0609] each R1bsis independently halo, oxo, OR3a’, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(:::())(R3a’), N(R3a’)(R’b’), or S(::::O)2R’a’;

[0610] each R3ais independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0611] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0612] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0613] In some embodiments, R1is 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 12-membered heterocyclyl is optionally substituted with one or more R1bs;

[0614] each R1bsis independently halo, oxo, OR3a’, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0615] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0616] each R3b’ is independently H, Ci-Ce alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0617] each R3"’ is independently H, Ci-Ce alkyl, Ci-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0618] In some embodiments, R1is 11 -membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 11 -membered heterocyclyl is optionally substituted with one or more R1bs;

[0619] each R1bsis independently halo, oxo, OR3a’, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(::::O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0620] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c' C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0621] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0622] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0623] In some embodiments, R1is 10-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 10-membered heterocyclyl is optionally substituted with one or more R1bs;

[0624] each R1bsis independently halo, oxo, ORja’, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0625] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0626] each R3b’ is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0627] each R3C’ is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0628] In some embodiments, R1is 9-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 9-membered heterocyclyl is optionally substituted with one or more R1bs;

[0629] each R1bsis independently halo, oxo, ORja’, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0630] each R3a’ is independently H, Ci-Ce alkyl, Ci-C6 haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0631] each R3b’ is independently H, Ci-Ce alkyl, Cj-Cc, haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0632] each R3c’ is independently H, Ci-Ce alkyl, Ci-Cc, haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0633] In some embodiments, R1is 8-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 8-membered heterocyclyl is optionally substituted with one or more R1bs;

[0634] each R1bsis independently halo, oxo, OR3a’, Ci-Ce alkyl, Cj-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(:::())(R3a’), N(R3a’)(R’b’), or S(=O)2R’a’;

[0635] each R3ais independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0636] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0637] each R3C’ is independently H, Ci-Ce alkyl, Ci-Cg haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0638] In some embodiments, R1is 7-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 7-membered heterocyclyl is optionally substituted with one or more R,bs;

[0639] each R1bsis independently halo, oxo, OR3a’, Ci-Ce alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0640] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0641] each R3b’ is independently H, Ci-Ce alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0642] each R3"’ is independently H, Ci-Ce alkyl, Ci-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0643] In some embodiments, R1is 6-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 6-membered heterocyclyl is optionally substituted with one or more R1bs;

[0644] each R1bsis independently halo, oxo, OR3a’, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(::::O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0645] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c' C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0646] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0647] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0648] In some embodiments, R1is 5-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 5-membered heterocyclyl is optionally substituted with one or more R1bs;

[0649] each R1bsis independently halo, oxo, ORja’, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0650] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0651] each R3b’ is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0652] each R3C’ is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0653] In some embodiments, R1is 4-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 4-membered heterocyclyl is optionally substituted with one or more R1bs;

[0654] each R1bsis independently halo, oxo, ORja’, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;

[0655] each R3a’ is independently H, Ci-Ce alkyl, Ci-C6 haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0656] each R3b’ is independently H, Ci-Ce alkyl, Cj-Cc, haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0657] each R3c’ is independently H, Ci-Ce alkyl, Ci-Cc, haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0658] In some embodiments, R1is 3-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3 -membered heterocyclyl is optionally substituted with one or more R1bs;

[0659] each R1bsis independently halo, oxo, OR3a’, Ci-Ce alkyl, Cj-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(:::())(R3a’), N(R3a’)(R’b’), or S(=O)2R’a’;

[0660] each R3ais independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0661] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0662] each R3C’ is independently H, Ci-Ce alkyl, Ci-Cg haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0663] In some embodiments, R1is C3-C12 cycloalkyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C12 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0664] each R1csis independently halo, oxo, Ci-C6 alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more C1-C6 alkoxy; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0665] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0666] each R3b’ is independently H, Ci-Ce alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0667] each R3"’ is independently H, Ci-Ce alkyl, Ci-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0668] In some embodiments, R1is C3-C11 cycloalkyl substituted with one or more 3- to 12- membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C11 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0669] each R1csis independently halo, oxo, Ci-Ce alkyl, Cj-Ce haloalkyl, C(=::O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Ce alkoxy;

[0670] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c' C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0671] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0672] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0673] In some embodiments, R1is C3-C10 cycloalkyl substituted with one or more 3- to 12- membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C10 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0674] each Rlesis independently halo, oxo, Ci-Ce alkyl, C1-C6 haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more C1-C6 alkoxy;

[0675] each R3a’ is independently H, Ci-Ce alkyl, Ci-Cg haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0676] each R3b’ is independently H, Ci-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0677] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0678] In some embodiments, R1is C3-C9 cycloalkyl substituted with one or more 3- to 12- membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom rmg members; and wherein each of the C3-C9 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0679] each Rlesis independently halo, oxo, Ci-C6 alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Ce alkoxy;

[0680] each R3iis independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0681] each R3b’ is independently I I, Ci-Ce alkyl, Cj-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0682] each R3C’ is independently II, C1-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0683] In some embodiments, R1is C3-C8 cycloalkyl substituted with one or more 3- to 12- membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom rmg members; and wherein each of the C3-C8 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0684] each R1csis independently halo, oxo, Ci-C6 alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Ce alkoxy;

[0685] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0686] each R3b’ is independently H, Ci-Ce alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0687] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0688] In some embodiments, R1is C3-C7 cycloalkyl substituted with one or more 3- to 12- membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C7 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0689] each Rlesis independently halo, oxo, Ci-C6 alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Ce alkoxy;

[0690] each R3a’ is independently H, Ci-Ce alkyl, Ci-C6 haloalkyl, C(O)RJC’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0691] each R3b’ is independently I I, Ci-Ce alkyl, Cj-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0692] each R3C’ is independently II, C1-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0693] In some embodiments, R1is C3-C6 cycloalkyl substituted with one or more 3- to 12- membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C6 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0694] each R1csis independently halo, oxo, Ci-C6 alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Ce alkoxy;

[0695] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0696] each R3b’ is independently H, Ci-Ce alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0697] each R3e’ is independently H, Ci-Ce alkyl, Ci-Cg haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0698] In some embodiments, R1is C3-C5 cycloalkyl substituted with one or more 3- to 12- membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C5 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0699] each Rlesis independently halo, oxo, Ci-Ce alkyl, C1-C6 haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Ce alkoxy;

[0700] each R3a’ is independently H, Ci-Ce alkyl, Ci-C6 haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0701] each R3b’ is independently H, Ci-Ce alkyl, Cj-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0702] each R3C’ is independently II, C1-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0703] In some embodiments, R1is C3-C4 cycloalkyl substituted with one or more 3- to 12- membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C4 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0704] each R1csis independently halo, oxo, Ci-C6 alkyl, Ci-Ce haloalkyl, C(::::())(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Ce alkoxy;

[0705] each R3ais independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0706] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0707] each R3C’ is independently H, Ci-Ce alkyl, Ci-Cg haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0708] In some embodiments, R1is cyclopropyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0709] members; and wherein each of the cyclopropyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0710] each Rlesis independently halo, oxo, Ci-Ce alkyl, Ci-C6 haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Co alkoxy;

[0711] each R3a’ is independently H, Ci-Ce alkyl, Ci-C6 haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0712] each R3b’ is independently H, Ci-Ce alkyl, Cj-Cx haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0713] each R3C’ is independently H, Ci-Ce alkyl, Ci-Cc, haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0714] In some embodiments, R1is cyclobutyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the cyclobutyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0715] each R1csis independently halo, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, C(::::())(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Ce alkoxy;

[0716] each R3ais independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0717] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0718] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0719] In some embodiments, R1is cyclopentyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the cyclopentyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0720] each Rlesis independently halo, oxo, Ci-Ce alkyl, Ci-C6 haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Co alkoxy;

[0721] each R3a’ is independently H, Ci-Ce alkyl, Ci-C6 haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0722] each R3b’ is independently H, Ci-Ce alkyl, Cj-Cx haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0723] each R3c’ is independently H, Ci-Ce alkyl, Ci-Cc, haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0724] In some embodiments, R1is cyclohexyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the cyclohexyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0725] each R1csis independently halo, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, C(::::())(R3a’), N(R3a’)(R3b’), OR3aor S(::::())2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Ce alkoxy;

[0726] each R3ais independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0727] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0728] each R3C’ is independently H, Ci-Ce alkyl, Ci-Cg haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0729] In some embodiments, R1is cycloheptyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the cycloheptyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0730] each R1csis independently halo, oxo, Ci-C6 alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more C1-C6 alkoxy; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0731] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0732] each R3b’ is independently H, Ci-Ce alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl; and

[0733] each R3"’ is independently H, Ci-Ce alkyl, Ci-C6 haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0734] In some embodiments, R1is cyclooctyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the cyclooctyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0735] each R1csis independently halo, oxo, Ci-Ce alkyl, Cj-Ce haloalkyl, C(===O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Ce alkoxy;

[0736] each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c' C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0737] each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0738] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0739] In some embodiments, R1is cyclononyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the cyclononyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0740] each Rlesis independently halo, oxo, Ci-Ce alkyl, C1-C6 haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more C1-C6 alkoxy;

[0741] each R3a’ is independently H, Ci-Ce alkyl, Ci-Cg haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy; Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0742] each R3b’ is independently H, Ci-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0743] each R3C’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0744] In some embodiments, R1is cyclodecyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the cyclodecyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;

[0745] each Rlesis independently halo, oxo, Ci-C6 alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Ce alkoxy;

[0746] each R3iis independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;

[0747] each R3b’ is independently I I, Ci-Ce alkyl, Cj-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; and

[0748] each R3C’ is independently II, C1-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0749] In some embodiments, R1is:

[0750]

[0751] Attorney Docket No.: SYND-063 / 001WO 43707-02984FF

[0752] LA JWVJWV, ’;OMe0o ( ^3 NH2N " S NMH i 7 - 7 b b. b y: AAAT 5 AAAT,

[0753] / N ‘ ‘ v 3 $ -2 o ” ~, ', <A v9 9

[0754] H Jl KI N I M N M N.

[0755] 9 Y Y Y Y Y Y Y Y.

[0756] »VU!V 4 uoinnwjv JVW JWV, - p v ww, V tv - ’Y. V W.?.

[0757] ’ I N z\y.

[0758] X—M S 1 < / > Z — N\Z i " YX ''VX O \? v v

[0759]

[0760] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0761] OMe OEt

[0762] In some embodiments, R1is:

[0763]

[0764] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0765] /

[0766]

[0767] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0768] OH

[0769]

[0770] . / ww* In some embodiments, R2is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, C6-C10 Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0771] aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyi is optionally substituted with one or more halo, OH, oxo, CN, or N(R4a’)(R4b’), wherein each R4a’ and R4b’ is independently H, Ci-C6 alkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyi.

[0772] In some embodiments, R2is H.

[0773] In some embodiments, R2is Ci-Ce alkyl.

[0774] In some embodiments, R2is C1-C5 alkyl.

[0775] In some embodiments, R2is Cj-C4 alkyl.

[0776] In some embodiments, R2is C1-C3 alkyl.

[0777] In some embodiments, R2is C1-C2 alkyl.

[0778] In some embodiments, R2is methyl.

[0779] In some embodiments, R2is ethyl.

[0780] In some embodiments, R2is propyl.

[0781] In some embodiments, R2is isopropyl.

[0782] In some embodiments, R2is butyl.

[0783] In some embodiments, R2is tert-butyl.

[0784] In some embodiments, R2is pentyl.

[0785] In some embodiments, R2is hexyl.

[0786] In some embodiments, Z is O, CH2, or NH.

[0787] In some embodiments, Z is O.

[0788] In some embodiments, Z is CH2.

[0789] In some embodiments, Z is NH.

[0790] In some embodiments, Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl or 6- to 10-membered heteroaryl is optionally substituted with one or more Ci-C6 alkyl, halo, OH, CN, or Ci-Ce alkoxy.

[0791] In some embodiments, Ring A is 6- to 10-membered aryl optionally substituted with one or more C1-C6 alkyl, halo, OH, CN, or Ci-C6 alkoxy.

[0792] In some embodiments, Ring A is 6- to 9-membered aryl optionally substituted with one or more Ci-Ce alkyl, halo, OH, CN, or Ci-Ce alkoxy.

[0793] In some embodiments, Ring A is 6- to 8-membered aryl optionally substituted with one or more C1-C6 alkyl, halo, OH, CN, or C1-C6 alkoxy. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0794] In some embodiments, Ring A is 6- to 7-membered aryl optionally substituted with one or more Ci-Cg alkyl, halo, OH, CN, or Ci-Cg alkoxy.

[0795] In some embodiments, Ring A is a phenyl ring.

[0796] In some embodiments, Ring A is a phenyl ring optionally substituted with one or more Ci-Cg alkyl, halo, OH, CN, or Ci-Cg alkoxy.

[0797] In some embodiments, Ring A is 6- to 10-membered heteroaryl optionally substituted with one or more Ci-Cg alkyl, halo, OH, CN, or Ci-Cg alkoxy.

[0798] In some embodiments. Ring A is 6- to 9-membered heteroaryl optionally substituted with one or more Ci-Cg alkyl, halo, OH, CN, or Ci-Cg alkoxy.

[0799] In some embodiments. Ring A is 6- to 8-membered heteroaryl optionally substituted with one or more Ci-Cg alkyl, halo, OH, CN, or Ci-Cg alkoxy.

[0800] In some embodiments, Ring A is 6- to7-membered heteroaryl optionally substituted with one or more Ci-Cg alkyl, halo, OH, CN, or C1-C6 alkoxy.

[0801] In some embodiments, Ring A is a pyridine ring optionally substituted with one or more Ci-Cg alkyl, halo, OH, CN, or C1-C6 alkoxy.

[0802] In some embodiments, Ring A is a pyridine ring.

[0803]

[0804] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0805]

[0806] In some embodiments, X3is H or Ci-Ce alkyl, wherein the Ci-Cg alkyl is optionally substituted with one or more halo, OR4a, oxo, CN, C(=O)N(R4a)(R4b), or N(R4a)(R4b); wherein:

[0807] each R4ais independently H, CN, or Ci-Ce alkyl optionally substituted with Ce-Cio aryl or N(R4a’)(R4b’);

[0808] each R4bis independently H, S(=O)2R4b’, C(O)OR4b’, C(O)R4b’, C(O)NR4a’R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-C6 alkyl, C3-C12 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-C6 alkyl is optionally substituted with C1-C6 alkoxy or C(O)N(R4a’)(R4b’); and

[0809] each R4a’ and R4b’ is independently H, Ci-Ce alkyl, Ca-Cj? cycloalkyl, or 3- to 12-membered heterocyclyl.

[0810] In some embodiments, X3is H,

[0811] In some embodiments, X3is C1-C6 alkyl.

[0812] In some embodiments, X3is C1-C5 alkyl.

[0813] In some embodiments, X3is C1-C4 alkyl. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0814] In some embodiments, X3is C1-C3 alkyl.

[0815] In some embodiments, X3is C1-C2 alkyl.

[0816] In some embodiments, X3is methyl.

[0817] In some embodiments, X3is ethyl.

[0818] In some embodiments, X3is propyl.

[0819] In some embodiments, X3is isopropyl.

[0820] In some embodiments, X3is butyl.

[0821] In some embodiments, X3is tert-butyl.

[0822] In some embodiments, X3is Ci-Cg alkyl substituted with one or more -OH.

[0823] In some embodiments, X3is C1-C5 alkyl substituted with one or more -OH.

[0824] In some embodiments, X3is C1-C4 alkyl substituted with one or more -OH.

[0825] In some embodiments, X3is C1-C3 alkyl substituted with one or more -OH.

[0826] In some embodiments, X3is C1-C2 alkyl substituted with one or more -OH.

[0827] In some embodiments, X3is Ci-Cg alkyl substituted with one or more -OH.

[0828] In some embodiments, X3is C1-C5 alkyl substituted with one or more -OH.

[0829] In some embodiments, X3is C1-C4 alkyl substituted with one or more -OH.

[0830] In some embodiments, X3is C1-C3 alkyl substituted with one or more -OH.

[0831] In some embodiments, X3is C1-C2 alkyl substituted with one or more -OH.

[0832] In some embodiments, X3is -CH2(OH), -CH2-CH2(OH), or -CH2-CH2-CH2(OH).

[0833] In some embodiments, X3is Ci-Ce alkyl substituted with one or more OR4a; wherein each R4ais independently H, CN, or Ci-Cg alkyl optionally substituted with Cg-Cio aryl or N(R4a)(R4b’), wherein each R4aand R4b’ is independently H, Ci-Cg alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0834] In some embodiments, X3is C1-C5 alkyl substituted with one or more OR4a; wherein each R4ais independently H, CN, or Ci-Ce alkyl optionally substituted with Ce-Cio aryl or N(R4a’)(R4b’), wherein each R4a’ and R4b’ is independently H, Ci-Cg alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0835] In some embodiments, X3is C1-C4 alkyl substituted with one or more OR4a; wherein each R4ais independently H, CN, or Ci-Cg alkyl optionally substituted with Cg-Cio aryl or N(R4a’)(R4b’), wherein each R4a’ and R4b’ is independently H, Ci-Ce alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0836] In some embodiments, X3is C1-C3 alkyl substituted with one or more OR4a; wherein each R4ais independently H, CN, or Ci-Cg alkyl optionally substituted with Cg-Cio aryl or N(R4a’)(R4b’), wherein each R4a’ and R4b’ is independently H, Ci-Cg alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0837] In some embodiments, X3is C1-C2 alkyl substituted with one or more OR4a; wherein each R4ais independently H, CN, or Ci-Cg alkyl optionally substituted with Cg-Cio aryl or N(R4a’)(R4b’), wherein each R4a’ and R4b’ is independently H, Ci-Cg alkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0838] In some embodiments, X3is Ci-Cg alkyl substituted with one or more oxo.

[0839] In some embodiments, XJis C1-C5 alkyl substituted with one or more oxo.

[0840] In some embodiments, X3is C1-C4 alkyl substituted with one or more oxo.

[0841] In some embodiments, X3is C1-C3 alkyl substituted with one or more oxo.

[0842] In some embodiments, X3is C1-C2 alkyl substituted with one or more oxo.

[0843] In some embodiments, X3is Ci-Cg alkyl substituted with one or more CN.

[0844] In some embodiments, X3is C1-C5 alkyl substituted with one or more CN.

[0845] In some embodiments, X3is C1-C4 alkyl substituted with one or more CN.

[0846] In some embodiments, X3is C1-C3 alkyl substituted with one or more CN.

[0847] In some embodiments, X3is C1-C2 alkyl substituted with one or more CN.

[0848] In some embodiments, X3is Ci-Ce alkyl substituted with one or more C(::::O)N(R4a)(R4b); wherein:

[0849] each R4ais independently H, CN, or Ci-Ce alkyl optionally substituted with Ce-Cio aryl or N(R4a’)(R4b’);

[0850] each R4bis independently H, S(=O)2R4b’, C(O)OR4b’, C(O)R4b’, C(O)NR4a,R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-Cg alkyl, C3-C12 cycloalkyl, C&.10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Cg alkyl is optionally substituted with Ci-Cg alkoxy or C(O)N(R4a’)(R4b’); and

[0851] each R4a’ and R4b’ is independently H, Ci-Cg alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0852] In some embodiments, X3is C1-C5 alkyl substituted with one or more C(=O)N(R4a)(R4b); wherein: Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0853] each R4ais independently H, CN, or Ci-Cg alkyl optionally substituted with Cg-Cio aryl or N(R4a’)(R4b’);

[0854] each R4bis independently H, S(=O)2R4b’, C(O)OR4b’, C(O)R4b’, C(O)NR4a’R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-Cg alkyl, C3-C12 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Cg alkyl is optionally substituted with Ci-Cg alkoxy or C(O)N(R4a’)(R4b’); and

[0855] each R4a’ and R4b’ is independently H, C1-C6alkyl, C3-C12cycloalkyl, or 3- to 12-membered heterocyclyl.

[0856] In some embodiments, X3is C1-C4 alkyl substituted with one or more C(=O)N(R4a)(R4b); wherein:

[0857] each R4ais independently H, CN, or Ci-Cg alkyl optionally substituted with Cg-Cio aryl or N(R4a’)(R4b’);

[0858] each R4bis independently H, S(===O)2R4b’, C(O)OR4b’, C(())R4b’, C(O)NR4a’R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-Cg alkyl, C3-C12 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Cg alkyl is optionally substituted with Ci-Cg alkoxy or C(O)N(R4a’)(R4b’); and

[0859] each R4a’ and R4b’ is independently H, Ci-Cg alkyl, C3-C12cycloalkyl, or 3- to 12- membered heterocyclyl.

[0860] In some embodiments, X3is C1-C3 alkyl substituted with one or more C(::::O)N(R4a)(R4b); wherein:

[0861] each R4ais independently H, CN, or Ci-Cg alkyl optionally substituted with Cg-Cio aryl or N(R4a’)(R4b’);

[0862] each R4bis independently H, S(=O)2R4b’, C(O)OR4b’, C(O)R4b’, C(O)NR4a,R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-Cg alkyl, C3-C12 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Cg alkyl is optionally substituted with Ci-Cg alkoxy or C(O)N(R4a’)(R4b’); and

[0863] each R4a’ and R4b’ is independently H, Ci-Cg alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0864] In some embodiments, X3is C1-C2 alkyl substituted with one or more C(=O)N(R4a)(R4b); wherein: Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0865] each R4ais independently H, CN, or Ci-Cg alkyl optionally substituted with Cg-Cio aryl or N(R4a’)(R4b’);

[0866] each R4bis independently H, S(=O)2R4b’, C(O)OR4b’, C(O)R4b’, C(O)NR4a’R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-Cg alkyl, C3-C12 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Cg alkyl is optionally substituted with Ci-Cg alkoxy or C(O)N(R4a’)(R4b’); and

[0867] each R4a’ and R4b’ is independently H, C1-C6alkyl, C3-C12cycloalkyl, or 3- to 12-membered heterocyclyl.

[0868] In some embodiments, X3is C1-C6alkyl substituted with one or more N(R4a)(R4b); wherein: each R4ais independently H, CN, or C1-C6alkyl optionally substituted with C6-C10aryl or N(R4a’)(R4b’);

[0869] each R4bis independently H, S(==O)2R4b’, C(O)()R4b’, C(O)R4b’, C(())NR4a’R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-Cg alkyl, C3-C12 cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Cj-Cg alkyl is optionally substituted with C1-C6 alkoxy or C(O)N(R4a’)(R4b’); and

[0870] each R4a’ and R4b’ is independently H, Ci-C alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0871] In some embodiments, X3is C1-C5 alkyl substituted with one or more N(R4a)(R4b); wherein: each R4ais independently H, CN, or Ci-Cg alkyl optionally substituted with Cg-Cio aryl or N(R4a’)(R4b’);

[0872] each R4bis independently H, S(=O)2R4b’, C(O)OR4b’, C(O)R4b’, C(O)NR4aR4b’, C(O)CH2-N(R4a’)(R4b’), Ci-Cg alkyl, C3-C12 cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Cg alkyl is optionally substituted with Ci-Cg alkoxy or C(O)N(R4a’)(R4b’); and

[0873] each R4a’ and R4b’ is independently H, Ci-Cg alkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0874] In some embodiments, XJis C1-C4 alkyl substituted with one or more N(R4a)(R4b); wherein: each R4ais independently H, CN, or Ci-Cg alkyl optionally substituted with Cg-Cio aryl or N(R4a’)(R4b’);

[0875] each R4bis independently H, S(=O)2R4b’, C(O)OR4b’, C(O)R4b’, C(O)NR4a’R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-Cg alkyl, C3-C12 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0876] or 3- to 12-membered heterocyclyl, wherein the Ci-Cg alkyl is optionally substituted with Ci-Cg alkoxy or C(O)N(R4a’)(R4b’); and

[0877] each R4a’ and R4b’ is independently H, Ci-Cg alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0878] In some embodiments, X3is C1-C3 alkyl substituted with one or more N(R4a)(R4b); wherein: each R4ais independently H, CN, or Ci-Cg alkyl optionally substituted with Cg-Cio aryl or N(R4a’)(R4b’);

[0879] each R4bis independently H, S(=O)2R4b’, C(O)OR4b’, C(O)R4b’, C(O)NR4a’R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-Cg alkyl, C3-C12 cycloalkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Cg alkyl is optionally substituted with Ci-Cg alkoxy or C(O)N(R4a’)(R4b’); and

[0880] each R4a’ and R4b’ is independently H, Ci-C alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0881] In some embodiments, X3is Cj-C2alkyl substituted with one or more N(R4a)(R4b); wherein: each R4ais independently H, CN, or Ci-Cg alkyl optionally substituted with Cg-Cio aryl or N(R4a’)(R4b’);

[0882] each R4bis independently H, S(=O)2R4b'C(O)OR4b’, C(())R4b’, C(O)NR4a’R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-Cg alkyl, C3-C12 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Cg alkyl is optionally substituted with Ci-Cg alkoxy or C(O)N(R4a’)(R4b’); and

[0883] each R4a’ and R4b’ is independently H, Ci-Cg alkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0884] In some embodiments, R3is H, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-Cio aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, C(O)(R4a), or C(O)O-C(R4a)2-OC(O)(R4a), wherein the Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Ci-Cg alkoxy, C3-C12cycloalkyl, Cg-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R3a; wherein:

[0885] each R3ais independently halo, OR4a, oxo, C(O)O(R4a), CN, C(=O)N(R4a)(R4b), OC(O)N(R4a)(R4b), S(=O)2R4b’, N(R4a)(R4b), Ci-Cg alkyl, C3-C12cycloalkyl, Ci-Cg alkoxy, Cg-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the Ci-Cg alkyl, C3-Ci2cycloalkyl, Cg-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0886] is optionally substituted with one or more substituent independently selected from halo, O(R4a’), oxo, CN, C(O)OR4a’, OC(O)N(R4a’)(R4b’), N(R4a’)(R4b’), N(R4a’)C(O)(R4b’), N(R4a’)C(O)O(R4b’), Ci-Ce alkyl that is optionally substituted with O(R4a), and 3- to 12-membered heterocyclyl that is optionally substituted with oxo;

[0887] each R4ais independently H, CN, or Ci-Ce alkyl optionally substituted with Ce-Cio aryl or N(R4a’)(R4b’);

[0888] each R4bis independently H, S(=O)2R4b’, C(O)OR4b’, C(O)R4b’, C(O)NR4a’R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-C6alkyl, C3-C12 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Ce alkyl is optionally substituted with Ci-Ce alkoxy or C(O)N(R4a’)(R4b’); and

[0889] each R4a’ and R4b’ is independently H, Ci-Ce alkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

[0890] In some embodiments, R3is H.

[0891] In some embodiments, R3is Ci-Ce alkyl.

[0892] In some embodiments, R3is C1-C5alkyl.

[0893] In some embodiments, R3is C1-C4 alkyl.

[0894] In some embodiments, R3is C1-C3alkyl.

[0895] In some embodiments, R3is C1-C2 alkyl.

[0896] In some embodiments, R3is methyl.

[0897] In some embodiments, R3is ethyl.

[0898] In some embodiments, R3is propyl.

[0899] In some embodiments, R3is isopropyl.

[0900] In some embodiments, R3is butyl.

[0901] In some embodiments, R3is tert-butyl.

[0902] In some embodiments, R3is Ci-Ce alkyl substituted with one or more R3a.

[0903] In some embodiments, R3is C1-C5 alkyl substituted with one or more R3a

[0904] In some embodiments, R3is C1-C4 alkyl substituted with one or more R3a.

[0905] In some embodiments, R3is C1-C3 alkyl substituted with one or more R3a

[0906] In some embodiments, R3is Ci-C2alkyl substituted with one or more R3a.

[0907] In some embodiments, R3is methyl optionally substituted with one OR4aIn some embodiments, R4ais methyl. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0908] In some embodiments, R3is ethyl optionally substituted with one OR4a. In some embodiments, R4ais methyl.

[0909] In some embodiments, R3is propyl optionally substituted with one OR4a. In some embodiments, R4ais methyl.

[0910] In some embodiments, R3is isopropyl optionally substituted with one OR4aIn some embodiments, R4ais methyl.

[0911] In some embodiments, R3is butyl optionally substituted with one OR4a. In some embodiments, R4ais methyl.

[0912] In some embodiments, R3is tert-butyl optionally substituted with one OR4a. In some embodiments, R4ais methyl.

[0913] In some embodiments, R3is pentyl optionally substituted with one OR4a. In some embodiments, R4ais methyl.

[0914] In some embodiments, R3is hexyl optionally substituted with one OR4a. In some embodiments, R4ais methyl.

[0915] In some embodiments, R3is C2-C6 alkenyl optionally substituted with one or more R3a. In some embodiments, R3is C2-C5 alkenyl optionally substituted with one or more R3a. In some embodiments, R3is C2-C4 alkenyl optionally substituted with one or more R3a. In some embodiments, R3is C2-C3 alkenyl optionally substituted with one or more R3a. In some embodiments, R3is C2-C6 alkynyl optionally substituted with one or more R’a. In some embodiments, R3is C2-C5 alkynyl optionally substituted with one or more R3a. In some embodiments, R3is C2-C4 alkynyl optionally substituted with one or more R3a. In some embodiments, R3is C2-C3 alkynyl optionally substituted with one or more R3a. In some embodiments, R3is Ci-Ce alkoxy optionally substituted with one or more R3a. In some embodiments, R3is C1-C5 alkoxy optionally substituted with one or more R3a. In some embodiments, R3is C1-C4 alkoxy optionally substituted with one or more R3a. In some embodiments, R3is C1-C3 alkoxy optionally substituted with one or more R3a. In some embodiments, R3is C1-C2 alkoxy optionally substituted with one or more R3a. In some embodiments, R3is a C3-C12 cycloalkyl optionally substituted with one or more R3a

[0916] In some embodiments, R3is a C3-C11 cycloalkyl optionally substituted with one or more R3a Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0917] In some embodiments, R3is a C3-C10 cycloalkyl optionally substituted with one or more R3a

[0918] In some embodiments, R3is a C3-C9 cycloalkyl optionally substituted with one or more R3a

[0919] In some embodiments, R3is a C3-C8 cycloalkyl optionally substituted with one or more R3a

[0920] In some embodiments, R3is a C3-C7 cycloalkyl optionally substituted with one or more R3a

[0921] In some embodiments, R3is a C3-C6 cycloalkyl optionally substituted with one or more R3a

[0922] In some embodiments, R3is a C3-C5 cycloalkyl optionally substituted with one or more R3a

[0923] In some embodiments, R3is a C3-C4 cycloalkyl optionally substituted with one or more R3a

[0924] In some embodiments, R3is a C6-C10aryl optionally substituted with one or more R3a. In some embodiments, R3is a C6-C9aryl optionally substituted with one or more R3a. In some embodiments, R3is a C6-C8aryl optionally substituted with one or more R3a. In some embodiments, R3is a C6-C7aryl optionally substituted with one or more R3a. In some embodiments, R3is a 5- to 10-membered heteroaryl optionally substituted with one or more R3a.

[0925] In some embodiments, R3is a 5- to 9-membered heteroaryl optionally substituted with one or more R3a.

[0926] In some embodiments, R3is a 5- to 8-membered heteroaryl optionally substituted with one or more R3a.

[0927] In some embodiments, R3is a 5- to 7-membered heteroaryl optionally substituted with one or more R3a.

[0928] In some embodiments, R3is a 5- to 6-membered heteroaryl optionally substituted with one or more R3a.

[0929] In some embodiments, R3is a 3- to 12-membered heterocyclyl optionally substituted with one or more R3a. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0930] In some embodiments, R3is a 3- to 11-membered heterocyclyl optionally substituted with one or more R3a.

[0931] In some embodiments, R3is a 3- to 10-membered heterocyclyl optionally substituted with one or more R3a.

[0932] In some embodiments, R3is a 3- to 9-membered heterocyclyl optionally substituted with one or more R3a.

[0933] In some embodiments, R3is a 3- to 8-membered heterocyclyl optionally substituted with one or more R3a.

[0934] In some embodiments, R3is a 3- to 7-membered heterocyclyl optionally substituted with one or more R3a.

[0935] In some embodiments, R3is a 3- to 6-membered heterocyclyl optionally substituted with one or more R3a.

[0936] In some embodiments, R3is a 3- to 5-membered heterocyclyl optionally substituted with one or more R3a.

[0937] In some embodiments, R3is a 3- to 4-membered heterocyclyl optionally substituted with one or more R3a.

[0938] In some embodiments, R3is C(O)(R4a), wherein:

[0939] R4ais H, CN, or Ci-Ce alkyl optionally substituted with Ce-Cio aryl or N(R4a’)(R4b’); and

[0940] each R4a’ and R4b’ is independently H, Ci-Ce alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl.

[0941] O

[0942] In some embodiments, R3is

[0943] I

[0944]

[0945] n some embodiments, R3is C(O)O-C(R4a)2-OC(O)(R4a), wherein:

[0946] each R4ais independently H, CN, or Ci-Ce alkyl optionally substituted with Ce-Cio aryl or N(R4a’)(R4b’); and

[0947] each R4a’ and R4b’ is independently H, Ci-Ce alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0948] In some embodiments, R3is

[0949]

[0950] - or In some embodiments, R3is Ci-Ce alkyl substituted with one or more R3a, wherein:

[0951] each R3ais independently OR4a, Ce-Cio aryl, or 3- to 12-membered heterocyclyl; and

[0952] each R4ais independently H, CN, or Ci-Ce alkyl.

[0953] In some embodiments, R3is C1-C5 alkyl substituted with one or more R3a, wherein:

[0954] each R3ais independently OR4a, Ce-Cio aryl, or 3- to 12-membered heterocyclyl; and

[0955] each R4ais independently H, CN, or Ci-Ce alkyl.

[0956] In some embodiments, R3is Cj-C4 alkyl substituted with one or more R3a, wherein:

[0957] each R3ais independently OR4a, Ce-Cio aryl, or 3- to 12-membered heterocyclyl; and

[0958] each R4ais independently H, CN, or Ci-C6 alkyl.

[0959] In some embodiments, R3is C1-C3alkyl substituted with one or more R3a, wherein:

[0960] each R3ais independently OR4a, C6-C10aryl, or 3- to 12-membered heterocyclyl; and

[0961] each R4ais independently H, CN, or C1-C6alkyl.

[0962] In some embodiments, R3is Cj-C? alkyl substituted with one or more R3a, wherein:

[0963] each R3ais independently OR4a, Co-Cio aryl, or 3- to 12-membered heterocyclyl; and

[0964] each R4ais independently H, CN, or Ci-C6 alkyl.

[0965] In some embodiments, R3is methyl substituted with one or more R3a, wherein:

[0966] each R3ais independently OR4a, C6-C10aryl, or 3- to 12-membered heterocyclyl; and

[0967] each R4ais independently H, CN, or C1-C6alkyl.

[0968] In some embodiments, R3is ethyl substituted with one or more R3a, wherein: Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0969] each R3ais independently OR4a, Cg-Cio aryl, or 3- to 12-membered heterocyclyl; and

[0970] each R4ais independently H, CN, or Ci-Cg alkyl.

[0971] In some embodiments, R3is propyl substituted with one or more R3a, wherein:

[0972] each R3ais independently OR4a, Cg-Cio aryl, or 3- to 12-membered heterocyclyl; and

[0973] each R4ais independently H, CN, or Ci-Cg alkyl.

[0974] In some embodiments, R3is methyl substituted with one or more R3a, wherein each R3ais independently C6-C10aryl.

[0975] In some embodiments, R3is methyl substituted with one phenyl.

[0976] In some embodiments, R3is ethyl substituted with one or more R3a, wherein each R3ais independently Cg-Cio aryl.

[0977] In some embodiments, R3is propyl substituted with one or more R3a, wherein each R3ais independently Cg-Cio aryl.

[0978] In some embodiments, R3is isopropyl substituted with one or more R3a, wherein each R3ais independently C6-C10aryl.

[0979] In some embodiments, R3is butyl substituted with one or more R3a, wherein each R3ais independently Cg-Cio aryl.

[0980] In some embodiments, R3is tert-butyl substituted with one or more R3a, wherein each R3ais independently C’e-Cio aryl.

[0981] In some embodiments, R3is pentyl substituted with one or more R3a, wherein each R3ais independently Cg-Cio aryl.

[0982] In some embodiments, R3is hexyl substituted with one or more R3a, wherein each R3ais independently C6-C10aryl.

[0983] In some embodiments, R3is C1-C6alkyl substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0984] In some embodiments, R3is C1-C5alkyl substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0985] In some embodiments, R3is C1-C4alkyl substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[0986] In some embodiments, R3is C1-C3 alkyl substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0987] In some embodiments, R3is C1-C2 alkyl substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0988] In some embodiments, R3is methyl substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0989] In some embodiments, R3is ethyl substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0990] In some embodiments, R3is propyl substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0991] In some embodiments,

[0992]

[0993] R3is

[0994] In some embodiments, R3is isopropyl substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0995] In some embodiments, R3is butyl substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0996] In some embodiments, R3is t -butyl substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0997] In some embodiments, R3is pentyl substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0998] In some embodiments, R3is hexyl substituted with one or more R3a, wherein each R3ais independently 3- to 12-membered heterocyclyl.

[0999] In some embodiments, R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected.

[1000] N

[1001] In some embodiments,

[1002]

[1003] In some embodiments, n is 1.

[1004] In some embodiments, n is 2.

[1005] In some embodiments, n is 3. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1006] In some embodiments, W is CH, Y is N, Z is O, and Ring A is

[1007]

[1008] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1009]

[1010]

[1011] Attorney Docket No.: SYND-063 / 001WO 43707-02984 In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1012]

[1013]

[1014] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1015]

[1016] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1017]

[1018] F3C..0,. Y H M N N N N

[1019] isopropyl; and R1is Y V Y Y~” Y

[1020]

[1021] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1022]

[1023] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1024] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1025]

[1026] or is H, methyl, or ethyl.

[1027] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1028]

[1029] methyl, or ethyl; R2is isopropyl;

[1030]

[1031] and R1is

[1032] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1033]

[1034] O

[1035] methyl, or ethyl; R2is isopropyl; a

[1036]

[1037] nd R1is

[1038] W

[1039]

[1040] Attorney Docket No.: SYND-063 / 001WO 43707-02984 In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1041]

[1042]

[1043] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1044]

[1045]

[1046] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1047]

[1048] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1049]

[1050] F3C^O..

[1051] H I I I KI N N N N

[1052] o <y> <y> methyl, or ethyl; R2is isopropyl; a

[1053]

[1054] nd R1is

[1055]

[1056] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1057]

[1058] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1059] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1060]

[1061] ■ R3is H,

[1062] methyl, ethyl, isopropyl, tert-butyl,

[1063]

[1064] , or; and X3is H, methyl, or ethyl.

[1065] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1066]

[1067] or R3is H

[1068] ^O methyl, ethyl, isopropyl, tert-butyl,

[1069]

[1070] or X3is H,

[1071] N N

[1072] methyl, or ethyl; R2is isopropyl;

[1073]

[1074] and R1is or

[1075] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1076]

[1077] methyl, ethyl, isopropyl, tert-butyl,

[1078]

[1079] NH

[1080] methyl, or ethyl; R2is isopropyl; a

[1081]

[1082] nd R1i Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1083]

[1084] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1085]

[1086]

[1087] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1088]

[1089] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1090]

[1091] methyl, ethyl, isopropyl, tert-butyl,

[1092]

[1093]

[1094] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1095]

[1096] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1097]

[1098] methyl, ethyl, isopropyl, tert-butyl,

[1099]

[1100]

[1101] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1102]

[1103] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1104]

[1105] methyl, ethyl, isopropyl, tert-butyl,

[1106]

[1107] or OMe

[1108] methyl, or ethyl; R2is isopropyl; and R1is

[1109]

[1110] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1111] N N

[1112] i

[1113]

[1114] sopropyl; and R1is or Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1115]

[1116] Attorney Docket No.: SYND-063 / 001WO 43707-02984 In some embodiments, W is CH; Y is N; Z is O;

[1117]

[1118] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1119] F3C^O., | H I I I hj N N N N isopropyl: and R1is Y YYY V

[1120]

[1121] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1122]

[1123] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1124] OMe OEt

[1125]

[1126] In some embodiments, W is CH, Y is N, Z is O, Ring A is

[1127]

[1128] and n is 1, 2, or 3.

[1129] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1130]

[1131] isopropyl; R1is

[1132]

[1133] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1134]

[1135] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1136]

[1137] is F NH2— N isopropyl; R1is

[1138]

[1139] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1140]

[1141] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1142]

[1143] Attorney Docket No.: SYND-063 / 001WO 43707-02984 F

[1144]

[1145] ; and n is 1, 2, or 3.

[1146] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1147]

[1148]

[1149] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1150] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1151]

[1152] or methyl, or ethyl; and n is 1, 2, or 3.

[1153] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1154]

[1155] methyl, or ethyl; R2is isopropyl; R

[1156]

[1157] 1is

[1158] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1159]

[1160]

[1161] Attorney Docket No.: SYND-063 / 001WO 43707-02984 In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1162]

[1163]

[1164] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1165] ^9 0 0 Q O A) Q V YC ]

[1166] F

[1167] % 8 v “? ™? -?

[1168]

[1169] or, / uvv; and n is 1, 2, or 3.

[1170] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1171]

[1172] methyl, or ethyl; R2is isopropyl; R

[1173]

[1174] 1is

[1175]

[1176] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1177]

[1178] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1179] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1180]

[1181] methyl, ethyl, isopropyl, tert-butyl,

[1182]

[1183] methyl, or ethyl; and n is 1, 2, or 3.

[1184] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1185]

[1186] methyl, ethyl, isopropyl, tert-butyl

[1187]

[1188] , or; X3is H,

[1189] N N

[1190] methyl, or ethyl; R2is isopropyl; R

[1191]

[1192] 1is or and n is 1, 2, or 3,

[1193] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1194]

[1195] is H,

[1196] methyl, ethyl, isopropyl, tert-butyl,

[1197]

[1198] is H.

[1199] NH2

[1200] NH

[1201] methyl, or ethyl; R2is isopropyl; R

[1202]

[1203] 1is Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1204]

[1205] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1206]

[1207]

[1208] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1209]

[1210] in Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1211]

[1212] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1213]

[1214] methyl, ethyl, isopropyl, / ert-butyl,

[1215]

[1216] methyl, or ethyl; R2is isopropyl; R

[1217]

[1218] 1is

[1219]

[1220] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1221]

[1222] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1223]

[1224] methyl, ethyl, isopropyl, tert-butyl,

[1225]

[1226] , or OMe F

[1227] methyl, or ethyl; R2is isopropyl; R

[1228]

[1229] 1is Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1230]

[1231] In some embodiments, W is CH, Y is N, Z is O, is 1, 2, or 3.

[1232] In some embodiments, W

[1233]

[1234] is CH; Y is N; Z is O; isopropyl; R

[1235]

[1236] 1is Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1237]

[1238] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1239]

[1240] In some embodiments, W is CH; Y is N; Z is O;

[1241] isopropyl; R

[1242]

[1243] 1is Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1244]

[1245] In some embodiments, W is CH; Y is N; Z is O;

[1246] F,o F3C.0 s=o F N N N N NMN

[1247] isoprop

[1248]

[1249] yl; R1is Y „VY Y JWtf YV V Y Y Y / VW

[1250]

[1251] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1252] and n is 1, 2, or 3. In some embodiments, W is CH; Y is N; Z is O;

[1253] OMe

[1254]

[1255] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1256]

[1257] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1258]

[1259] ; and X3is H, methyl, or ethyl.

[1260]

[1261] N N

[1262] ; X3is H, methyl, or ethyl; R2is isopropyl; and R1is or

[1263]

[1264] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1265]

[1266] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1267]

[1268] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1269]

[1270] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1271]

[1272] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1273]

[1274]

[1275] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1276] OMe OEt

[1277] zvw* zuw OH

[1278]

[1279] or In some embodiments, W is CH; Y is N; Z is O; Ring A. is

[1280]

[1281] r 3.

[1282]

[1283] Attorney Docket No.: SYND-063 / 001WO 43707-02984 In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1284]

[1285]

[1286] ; and n is 1, 2, or 3.

[1287] In some embodiments, W is CH; Y is N; Z is O; Ring A is

[1288]

[1289] or

[1290]

[1291] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1292] n is 1, 2, or 3.

[1293]

[1294] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1295]

[1296] Attorney Docket No.: SYND-063 / 001WO 43707-02984 or ■ / vw; and n is 1, 2, or 3.

[1297]

[1298] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1299] OMe OEt

[1300]

[1301] In some embodiments, W is N, Y is N, Z is O, and Ring A is

[1302]

[1303] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1304]

[1305]

[1306] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1307]

[1308] isopropyl; a

[1309]

[1310] nd R1is Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1311]

[1312] In some embodiments, W is N; Y is N; Z is O; Ring

[1313]

[1314] A

[1315]

[1316] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1317] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1318]

[1319] F3C^O NZNXN N N

[1320] isopropyl: and R1is V Y YY v

[1321]

[1322] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1323]

[1324] F3C^O \Z T H N N, N N N isopropyl; a

[1325]

[1326] nd R1is Y Y V Y~~~ Y Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1327]

[1328] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1329]

[1330] isopropyl; and R1is

[1331]

[1332] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1333]

[1334] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1335]

[1336] H, methyl, or ethyl.

[1337] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1338]

[1339] methyl, or ethyl; R2is isopropyl; a

[1340]

[1341] nd R1is

[1342] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1343]

[1344] O

[1345]

[1346] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1347]

[1348] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1349]

[1350] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1351]

[1352] F3methyl, or ethyl; R2is isopropyl; a

[1353]

[1354] nd R1is Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1355]

[1356] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1357]

[1358] is H, methyl, or ethyl.

[1359] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1360]

[1361] methyl, ethyl, isopropyl, tert-butyl,

[1362]

[1363] methyl, or ethyl; R2is isopropyl;

[1364]

[1365] and R1is

[1366] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1367]

[1368] methyl, ethyl, isopropyl, tert-butyl,

[1369]

[1370] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1371]

[1372] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1373]

[1374] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1375]

[1376] methyl, ethyl, isopropyl, tert-butyl,

[1377]

[1378]

[1379] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1380]

[1381] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1382]

[1383] methyl, ethyl, isopropyl, tert-butyl,

[1384]

[1385]

[1386] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1387] F

[1388]

[1389] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1390]

[1391] ; R3is H, methyl, ethyl, isopropyl, tert-butyl,

[1392]

[1393] or OMe

[1394] methyl, or ethyl; R2is isopropyl; and R1is

[1395]

[1396] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1397] N N

[1398] i

[1399]

[1400] sopropyl; and R1is or Attorney Docket No.: SYND-063 / 001WO 43707-02984 In some embodiments, W is N; Y is N; Z is O;

[1401]

[1402] Attorney Docket No.: SYND-063 / 001WO 43707-02984 OMe

[1403] ? v V

[1404]

[1405] In some embodiments, W is N; Y is N; Z is O;; and R1is

[1406]

[1407] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1408]

[1409] In some embodiments, W is N; Y is N; Z is O;

[1410]

[1411] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1412]

[1413] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1414] In some embodiments, W is N, Y is N, Z is O, Ring A is

[1415]

[1416] 1, 2, or 3.

[1417] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1418]

[1419] R2is

[1420] isopropyl; R1is

[1421]

[1422] Attorney Docket No.: SYND-063 / 001WO 43707-02984 In some embodiments, W is N; Y is N; Z is O; Ring A is

[1423]

[1424]

[1425] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1426]

[1427] Attorney Docket No.: SYND-063 / 001WO 43707-02984 F

[1428]

[1429] ; and n is 1, 2, or 3.

[1430] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1431]

[1432]

[1433] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1434] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1435]

[1436] methyl, or ethyl; and n is 1, 2, or 3.

[1437] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1438]

[1439] methyl, or ethyl; R2is isopropyl; R

[1440]

[1441] 1is

[1442]

[1443] Attorney Docket No.: SYND-063 / 001WO 43707-02984 In some embodiments, W is N; Y is N; Z is O; Ring A is

[1444]

[1445]

[1446] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1447] F

[1448]

[1449] ; and n is 1, 2, or 3.

[1450] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1451]

[1452] methyl, or ethyl; R2is isopropyl; R

[1453]

[1454] 1is

[1455]

[1456] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1457]

[1458] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1459] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1460]

[1461] or; R3is H,

[1462] methyl, ethyl, isopropyl, tert-butyl,

[1463]

[1464] or is H, methyl, or ethyl; and n is 1, 2, or 3.

[1465] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1466]

[1467] or; R3is H,

[1468] methyl, ethyl, isopropyl, tert-butyl,

[1469]

[1470] , or is H,

[1471] N N

[1472] methyl, or ethyl; R2is isopropyl; R

[1473]

[1474] 1is or; and n is 1, 2, or 3.

[1475] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1476]

[1477] is H,

[1478] methyl, ethyl, isopropyl, tert-butyl,

[1479]

[1480] is H,

[1481] NH2NH

[1482] methyl, or ethyl; R2is isopropyl;

[1483]

[1484] R1is Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1485]

[1486] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1487]

[1488] is H, methyl, ethyl, isopropyl, tert-butyl,

[1489]

[1490] is H,

[1491] NH2NH

[1492] methyl, or ethyl; R2is isopropyl; R

[1493]

[1494] 1is Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1495]

[1496] methyl, or ethyl; R2is isopropyl; R

[1497]

[1498] 1is

[1499]

[1500] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1501] F

[1502]

[1503] ; and n is 1, 2, or 3.

[1504] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1505]

[1506] ; R3is H, methyl, ethyl, isopropyl, / ert-butyl,

[1507]

[1508] is H

[1509] methyl, or ethyl; R2is isopropyl; R

[1510]

[1511] 1O

[1512]

[1513] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1514]

[1515] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1516]

[1517] methyl, ethyl, isopropyl, tert-butyl,

[1518]

[1519]

[1520] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1521] AXNX

[1522] i

[1523]

[1524] sopropyl; R1is or; and n is 1, 2, or 3. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1525]

[1526] Attorney Docket No.: SYND-063 / 001WO 43707-02984 o; and n is 1, 2, or 3. In some embodiments, W is N; Y is N; Z is 0;

[1527] F3C^O H I N N N N N

[1528] <5 y yV'-' V

[1529]

[1530] Attorney Docket No.: SYND-063 / 001WO 43707-02984 F I

[1531] In some embodiments, W is N; Y is N; Z is O;

[1532]

[1533] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1534] In some embodiments, W is N; Y is N; Z is O;

[1535]

[1536] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1537] OH

[1538]

[1539] In some embodiments, W is N, Y is CH, Z is O, and Ring A is

[1540]

[1541] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1542]

[1543] N

[1544] isopropyl; a

[1545]

[1546] nd R1is

[1547] In some embodiments,

[1548]

[1549] W is CH; Z is O; Ring A is

[1550]

[1551] NH2

[1552] isopropyl; a

[1553]

[1554] nd R1is Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1555]

[1556] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1557]

[1558]

[1559] Attorney Docket No.: SYND-063 / 001WO 43707-02984 In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1560]

[1561]

[1562] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1563]

[1564] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1565]

[1566]

[1567] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1568] OMe OEt

[1569]

[1570] N

[1571] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1572]

[1573] ; and X3is H, methyl, or ethyl.

[1574] N

[1575] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1576]

[1577] ; X3is H, methyl, or ethyl; R2is isopropyl; a

[1578]

[1579] nd R1is JWV' 0J*

[1580] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1581]

[1582] X3is H,

[1583] NH2NH

[1584] methyl, or ethyl; R2is isopropyl; a

[1585]

[1586] nd R1is 707-02984

[1587] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1588]

[1589] Attorney Docket No.: SYND-063 / 001WO 43707-02984 In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1590]

[1591]

[1592] methyl, or ethyl; R2is isopropyl; a

[1593]

[1594] nd R1is Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1595] 5

[1596]

[1597] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1598]

[1599] is H, methyl, or ethyl.

[1600] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1601]

[1602] methyl, ethyl, isopropyl, tert-butyl,

[1603]

[1604] methyl, or ethyl; R2is isopropyl;

[1605]

[1606] and R1is

[1607] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1608]

[1609] methyl, ethyl, isopropyl, tert-butyl,

[1610]

[1611] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1612]

[1613] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1614]

[1615]

[1616] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1617]

[1618] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1619]

[1620] methyl, ethyl, isopropyl, tert-butyl,

[1621]

[1622]

[1623] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1624]

[1625] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1626]

[1627] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1628]

[1629] methyl, ethyl, isopropyl, tert-butyl,

[1630]

[1631]

[1632] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1633]

[1634] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1635]

[1636] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1637]

[1638] In some embodiments, W is N; Y is CH; Z is 0;

[1639] F3C^O | J o S=O I i N N

[1640] <^> <^ <^> <^ <^> " A €> <> isopropyl; and R1is v / WV x / WV AfUV <7VW « / WV / ww^ * / wv / ww 5 5 9

[1641]

[1642] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1643]

[1644] In some embodiments, W is N; Y is CH; Z is O;

[1645] F3C^O >7 O | H I I Iu-y s~o N N N N NFN N

[1646] isopropyl; and R1is Y YY^ Y Y Y Y

[1647]

[1648] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1649] In some embodiments, W is N; Y is CH: Z is O'

[1650] OH

[1651]

[1652] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1653] In some embodiments, W is N, Y is CH, Z is O, Ring A is

[1654]

[1655] and n is 1, 2, or 3.

[1656] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1657]

[1658] isopropyl; R

[1659]

[1660] 1is

[1661] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1662]

[1663]

[1664] Attorney Docket No.: SYND-063 / 001WO 43707-02984 In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1665]

[1666]

[1667] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1668] N N

[1669] N

[1670] s zw F

[1671] | / Z'S‘O N

[1672] N

[1673]

[1674] AA / V Q|*; and n is 1, 2, or 3,

[1675] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1676]

[1677]

[1678] Attorney Docket No.: SYND-063 / 001WO 43707-02984 F

[1679]

[1680] ; and n is 1, 2, or 3.

[1681] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1682]

[1683] R2is

[1684]

[1685] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1686] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1687]

[1688] methyl, or ethyl; and n is 1, 2, or 3.

[1689] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1690]

[1691] methyl, or ethyl; R2is isopropyl; R

[1692]

[1693] 1is

[1694] In some embodiments, W is N; Y is CH; Z is O; Ring A

[1695]

[1696] is

[1697]

[1698] Attorney Docket No.: SYND-063 / 001WO 43707-02984 In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1699]

[1700]

[1701] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1702]

[1703] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1704]

[1705] F3C^O..

[1706] T H I I! M N N N N Y Y YVv methyl, or ethyl; R2is isopropyl; R

[1707]

[1708] 1is

[1709]

[1710] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1711] ; and n is 1, 2, or 3.

[1712] OH

[1713]

[1714] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1715] In some embodiments, W is N; Y is CH; Z is O; Ring

[1716]

[1717] A is

[1718] methyl, ethyl, isopropyl, tert-butyl.

[1719]

[1720] methyl, or ethyl; and n is 1, 2, or 3.

[1721] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1722]

[1723] methyl, ethyl, isopropyl, tert-butyl,

[1724]

[1725] methyl, or ethyl; R2is isopropyl; R

[1726]

[1727] lis

[1728] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1729]

[1730]

[1731] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1732]

[1733] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1734]

[1735] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1736]

[1737] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1738]

[1739]

[1740] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1741] F

[1742]

[1743] ; and n is 1, 2, or 3.

[1744] In some embodiments, W is N; Y is CH; Z is O; Ring A is

[1745]

[1746] methyl, ethyl, isopropyl, tert-butyl,

[1747]

[1748] , or OMe F

[1749] methyl, or ethyl; R2is isopropyl; R

[1750]

[1751] 1is Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1752]

[1753] In some embodiments, W is N;

[1754]

[1755] ; and X3is H, methyl, or ethyl.

[1756] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1757]

[1758]

[1759] or N N

[1760] is H, methyl, or ethyl; R2is isopropyl; and R1is or

[1761]

[1762] Attorney Docket No.: SYND-063 / 001WO 43707-02984 In some embodiments, W is N; Y is N; Z is O; Ring A is

[1763]

[1764]

[1765] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1766]

[1767] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1768]

[1769] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1770]

[1771] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1772] OH

[1773]

[1774] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1775]

[1776]

[1777] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1778]

[1779] or 3.

[1780]

[1781] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1782] o

[1783] zvvv'; and n is 1, 2, or 3.

[1784]

[1785] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1786]

[1787] n is 1, 2, or 3.

[1788] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1789]

[1790]

[1791] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1792]

[1793] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1794]

[1795] or ■ / vw; and n is 1, 2, or 3.

[1796] In some embodiments, W is N; Y is N; Z is O; Ring A is

[1797]

[1798]

[1799] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1800] XN,XNZ

[1801]

[1802] isopropyl; R1is or; and n is 1, 2, or 3. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1803]

[1804] Attorney Docket No.: SYND-063 / 001WO 43707-02984 o; and n is 1, 2, or 3. In some embodiments, W is N; Y is CH; Z is O;

[1805]

[1806] Attorney Docket No.: SYND-063 / 001WO 43707-02984 Y N

[1807] nw,or•and n is 1, 2, or 3.

[1808] In some embodiments, W is N; Y is CH; Z is O;

[1809]

[1810] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1811]

[1812] In some embodiments, W is N; Y is CH; Z is O;

[1813] OMe OMe isopropyl; R

[1814]

[1815] 1is Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1816] OEt

[1817]

[1818] In some embodiments, the compound is of Formula I’, I, I-a, I-b, or I-c combined with any of the embodiments described herein.

[1819] Any of the groups described above for any variable can be combined with any of the other groups described above, where applicable, for any of the Formulae described herein.

[1820] Representative compounds of the present disclosure are shown in the table below. Attorney Docket No.: SYND-063 / 001WO 43707-02984 Table 1. Representative Compounds of the Present Disclosure

[1821] Compound Structure IUPAC Name

[1822] No.

[1823] - - 1 2-((4-(6-((6-Benzyl-5,6,7,8-tetrahydro- 1,6-naphthyridin-4-yl)oxy)-2- azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)-5-tluoro-7V-isopropyl-A7-(l- A

[1824] (2,2, 2-tr ifl uor oacety l)azeti din- 3 - yljbenzamide

[1825] 2 Ar-(Azetidin-3-yl)-5-fluoro-7V-isopropyl- 2-((4-(6-((5,6,7,8-tetrahydro-l,6- naphthyridin-4-yl)oxy)-2- \ F= azaspiro [3.3] heptan-2-y l)py rimi din- 5 - / / A~ y 1) oxy)benzam ide

[1826] W

[1827] V Y X

[1828] 3 - yV-(l-Acetylazetidin-3-yl)-5-fluoro-N- isopropyl-2-((4-(6-((5,6,7,8-tetrahydro- A l,6-naphthyridin-4-yl)oxy)-2- Y azaspiro[3.3]heptan-2-yl)pyrimidin-5- y I) oxy)benzam ide

[1829] s 2

[1830] Y N

[1831] o u

[1832] 4 5-Fluoro-A-isopropyl-2-((4-(6-((6- methy 1 - 5,6, 7, 8-tetrahy dr o- 1, 6- naphthyridin-4-yl)oxy)-2- azaspiro [3.3] heptan-2-y l)py rimi din- 5 - yl)oxy)-A-( 1 -methy lazetidin-3- yl)benzamide

[1833]

[1834] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1835] (J?)-5-Fluoro-A-isopropyl-A|r-(pyrrolidin- 3-yl)-2-((4-(6-((5,6,7,8-tetrahydro-L6- L h naphthyridin-4-yl)oxy)-2- azaspiro [3.3 j hep tan-2-y 1 )py rimidi n- 5 - HN — i 1 yl)oxy)benzamide

[1836] (RH Z\

[1837] yo V

[1838] F XJ °Y N5N

[1839] ()-5-Fluoro--isopropyl--(pyrrolidin- 3-yl)-2-((4-(6-((5,6,7,8-tetrahydro-l,6- naphthyridin-4-yl)oxy)-2- azaspiro [3.3] heptan- 2-yl )py rimidi n- 5 - yl)oxy)benzamide

[1840] z\ / \ \

[1841] / \ \ X TZ / C X ( o z z z — —f—z

[1842] HN"^ A-((l r,3r)-3 -Acetamidocyclobuty 1 )-5- o

[1843] O fluoro-7V-isopropyl-2-((4-(6-((5, 6,7,8- yh tetrahydro- 1,6-naphthyridin-4-yl)oxy)- r \= / 2-azaspir o [3.3] heptan-2-y l)pyrimidin- 5 - X W r “■>““ \^ z^. / \

[1844] yl) oxy) benzamide

[1845] N

[1846] F £ -j‘t Ns

[1847] -((1,3)-3-Aminocyclobutyl)-5- fluoro-A-isopropyl-2-((4-(6-((5, 6,7,8- IlNtetrahydro- 1,6-naphthyridin-4-yl)oxy)- NH22-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl) oxy) benzamide

[1848] ^Y0<?

[1849]

[1850] F'^-^ N Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1851] HN" X N-((lr,3r)*3-Aminocyclobutyl)-5- fluoro-7V-isopropyl-2-((4-(6-((5, 6,7,8- Y^N tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide

[1852] r I o x

[1853] F' N

[1854] ; V-((ls, 3s)' -3- (Dimethylamino)cyclobutyl)-5-fluoro- N-isopropyl-2-((4-(6-((5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yI)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide

[1855] A /

[1856] < X. V o z zz — — '— "

[1857] / \ \ xz _z \

[1858] HN'^N A'-((lr,3r)-3- o (Dimethylamino)cyclobutyl)-5-fluoro- IIN7V-isopropyl-2-((4-(6-((5, 6,7,8- < > A ZZ" “ =

[1859] / V tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl) oxy) benzamide

[1860] y y N

[1861] ' X XX X

[1862] JO o

[1863] F ''--' "!■•;

[1864] HN'^X N-(3-Aminobicyclo[1.1.1]pentan-1-yl)- 0% 5-fluoro-A'7-isopropyl-2-((4-(6-((5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)- ^NH2ch J J

[1865] 2-azaspir o [3.3 ] heptan-2-y l)py ri midi n- 5 - y I) oxy)benzam ide

[1866] .. NN NX N

[1867] sX^o X

[1868] Il Y II

[1869] F'^'^X <N-X

[1870]

[1871] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1872] N-(3-(Dimethylamino)bicyclo[1.1.1]pentan- l-yl)-5-fluoro-A-isopropyl-2-((4-(6- ((5,6,7,8-tetrahydro-l,6-naphthyridin-4- yl)oxy )-2-azaspiro [3.3 ]heptan-2- yl)pyrimidin-5-yl)oxy)benzamide

[1873] "" N (5)-5-Fluoro-7V-isopropyl-2-((4-(6-((6- methy 1- 5,6, 7, 8-tetrahy dr o- 1,6- QX iXXNnaphthyridin-4-yI)oxy)-2- HN— i 1 azaspiro[3.3]heptan-2-yl)pyrimidin-5- / \ Z\

[1874] yI)oxy)-Ar-(pyrrolidin-3-yl)benzamide

[1875] (SH X

[1876] YNY° v

[1877] 1 Ax.0... X.

[1878] A F U o N

[1879] C X \ o z s z X O < v z z z — — — ' X. J / / / / / — — —!■\■ \ '• ('' (7?)-5-Fluoro-7V-isopropyl-2-((4-(6-((6- \ TZ / / _ \••• ■ methyl-5,6,7,8-tetrahydro-l,6- o o naphthyridin-4-yl)oxy)-2- A O \ - HN — \ 1 azaspiro [3.3] hep tan-2-y 1 )py rimidi n- 5 - Q xo vX'< ■. yl)oxy)-A-(pyrrolidin-3-yl)benzamide

[1880] ) £

[1881] y LL -z' X

[1882] / N o O

[1883] ' Ax. -O-. X.x

[1884] jj n

[1885] F"^- / 'N'

[1886] 5-Fluoro-N-isopropyl-JV-(piperidin-4- yl)-2-((4-(6-((5,6,7,8-tetrahydro- 1,6- naphthyridin-4-yl)oxy)-2- azaspiro [3.3] heptan-2-y l)py rimid in- 5 - yl) oxy) benzamide

[1887] HN'x^j 5-Fluoro-N-isopropyl-N-(1- yX-'N methylpiperidin-4-yl)-2-((4-(6-((5, 6,7,8-. L j tetrahydro- 1,6-naphthyridin-4-yl)oxy)- N 9 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- Q A yl)oxy)benzamide

[1888] YNY° v

[1889] F-X J Aj °Y^N

[1890]

[1891] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1892] 5-Fluoro--isopropyl--(1-(oxetan-3- yl)azetidin-3-yl)-2-((4-(6-((5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide

[1893] HN N-(1-Cyclobutylazetidin-3-yl)-5-fluoro- N-isopropyl-2-((4-(6-((5, 6,7,8- 90A tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspir o [3.3] heptan-2-y l)pyrimidin- 5 - 9 6 yl) oxy) benzamide

[1894] 'YNY° <2

[1895] A°7 NJ

[1896] HN N-((1S,3S)-3-(Dimethylamino)

[1897] cyclopentyl)-5-fluoro-A7-isopropyl-2- X / ? A

[1898] < o Z z\ / z z\ \ \ ^N

[1899] / z— '— " JU

[1900] — N (S) y / / z * \\ O ((4-(6-((5,6,7,8-tetrahydro-l,6- naphthyridin-4-yl) oxy)-2-azaspiro[3.3]

[1901] 7 9

[1902] (S) i X heptan-2-yl)pyrimidin-5- ) zx kA

[1903] VN"f° v y 1) oxy jbenzami de

[1904] / J Lt- -FAk <Nu

[1905] HN -((1,3)-3- V"' N (Dimethylamino)cyclopentyl)-5-fluoro- / AU

[1906] -NJS) O Ar-isopropyl-2-((4-(6-((5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yI)oxy)- (R 9) I 9 X 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- vy v y 1) oxy jbenzami de

[1907] ' Us. Us.

[1908] HN -((1,3)-3- kA

[1909] Y'' N (Dimethylammo)cyclopentyl)-5-fluoro- / A 9 Ar-isopropyl-2-((4-(6-((5, 6,7,8- — N (R) 0

[1910] tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- (R^ 5\ yl)oxy)benzamide

[1911] VNY° v

[1912] 17s. Os A

[1913]

[1914] F Aj x N Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1915] HN 7V-((LS’37?)-3- I 1 (Dimethylamino)cyclopentyl)-5-fluoro- / X JJ

[1916] -N (R) 0 -isopropyl-2-((4-(6-((5,6,7,8- tetrahydro-1,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3 ]heptan-2-yl)pyrimidin-5- (s)Y X

[1917] yl)oxy)benzamide

[1918] V Y° V

[1919] ’ XzoX

[1920] AX I J

[1921] -((1,3)-3- ■> Y'N (Dimethylamino)cyclopentyl)-5-fluoro- / XY -isopropyl-2-((4-(6-((6-methyl-5,6,7,8- — N (S) 0

[1922] tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspir o [3.3] heptan-2-y l)pyrimidin- 5 - (s)Y X

[1923] yl) oxy) benzamide

[1924] 7 '''A A N

[1925] '" X

[1926] 'XN'Y 5-Fluoro-7V-((3i?,4A!)-4-fluoro-l- methylpyrrolidin-3-yl)-7V-isopropyl-2- ((4-(6-((6-methyl-5,6,7,8-tetrahydro- \ o' ""

[1927] N— i (R) 1 l,6-naphthyridin-4-yl)oxy)-2- azaspiro[3.3]heptan-2-yl)pyrimidin-5- (R? XFX

[1928] y I) oxy)benzam ide

[1929] W V

[1930] ' X.o. X

[1931] 5-Fluoro--((3,4)-4-fluoro-1-methylpyrrolidin-3-yl)--isopropyl-2- ((4-(6-((5,6,7,8-tetrahydro-l,6- \ o AX

[1932] naphthy rid in-4-y 1) oxy) -2- (R) X

[1933] azaspiro [3.3 ] heptan-2-y l)py rimid in- 5 - (R)> / yl) oxy) benzamide

[1934] ■ysv° V

[1935] iXX

[1936] F ■- N

[1937] 5-Fluoro--((3,4)-4-fluoro-1-methylpyrrolidin-3-yl)--isopropyl-2- ((4-(6-((6-methyl-5,6,7,8-tetrahydro- \ o'XX

[1938] (S) 1 1,6-naphthyridin-4-yI)oxy)-2-< Kx / 'i''F \z azaspiro[3.3]heptan-2-yl)pyrimidin-5- (R) Y X

[1939] ^ N^.0 \ 2 y 1) oxy jbenzami de

[1940] y y N

[1941] 1,(X X

[1942] J J o

[1943]

[1944] F N Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1945] 5-Fluoro--((3,4)-3-fluoro-1- methylpiperidin-4-yl)-A7-isopropyl-2- J fi ' ((4-(6-((6-methyl-5,6,7,8-tetrahydro- 1,6-naphthyridin-4-yl) oxy)-2-azaspiro X S T -, - \ " [3.3] heptan-2-yl) pyrimidin-5-yl) oxy)

[1946] 7- benzamide

[1947] r. Ays. A n x-L

[1948] ON

[1949] ( / / \\z / ■ X > O Z'Zz_r / -“ r- / NZ v \z } 5 -Fl uoro- / V- ((3 S, 45) -3 -fl uoro- 1 - methylpiperidin-4-yl)- / V-isopropyl-2- w

[1950] ((4-(6-((6-methyl-S,6,7,8-tetrahydro- 1,6-naphthyridin-4-yl)oxy)-2- azaspiro[3.3]heptan-2-yl)pyrimidin-5- y 1) oxy)benzam ide

[1951] ZTK~

[1952] 5-Fluoro--((3,4)-3-fluoro-1- _ / / A

[1953] methylpiperidin-4-yl)-Ar-isopropyl-2- ^0^ z nZN / Nz / o— zzz-- / -- / -V~--^ ((4-(6-((6-methyl-5,6,7,8-tetrahydro- y= / / x \z /

[1954] 1,6-naphthyridin-4-yl)oxy)-2- o o

[1955] ;\ O \ W U- — azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide

[1956] _ / x _ _ \ Y

[1957] & A

[1958] / /

[1959] 5-Fluoro--((3,4)-3-fluoro-1- methylpiperidin-4-yl)-7V-isopropyl-2- ((4-(6-((6-methyl-5,6,7,8-tetrahydro- x JN, 0 Y"

[1960] s | l,6-naphthyridin-4-yl)oxy)-2- r "i (R) z\

[1961] \xX-v \z azaspiro [3.3] heptan-2-y l)py rimidin- 5 - (R);F7\

[1962] . Y N^ YO \ yl)oxy)benzamide

[1963] N2

[1964] / X. xO. A.

[1965] [l Y A;N

[1966] 5 -F luoro-A -( ( 3 S, 5R) - 5 -fluoro- 1 - methylpiperidin-3-yl)-A’-isopropyl-2- ((4-(6-((6-methyl-5,6,7,8-tetrahydro- 1,6-naphthyridin-4-yl)oxy)-2- azaspiro [3.3] heptan-2 -y l)py rimidin- 5 - yl)oxy)benzamide

[1967]

[1968] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1969] 5-Fluoro--((3,5)-5-fluoro-1- methylpiperidin-3-yl)-A-isopropyl-2- X ((4-(6-((6-methyl-5,6,7,8-tetrahydro- N^T* 1 1,6-naphthyridin-4-yl)oxy)-2- n — 1^ J (S) Z\

[1970] azaspiro [3.3 j hep tan-2-y 1 )py rimidi n- 5 - (S) \ Z Y 2 z=\ — — X

[1971] yl)oxy)benzamide

[1972] VNY° V

[1973] QY Z A AT N

[1974] J! J o H I

[1975] F X / / Z\\ /

[1976] X Xzz / \ 5-Fluoro-A’-isopropyl-Ar-((3^,4J?)-4- methoxy- 1 -methylpyrrolidin-3 -yl)-2- SfS w ((4-(6-((6-methyl-5,6,7,8-tetrahydro- N— x (R) 1 1,6-naphthyridin-4-yl)oxy)-2-,„Sx / ^'OMe \ / azaspiro [3.3 ] heptan-2-y 1 )py rimidin- 5 - (R):

[1977] W O yl) oxy) benzamide

[1978] ' X. -CX X

[1979] / j Y jj

[1980] F' -^ >r

[1981] 5-Fluoro--isopropyl--((3,4)-4-methoxy-1-methylpyrrolidin-3-yl)-2- y / ^ / Nz\ / ((4-(6-((6-methyi-5,6,7,8-tetrahydro- o ® l,6-naphthyridin-4-yl)oxy)-2-? e azaspiro [3.3 ] heptan-2-y l)py rimi din- 5 - y 1Z Yi- v::: y 1) oxy)benzam ide

[1982] )g -z■—y~z

[1983] 5-Fluoro-A7-isopropyl-Ar-(2-methyl-2- 1 || N azaspiro[3.3]heptan-6-yl)-2-((4-(6- / \ 0 ((5,6,7, 8-tetrahydro- 1,6-naphthyri din-4- yI)oxy)-2-azaspiro [3.3 ]heptan-2- yl)pyrimidin-5-yl)oxy)benzamide

[1984] Y N

[1985] ' X yx X

[1986] F'XX^ N

[1987] 5-Fluoro-A-isopropyl-2-((4-(6-((6- methy 1 - 5,6, 7, 8-tetrahy dr o- 1, 6- naphthyridin-4-yl)oxy)-2- azaspiro [3.3] heptan-2-y l)py rimi din- 5 - yl)oxy)-7V-(2-methyl-2- azaspiro[3.3]heptan-6-yl)benzamide

[1988]

[1989] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[1990] ()-5-Fluoro--isopropyl--(1-methyl-5-oxopyrrolidin-3-yl)-2-((4-(6-((5,6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- (1 / -n — yl)oxy)benzamide

[1991] A, - “x

[1992] (X X? ^x

[1993] 4KX" YA> / \ o

[1994] p o

[1995] f\ / \\— - x \ z z -\ X Z X O z X 5 2 Z >) o z z ~z> — / — — — — z, —,.

[1996] H\ZN / / / V / v \ V^ \ ' \ v \''zy _ ()-5-Fluoro--isopropyl--(1-methyl- Zyv

[1997] Jj yJ 5-oxopyrrolidin-3-yl)-2-((4-(6-((5, 6,7,8- 1 JJ

[1998] \,0 O"^ tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspir o [3.3] heptan-2-y l)pyrimidin- 5 - H A yl) oxy) benzamide

[1999] (E2) Y X

[2000] Y Y N

[2001] | rj X Y, Y X N

[2002] Fx> V

[2003] -((1,3)-3-(Dimethylamino)-3-methylcyclobutyl)-5-fluoro--isopropyl-2-((4-(6-((5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide

[2004] HN -((1,3)-3-(Dimethylamino)-3-methylcyclobutyl)-5-fluoro-- / Ju isopropyl-2-((4-(6-((5,6,7,8-tetrahydro- 1,6-naphthyridin-4-yl)oxy)-2- J J azaspiro [3.3] heptan-2-y l)py rimidin- 5 - \. N^. O O yl)oxy)benzamide

[2005] Y N

[2006] A J

[2007] N-(( 1 s,3s)-3-(Dimethylamino)- 1 - a. methy Icy cl obutyI)-5 -fluoro-A7- isopropyl-2-((4-(6-((6-methyl-5, 6,7,8-, - A1tetrahydro- 1,6-naphthyridin-4-yI)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- y 1) oxy ) benzarm de

[2008] \X. Y3 <0>

[2009] Y Y N JUU

[2010]

[2011] F N Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2012] Ar-((1 r,3^)-3-(Dimethylamino)- 1 - methy lcyclobutyl)-5 -fluoro-A7- isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)- / ( z -n - i — 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- \ \ ' z - —. yl)oxy)benzamide

[2013] A / v

[2014] o

[2015] Z\ Z\ X o? ’z z z A — — —,

[2016] T / / / \ v \ \ \

[2017] , V-(3-(Dimethylamino)propyl)-5-fluoro-; xz- Ar-isopropyl-2-((4-(6-((5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide

[2018] _ / /

[2019] Ar-(2-(Dimethylamino)ethyl)-5-fluoro- J \ XX o < o < ze z z z z z--7——--7— - / V Z\ / / / \""

[2020] / ^ / V / z N\ Ar-isopropyl-2-((4-(6-((5, 6,7,8- q o tetrahydro- 1,6-naphthyridin-4-yl)oxy)- A W 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide

[2021] Z U. >, X > <—zr\) Z zZ

[2022] LL / _»*— "« Ml-x

[2023] Z — ' LU / \ - / \ - / - / Z’

[2024] / '

[2025] \ /

[2026] HN-^ AT-((15,45)-4- (Dimethylamino) cyclohexyl)- 5 -fluoro- N 1 J AMsopropyl-2-((4-(6-((5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro [3.3 ]heptan-2-yl)pyrimidin-5 - yl)oxy)benzamide

[2027] ' _x-L X

[2028] TfN

[2029] A-((lr,4r)-4- (Dimethylamino)cyclohexyl)-5-fluoro-. V-isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- y 1) oxy)benzam ide

[2030]

[2031] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2032] 5-Fluoro-7V-isopropyl-2-((4-(6-((6- methyl-5,6,7,8-tetrahydro-L6- naphthyridin-4-yl)oxy)-2- azaspiro [3.3 j hep tan-2-y 1 )py rimidi n- 5 - yl)oxy)-Af-(l-methylpipendin-4- A5 v "r_

[2033] yl)benzamide

[2034] o

[2035] O

[2036] ( / = / \ Z Z\

[2037] > xO z a z z—— — i

[2038] TM \ ' \

[2039] (7?)-5-Fluoro-vV-isopropyl-N-( 1 - methylpiperidin-3-yl)-2-((4-(6-((5,6,7,8- VZ~

[2040] tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide

[2041] ^ z.- ) \> _ / y /

[2042] / ( / _

[2043] (N)-5-Fluoro-N-isopropyl-2-((4-(6-((6-X. < < < >< V O

[2044] ^ / / \ / X \ / \z _Z / X o

[2045] \ o^ Z zzz z z Zt Z z — / —--J—————x' '

[2046] / methy 1- 5,6, 7, 8-tetrah y dr o- 1, 6- /

[2047] d o E o naphthyndm-4-yl)oxy)-2- \ O A - azaspiro [3.3] heptan- 2-y 1 )py rimidi n- 5 - yZZ- -- r}K-' yl)oxy)-jV-( 1 -m ethyl pipendin-3 - / x\<z~x-- > OT / —Zyl)benzamide

[2048] (D7)-5-Fluoro-Ar-isopropyl-2-((4-(6-((5- methy 1- 5,6, 7, 8-tetrahy dr o- 1,6- naphthyridin-4-yl)oxy)-2- azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)-A'r-((5')- 1 -methylpyrrolidin-3 - yl)benzamide

[2049]

[2050] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2051] ■■IN'"''; (D2)-5 -Fluoro-Ar-i sopropyl-2-((4-(6-((5 - (D2) \ 1

[2052] N methyl-5,6,7,8"tetrahydro-L6- 1 J naphthyridin-4-yl)oxy)-2- \ 9" azaspiro [3.3 j hep tan-2-y 1 )py rimidi n- 5 - 0 6 yl)oxy)-jV-((< S)- 1 -methylpyrrolidin-3- (S) r X yl)benzamide

[2053] XzO

[2054] A XoX

[2055] F U "" N '

[2056] (DI )-N-(( 1 r,3 r)-3 -(Dimethylam ino)-3 - HN'X methy lcyclobutyl)-5 -fluoro-A7- (Isomer 1) I I

[2057] ^X'N isopropyl-2-((4-(6-((5-methyl-5, 6,7,8- / AA tetrahydro- 1,6-naphthyridin-4-yl)oxy)- — N?0 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide

[2058] | p N

[2059] Y A

[2060] (D2)-N-(( 1 r,3 r)-3 -(Dimethylamino)-3 - HN'-'X methylcyclobutyl)-5-fluoro-A- (Isomer 2) 1 1

[2061] XP'N isopropyl-2-((4-(6-((5-methyl-5, 6,7,8- / AA tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide

[2062] r p N

[2063] ' A A

[2064] < V fiN

[2065] FAA HN'A (D7)-5-Fluoro-JV-isopropyl-A / -(3-(l- methylazetidin-3-yl)cyclobutyl)-2-((4- N ^r| - N (6-((5,6,7,8-tetrahydro-l,6- naphthyridin-4-yI)oxy)-2- i (oi) Y azaspiro [3.3 ] heptan-2-y l)py rim idin- 5 - yl)oxy)benzamide

[2066] \ O

[2067] i T o J

[2068] i y ii j

[2069]

[2070] F' / x^ Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2071] ( / ?2)-5-Fluoro-JV-isopropyl-? / -(3-(l- methylazetidin-3-yl)cyclobutyl)-2-((4- (6-((5,6,7,8-tetrahydro-l,6- naphthyridin-4-yl)oxy)-2- azaspiro [3.3 j hep tan-2-y 1 )py rimidi n- 5 - yl)oxy)benzamide

[2072] (DJ)-A / r-((lr,3r)-3-(Dimethy3amino)-3- methylcyclobutyl)-5-fluoro-2-((4-(6- ((5,6,8,9,10,10a-hexahydropyiTolo[2,l- / (Isom cero 1) H i f] [ 1,6]naphthyridin- 1 -yl)oxy)-2- — N?

[2073] y z- azaspiro [3.3 ] heptan-2-y l)py rimi din- 5 - \ Z —. _ / / A yl)oxy)-7V-isopropylbenzamide

[2074] / / ? O ( \

[2075] N 0C ( O z z z X - —— ' —'

[2076] / Z \ \ / T \ _

[2077] F;JO o o

[2078] <7? O

[2079] g _ / % \ / \ A — 6 N

[2080] / ) s * / —Z(D2)-AL

[2081] — y iz " / v= ((lr,3r)-3-(Dimethylamino)-3- / ■~-N methylcyclobutyl)-5-fluoro-2-((4-(6- (Isomer 2) \^X X ((5, 6, 8, 9, 10, 10a-hexahydropyrrolo[2, 1 - f] [ 1,6]naphthyridm- 1 -yl)oxy)-2- / AO

[2082] — N 0 " azaspiro [3.3] heptan-2-y l)py rimidin- 5 - yl)oxy)-7V-isopropylbenzamide y'V° <^>

[2083] JJ U F N

[2084] (S)-5-Fluoro-Ar-isopropyl-A / -( 1 - methy Ipyrrolidin- 3 -y l)-2- (( 5 - (6- ((5,6,7, 8-tetrahydro-L6-naphthyridin-4- y 1) oxy) -2-azaspiro [3.3] heptan-2-y 1) - l,2,4-triazin-6-yl)oxy)benzamide

[2085]

[2086] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2087] 5-Fluoro-7V-isopropyl-2-((5-(6-((6- methyl-5,6,7,8-tetrahydro-L6- naphthyridin-4-yl)oxy)-2- azaspiro [3.3 ]heptan-2-yl)- 1,2,4-triazin- 6-yl)oxy)-. V-(l-methylpiperidin-4- yl)benzamide

[2088] Ar-((lr,3r)-3-(DimethyIamino)-3- methy lcyclobutyl)-5 -fluoro-A7- isopropyl-2-((5-(6-((6-methyl-5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptan-2-y 1 )- 1,2,4- triazin-6-yl)oxy)benzamide

[2089] z —

[2090] _ / / \ \ T\x

[2091] MeO^ / x \^y / / \\

[2092] O z z z— ^ / ( \

[2093] -— -x, V-((lr,3r)-3-Aminocyclobutyl)-5- / xz v

[2094] fluoro-A-isopropyl-2-((4-(6-((6-(2- o o S^N

[2095] methoxyethyl)-5,6,7,8-tetrahydro-l,6- NH2h V naphthyridin-4-yl)oxy)-2- ZZZ ”””" Xzzzzx / azaspiro [3.3] heptan-2-y l)py rimi din- 5 - \ u. — \ \ ZZ \

[2096] y 1) oxy)benzam ide

[2097] x> Y°

[2098] p XZ\ / T Y -fvbj-Me<K / xN / x A^-((Ir,3r)-3- (Dimethylamino)cyclobutyl)-5-fluoro- IlNA7-isopropyl-2-((4-(6-((6-(2- methoxyethyl)-5,6,7,8-tetrahydro-l,6- naphthyridin-4-yl)oxy)-2- azaspiro[3.3 ]heptan-2-yl)pyrimidin-5- yl)oxy)benzannde

[2099] YY° "

[2100] OX[HJN

[2101]

[2102] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2103] 5-Fluoro-? / -isopropyl-A-(l- methylazetidin-3-yl)-2-((4-(6-((5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide

[2104] HN''" U (S)-5-Fluoro-Ar-isopropyl-A / -( 1 - ■y 'N methy Ipyrrolidin- 3-yl)-2-((4-(6- ((5,6,7,8-tetrahydro-l,6-naphthyridin-4- \ 0^^

[2105] N—> 1 yl)oxy)-2-azaspiro [3.3 ]heptan-2- O yl)pyrimidin-5-yl)oxy)benzamide

[2106] (S): A

[2107] \ \ Z

[2108] U.oJ k z —

[2109] F JU I J _ / /

[2110] N / A 7“

[2111] A< A \ y=

[2112] / / z \z \ \ H x \ \ _ \ XZz ( X v < X oK o z: zN H —f— — —' — — '’A (R)-5 -Fl uoro-A-isopropy 1 -N-( 1 - o o NA methylpyrrolidin-3-yl)-2-((4-(6- L Jj ((5,6,7,8-tetrahydro-l,6-naphthyridin-4- \ yJx o

[2113] N^ > z z zZ — \=~ — — \=\ \. Osll / z / yl)oxy)-2-azaspiro [3.3 ]heptan-2- \ A

[2114] 1 j _ / yl)pyrimidin-5-yl)oxy)benzamide

[2115] (R) I X

[2116] YNY° V

[2117] ' A. xx A

[2118] FAA

[2119] 5-Fluoro-AUsopropyl-JV-(l - (methylsulfonyl)azetidin-3-yl)-2-((4-(6- ((5,6,7,8-tetrahydro-l,6-naphthyridin-4- yl)oxy)-2-azaspiro [3.3 ]heptan-2- yl)pyrimidin-5-yl)oxy)benzamide

[2120]

[2121] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2122] (S)-7V-(1 -Acetylpyrrolidin-3-yl)-5- fluoro-AMsopropyl-2-((4-(6-((5, 6,7,8- 0 J| J tetrahydro- 1,6-naphthyridin-4-yl)oxy)- — - \ 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- N— y / k

[2123] yl)oxy)benzamide

[2124] (SH X

[2125] x y. N^ Y.0 \ 2

[2126] N

[2127] ' X. A-k X

[2128] n n

[2129] 'N-'

[2130] (5)-5-Fluoro-7V-isopropyl-A7-(l- (methylsulfonyl)pyrrolidin-3-yl)-2-((4- ~ N

[2131] 0 IIX _) | (6-((5,6,7,8-tetrahydro-l,6- — S.f O naphthyridin-4-yl)oxy)-2-N~\ A azaspiro [3.3] hep tan-2-y 1 )py rimidi n- 5 - O V yl)oxy)benzamide

[2132] Vf V

[2133] F v v

[2134] HN'X (A)-N-(l-Acetylpyrrolidin-3-yl)-5- fluoro-vV-isopropyl-2-((4-(6-((5, 6,7,8- V*N

[2135] O || J tetrahydro- 1,6-naphthyridin-4-yl)oxy)- -X O'^'^ 2-azaspir o [3.3 ] heptan-2-y l)py ri midi n- 5 - N — \ 1 y I) oxy)benzam ide

[2136] (R) I X

[2137] y y N

[2138] ', X X

[2139] FX X N HN'X (7?)-5 -Flu oro< V-isopropyl-Ar-( 1 - Ti N (methylsulfonyl)pyrrolidin-3-yl)-2-((4- 0 nzO J-l I (6-((5,6,7,8-tetrahydro-l,6- --S' 0 naphthyridin-4-yl)oxy)-2- N-A 1 azaspiro [3.3] heptan-2-y l)py rimidm- 5 - (R) i X yl)oxy)benzamide

[2140] XNY° V

[2141] FXX

[2142]

[2143] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2144] Af-(l-(2,2-Difluoroethyl)azetidin-3-yl)- 5-fluoro-Ar-isopropyl-2-((4-(6-((5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 1] - 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- < Z y>'——\- yl)oxy)benzamide

[2145] Qtx

[2146] o

[2147] \ / A== z\\ z

[2148] ) X XOZ z z —- / ” /

[2149] T / v \ \

[2150] / yv N-(3-Acetimidobicyclo[l.1,l]pentan-l- ^z— yl)-5-fluoro-A7-isopropyl-2-((4-(6- ((5,6,7,8-tetrahydro-l,6-naphthyridin-4- yl)oxy )-2-azaspiro [3.3 ]heptan-2- yl)pyrimidin-5-yl)oxy)benzamide

[2151] 7^Z. y —- ’

[2152] _ / / A

[2153] < X ( 1 y y y 0 y / XZ < / — / ), A\ X \.

[2154] / \ / \\ \ / \Z XZ \z xzz x _ X^ oz. z — —1—z■

[2155] z /

[2156] /

[2157] o o o N-((lr,3r)-3- Q \A--- (Dimethylamino)cyclobutyl)-5-fluoro- \ / . I / . / -■■h v

[2158] <^ _ > ZZ“ y y” z\.... - \ - / -- - ) ' N-isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- y LL 1JL Z LL - / \ —— tetrahydro- 1,6-naphthyridin-4-yI)oxy)- LL ' / 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- y 1) oxy jbenzami de

[2159] 7V-((1S,3S)-3- (Dimethylamino)cyclobutyl)-5-fluoro- Ar-isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide

[2160]

[2161] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2162] 7V-((ls,4s)-4- ( Dimethy lamino) cy clohexy 1 )- 5 -fl uoro- N-isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- '" N" 1 Jj tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- j yl)oxy)benzamide

[2163] y N

[2164] F A°A N

[2165] yV-((lr,3r)-3- VO (Dimethylamino)cyclobutyl)-5-fluoro-2- Al y

[2166] ((4-(6-((6-isobutyl-5,6,7,8-tetrahydro- ^y^ 1,6-naphthyridin-4-yl)oxy)-2- azaspiro [3.3] heptan-2-y l)py rimidin- 5 - yl)oxy)-A-isopropylbenzamide

[2167] \,iA y> \A

[2168] y y N

[2169] | / kxo. A- F O I N J

[2170] ; V-((lr,3r)-3- (Dimethylamino)cyclobutyl)-5-fluoro- A / r-isopropyl-2-((4-(6-((6-isopropyl- \| N

[2171] 5,6,7,8-tetrahydro-l,6-naphthyridin-4- ^y^ yl)oxy )-2-azaspiro [3.3 ]heptan-2- yl)pyrimidin-5-yl)oxy)benzamide

[2172] \ y^’A y° N

[2173] ' A. yx A.

[2174] Il y Y 'N

[2175] pA^y kNA

[2176] " N jV-((lr,3r)-3-Acetamidocyclobutyl)-5- fluoro-A-isopropyl-2-((4-(6-((6-methyl- o >kA 5,6, 7, 8-tetrahy dr o- 1, 6-naphthyridin-4- yl)oxy)-2-azaspiro [3.3]heptan-2- y Ijpyrimidin- 5-yl)oxy)benzamid e

[2177] X° J- IJ w

[2178]

[2179] F N Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2180] N-(3-Acetamidobicyclo[l.1,l]pentan-l- o yl)-5-fluoro-AMsopropyl-2-((4-(6-((6- methyl-5,6,7,8-tetrahydro-L6- naphthyridin-4-yl)oxy)-2- azaspiro [3.3 j hep tan-2-y 1 )py rimidi n- 5 - yl)oxy)benzamide

[2181] Y y N

[2182] m b

[2183] X'X (5)-5-Fluoro-Ar-isopropyl-2-((4-(6-((6- methy 1- 5,6, 7, 8-tetrahy dr o- 1,6- naphthyridin-4-yl)oxy)-2- \ 9^ azaspiro [3.3] heptan-2-y l)py rimid in- 5 - yl)oxy)-7V-( 1 -methy lpyrrolidin-3 - 0 6 z A— yljbenzamide

[2184] (S) £ X _ / /

[2185] < y N

[2186] ' X AX X 0 f J _y\ — — / NZ Z / / ^XH \

[2187] F' O o O N

[2188] yA)~ (5)-5-Fluoro-Ar-isopropyl-2-((4-(6-((6- methy 1- 5,6, 7, 8-tetrahy dr o- 1,6- Y\, QLxZ oZ' naphthyridin-4-yl)oxy)-2- / 2 $, ow= — azaspiro [3.3] heptan-2-y 1 )py rimidin- 5 - yl)oxy)-A-(l- (methylsulfonyl)pyrrolidin-3- yljbenzamide

[2189] (5')-A'r-( 1 -Acetylpyrrolidin-3-yl)-5- T fluoro-AMsopropyl-2-((4-(6-((6-methyl- V1XN

[2190] o i J 5, 6, 7, 8-tetrahy dr o- 1, 6-naphthyridin-4- -X. yl)oxy)-2-azaspiro [3.3 ]heptan-2- 1 yl)pyrimidin-5-yl)oxy)benzamide

[2191] (S) o Y < X>

[2192]

[2193] j J IL J Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2194] 7V-(l-Cyclobutylazetidin-3-yl)-5-fluoro- Ar-isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)- / 1 _ 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide

[2195] \ o

[2196] o

[2197] ( / == / \ X z\

[2198] ) X ) o z zz— / — / —

[2199] / v yv \

[2200] z / — Ar-((lr,3r)-3-(DimethyIamino)-3- 'Z--■ m ethy lcyclobutyI)-5 -fluoro-A7- isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yI)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide

[2201] C X ( O z: z z ' — — —

[2202] y^ / / z\z \z

[2203] o

[2204] Ar-((l.s\35)-3-(Dimethylammo)-3- methylcyclobutyl)-5-fluoro-A- LL, - llNisopropyl-2-((4-(6-((6-methyl-5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- x r y 1) oxy)benzam ide

[2205] w

[2206] iV-((lr,3r)-3- (Dimethylamino)cyclobutyl)-2-((4-(6- ((6-ethy 1- 5,6,7,8 -tetrahydro- 1,6- naphthyridin-4-yl)oxy)-2- azaspiro [3.3] heptan-2-y l)py rimid in- 5 - yl)oxy)-5-fluoro-? / -isopropylbenzamide y N

[2207] Il Il

[2208]

[2209] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2210] N-({lR,3S)-3- (Dimetiiylamino)cyclopentyl)-5-fluoro- N-isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- — N / (S) 0 AJJ tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- \=X yl)oxy)benzamide

[2211] (R) i

[2212] VfA M o V

[2213] JQ°KY / = / Z Z\\

[2214] / ZX / 7S Vx\ \.__- A^Z N-((lS,3R)-3- (Dimethylamino)cyclopentyl)-5-fluoro- Ar-isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- \ Z~

[2215] ^ / _ / A Z“ yl)oxy)benzamide

[2216] _ / / A

[2217] \ / / ( 0 X 2 Z z < — — > —' JA \

[2218] y Q / ^ 2^ / V\ Zz N - >—Z-—* N / '\ H \

[2219] / / \Z\ / \

[2220] o

[2221] MM Q o - \

[2222] N-(3-(Dimethylamino)bicyclo[1.1.1]pentan-1-yl)-5-fluoro-N-isopropyl-2-((4-(6-((6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide

[2223] N-(3-(Dimethylamino)propyl)-5-fluoro-N-isopropyl-2-((4-(6-((6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide

[2224]

[2225] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2226] 7V-(2-(Dimethylamino)ethyl)-5-fluoro- Ar-isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide

[2227] (S)-5-Fluoro-N-isopropyl-2-((5-(6-((6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-1,2,4-triazin-6-yl)oxy)-N-(1-methylpyrrolidin-3-yl)benzamide

[2228] (S) 1 X _ / / A

[2229] xyNy° N\ / 7 \\ ( )

[2230] ( Q Z Z Z — — f — Z XZ'

[2231] / \ / \ / X o < z ( z — — ' —'

[2232] / / V \ / z\ xz

[2233] IJ O F I NJ

[2234] (7?)-5-FIuoro-7V-isopropyl-2-((4-(6-((6- y \ f^Zj - / X \= methy 1 - 5,6, 7, 8-tetrahy dr o- 1,6- Z U_ — \ / naphthyridin-4-yl)oxy)-2- / / 7 / g “■” azaspiro [3.3] heptan -2-y l)py rimi dm- 5 - yl)oxy)-. V-(l-methylpiperidin-3- yl)benzamide

[2235] (D1)-5-Fluoro-N-isopropyl-2-((4-(6-((6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-N-(3-(1-methylazetidin-3-yl)cyclobutyl)benzamide

[2236] \ O

[2237] Y Y N

[2238] 1| / | X X / ° v p kM™

[2239]

[2240] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2241] (D2)-5-Fluoro-AMsopropyl-2-((4-(6-((6- methyl-5,6,7,8-tetrahydro-L6- naphthyridin-4-yl)oxy)-2- azaspiro [3.3 j hep tan-2-y 1 )py rimidi n- 5 - yl)oxy)-Ax(3-(l-methylazetidin-3- yl)cyclobutyl)benzamide

[2242] 2-((4-(6-((6-(3-(5-Oxa-2-azaspiro[3.4]octan-2-yl)propyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-(1-methylpiperidin-4-yl)benzamide

[2243] o £ _ / / A

[2244] ^NY° v

[2245] / \ X o < z ze z\ Z Z7 /

[2246] ——x \A \"

[2247] —

[2248] Au / A \Z \ x _ \z o zZ— '— —

[2249] „JU o O Iz

[2250] F o7 N

[2251] VZA c

[2252] 5-Fluoro-N-isopropyl-N-((1r,3r)-3-morpholinocyclobutyl)-2-((4-(6-((5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide

[2253] X'N'^X 5-Fluoro-A-isopropyl-2-((4-(6-((6- I X methy 1- 5,6, 7, 8-tetrahy dr o- 1,6- naphthyridin-4-yl)oxy)-2- O N O '' azaspiro [3.3] heptan-2-y l)py rimid in- 5 - yl)oxy)-? V-((lr,3r)-3- morpholinocyclobutyl)benzamide

[2254] TV J JU u

[2255]

[2256] F N Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2257] , V-((lr,3r)-3-(Azetidin-l-yl)cyclobutyl)- 5-fluoro-A7-isopropyl-2-((4-(6-((6- methyl-5,6,7,8-tetrahydro-L6- / naphthyridin-4-yl)oxy)-2- ( A “H / .\ / XZ\ \ ':< z z<) 1----1------\ * ^ azaspiro [3.3 j hep tan-2-y 1 )py rimidi n- 5 - yl)oxy)benzamide

[2258] jz v o ' \ —

[2259] o o

[2260] / _

[2261] Z / i\-•..

[2262] ^C^^°z zzA X^ o z z > z-—— / -—\ / Z / \ \

[2263] N-((1r,3r)-3-(5-Oxa-2-azaspiro[3.4]octan-2-yl)cyclobutyl)-5-fluoro-N-isopropyl-2-((4-(6-((6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide

[2264] _ / / Nk

[2265] X OX z z / z< -y--— - ZNZ^ \

[2266] )= /

[2267] O o

[2268] 5-Fluoro-A7-isopropyl-A7-(l- [ ( ■ ' isopropylazetidin-3-yl)-2-((4-(6- O ULk -X CZ ">z:,- ((5,6,7,8-tetrahydro-l,6-naphthyridm-4- yl)oxy)-2-azaspiro[3.3]heptan-2- yl)pyrimidin-5-yl)oxy)benzamide

[2269] 5-Fluoro-N-isopropyl-2-((4-(6-((6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-N-((1r,3r)-3-(pyrrolidin-1-yl)cyclobutyl)benzamide

[2270]

[2271] Attorney Docket No.: SYND-063 / 001WO 43707-02984 0 — \ A / V-((lr3r)-3-(6-()xa-2- O azaspiro[3.4]octan-2-yl)cyclobutyl)-5- X" Q Y ''N fluoro-AMsopropyl-2-((4-(6-((6-methyl- P'A-X' 5,6,7,8-tetrahydro-l,6-naphthyridin-4- yl)oxy )-2-azaspiro [3.3 ]heptan-2- yl)pyrimidin-5-yl)oxy)benzamide Or'°'XN

[2272] F JO t. N

[2273] 5-Fluoro-N-isopropyl-N-((1r,3r)-3-(3-methoxyazetidin-1-yl)cyclobutyl)-2-((4-(6-((6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide

[2274] \\ f _ / / A ^

[2275] _y\_^ / __o / \o A \ \ z z\ / , \A{ / \ z=- X v o X ( X ( ZV Q z z z o zzz < < — f — —z— ' — —■^==

[2276] / \\Zz < z z

[2277] / \ / Nz _z- / / ——

[2278] / x

[2279] o o o

[2280] o o YA- N-((lr,3r)-3-(2-Oxa-6- p AA ®--- y ( Z>|!- z\ / / \ H azaspiro[3.3]heptan-6-yl)cyclobutyl)-5- X / OZz"°° '^ >

[2281] / C"

[2282] ) k. - LL. O - fluoro-A'r-isopropyl-2-((4-(6-((6-methyl- / U” - 5, 6, 7, 8-tetrahy dr o- 1, 6-naphthyridin-4- yl)oxy)-2-azaspiro [3.3 ]heptan-2- yl)pyrimidin-5-yl)oxy)benzamide

[2283] N-((1r,3r)-3-(1-Oxa-6-azaspiro[3.3]heptan-6-yl)cyclobutyl)-5-fluoro-N-isopropyl-2-((4-(6-((6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide

[2284]

[2285] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2286] 5-Fluoro-A?-((Ir,3 / ')-3-(3-hydroxy-3- methylazetidin-l-yl)cyclobutyl)-7V- isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 3 -n

[2287] / 2l,. — 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide

[2288] b

[2289] (= / / 2 X > 2 — / / —

[2290] Arvt " 'AA Az- 5 -Fluoro-JV-((37?,45)-4-fluoro- 1 - methylpiperidin-3-yl)-Ar-isopropyl-2- ((4-(6-((6-methyl-5,6,7,8-tetrahydro- 0^ 1,6-naphthyridin-4-yl)oxy)-2- 'fjO <s) A azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide

[2291] (R) £ ''F><

[2292] .0 \, Z

[2293] A°A )^ ( (.2- jQ \ O 2Z 22^ / < — — —

[2294] F / O / z \ \ \ _ /

[2295] / N

[2296] O 5-Fluoro-Ar-((3^,4A)-4-fluoro-l- o

[2297] kA methylpiperidin-3-yl)-A'-isopropyl-2- \ / Z W o\>X

[2298] z / yZ®i',- ((4-(6-((6-methyl-5,6,7,8-tetrahydro- LL — 1,6-naphthyridin-4-yl)oxy)-2- azaspiro [3.3 ] heptan-2-y l)py rimid in- 5 - " CA 6

[2299] (R) 1F2\ yl) oxy) benzamide

[2300] \. N^.0 \,z

[2301] F A 6 N

[2302] Ar-((2> S',4JR)- 1,2-Dimethylpiperidin-4-yl)- 5-fluoro- / V-isopropyl-2-((4-(6-((6- methy 1 - 5,6, 7, 8-tetrahy dr o- 1,6- naphthyridin-4-yl)oxy)-2- azaspiro[3.3]heptan-2-yl)pyrimidin-5- y I) oxy)benzam ide

[2303]

[2304] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2305] A?-((2J?,47?)- 1,2-Dimethylpiperidin-4- XN yl)-5-fluoro-AMsopropyl-2-((4-(6-((6- methyl-5,6,7,8-tetrahydro-L6- N 1...0 Y naphthyridin-4-yl)oxy)-2- / / Sz -n CO — / -— r. _ z _ • / —

[2306] ( \ A \z.—.=x } (R) x azaspiro [3.3 j hep tan-2-y 1 )py rimidi n- 5 - =x

[2307] (R) f X yl)oxy)benzamide

[2308] 4z / 3-- XNQl v

[2309] °o—

[2310] T o O

[2311] X / '

[2312] ( / == / / Z\X \\ / X Z /

[2313] ) O x Z Z Z / / \ / 2Z — / — — f V x \ \.

[2314] Xyy_ jV-((3A?6A)-h6-Dimethylpiperidin-3-yl)- LZ' 5-fluoro-AMsopropyl-2-((4-(6-((6- methy 1 - 5,6, 7, 8-tetrahy dr o- 1, 6- naphthyridin-4-y!)oxy)-2- azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide

[2315] z.-- XZ

[2316] / rz \ \

[2317] X x o < zZ- — — — ' '

[2318] / \\z /

[2319] / A-((35',6 / ?)-l,6-Dimethylpiperidin-3-yl)- o

[2320] 5-fluoro- / V-isopropyl-2-((4-(6-((6- methy 1 - 5,6, 7, 8-tetrahy dr o- 1,6- x x:. naphthyridin-4-yl)oxy)-2- / . j» azaspiro[3.3]heptan-2-yl)pyrimidin-5- y I) oxy)benzam ide

[2321] AZ(35, 5A)- 1, 5 -Dimethy lpyrrolidin-3 - yI)-5-fluoro-AMsopropyl-2-((4-(6-((6- methy 1 - 5,6, 7, 8-tetrahy dr o- 1,6- naphthyridin-4-yl)oxy)-2- azaspiro[3.3]heptan-2-yl)pyrimidin-5- y I) oxy)benzam ide

[2322]

[2323] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2324] A7-((35', 5A)- 1, 5 - Dimethy lpyrrolidin-3 - yl)-5-fluoro-AMsopropyl-2-((4-(6-((6- methy 1- 5 Y, 7, 8-tetahy dr o- L 6- \

[2325] z z — naphthyridin-4-yl)oxy)-2- / / w m --- z azaspiro [3.3 j hep tan-2-y 1 )py rimidi n- 5 - yl)oxy)benzamide

[2326] >n~ Y

[2327] w ' °

[2328] o

[2329] > O X z z ~z — — —:.

[2330] -((1,3)-3- vz- (Dimethylamino)cyclohexyl)-5-fluoro- Ar-isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspir o [3.3] heptan-2-y l)pyrimidin- 5 - yl) oxy) benzamide

[2331] _

[2332] V f - (

[2333] V

[2334] N-((1S,3R)-3-(Dimethylamino)cyclohexyl)-5-fluoro-N-isopropyl-2-((4-(6-((6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide

[2335] \. N. ^0 \ /

[2336] Y N F N

[2337] '■'NX’x-i (7?)-5-Fluoro-7V-isopropyl-2-((4-(6-((6- methyl-5,6,7,8-tetrahydro-l,6- \ -N

[2338] naphthyridin-4-yl)oxy)-2- 0^ azaspiro [3.3] hep tan-2-y 1 )py rimidi n- 5 - A yl)oxy)-Ar-(2-methyl-5-oxa-2- (RX azaspiro[3.4] octan-7-y l)benzamide

[2339] x

[2340] y YN

[2341] * A.0. A

[2342]

[2343] FASA Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2344] 'xN'X (5)-5-Fluoro-Ar-isopropyl-2-((4-(6-((6- methyl-5,6,7,8-tetrahydro-L6- naphthyridin-4-yl)oxy)-2- / J "n — azaspiro [3.3 j hep tan-2-y 1 )py rimidi n- 5 - yl)oxy)-7V-(2-tnethyl-5-oxa-2- azaspiro[3.4]octan-7-yl)benzamide

[2345] tn 1v\ o — r

[2346] v Y° o / _ / \ / / \\ T< N>

[2347] ) X O?:i— / —•—Z / / N, / V x \ \, _

[2348] F / / y__

[2349] \ z— N-((15,45)-4-(Dimetliylamino)-4- methylcyclohexyl)-5-fluoro-A’- i isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- --N / / Si

[2350] N 0 " tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- y I) oxy)benzam ide

[2351] w

[2352] N

[2353] F' N

[2354] N-((1r,4r)-4-(Dimethylamino)-4-methylcyclohexyl)-5-fluoro-N-isopropyl-2-((4-(6-((6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide

[2355] V i

[2356] \ X", N. Y, Q \ /

[2357] N

[2358] i A „o. X

[2359] Y X " T|N

[2360] pXz

[2361] N-((1s,3r)-3-(Dimethylamino)-3-ethylcyclobutyl)-5-fluoro-N-isopropyl-2-((4-(6-((5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide

[2362]

[2363] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2364] N-((1s,3r)-3-(Dimethylamino)-3-ethylcyclobutyl)-5-fluoro-N-isopropyl- 2-((4-(6-((6-methyl-5,6,7,8-tetrahydro- \ / ( 'll - 1,6-naphthyridin-4-yl)oxy)-2- azaspiro [3.3 j hep tan-2-y 1 )py rimidi n- 5 - yl)oxy)benzamide

[2365] o

[2366] OX Z Z 2 J;) - - / /

[2367] XX / ^ ' \z"z _~

[2368] Ar-(4- (Dimethylamino)bicyclo[2, 1.1 ]hexan- 1 - yl)-5-fluoro-A-isopropyl-2-((4-(6-((6- methy 1- 5,6, 7, 8-tetrah y dr o- 1, 6- naphthyridin-4-yl)oxy)-2- azaspiro [3.3] hep tan-2-y 1 )py rimidi n- 5 - 7A~

[2369] _ / / A yl)oxy)benzamide

[2370] VM

[2371] y V / / / \_z \

[2372] o

[2373] 5-Fluoro-JV-isopropyl-2-((4-(6-((6- y VZAJx methyl-6,7-dihydro-5H-pyrrolo[3,4- z L\ / / — \=" b]pyridin-4-yl)oxy)-2- x x X

[2374] z" - ' azaspiro [3.3] heptan-2-y l)py rimidm- 5 - yl)oxy)-A’-((25,4r)-5-methyl-5- azaspiro[3.4]octan-2-yl)benzamide

[2375] HNX 5 -Fluoro-AT-isopropyl-Ar-((2s\4r)-5- methyl- 5-azaspiro [3.4] octan-2-yl)-2-((4- (6-((5,6,7,8-tetrahydro-l,6- r-y AZ naphthyridin-4-yl)oxy)-2- azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide

[2376] x x

[2377] IT U

[2378]

[2379] F- N Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2380] 5-Fluoro-7V-isopropyl-2-((4-(6-((6- methyl-5,6,7,8-tetrahydro-L6- naphthyridin-4-yl)oxy)-2- m

[2381] azaspiro [3.3 j hep tan-2-y 1 )py rimidi n- 5 - ( A — / \ yl)oxy)-Ar-((4r,6s)- 1 -methyl- 1 - X / )z?,—=\\ -n

[2382] azaspiro[3.3 ]heptan-6-yl)benzamide

[2383] C y /

[2384] QI o

[2385] < / / == o

[2386] X / \Z / / / = / v X \ \ Z Z\\ _

[2387] O Z Z x z) > — — — / !

[2388] \ / TZ / V X ' \y

[2389] N-((4r,6s)-1-Ethyl-1- azaspiro [3.3 ]heptan-6-yl)- 5-fluoro-7V- isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide

[2390] Z=r<

[2391] ' zL AX zL r\

[2392] [l X| O ( 2z — — / — z x / j

[2393] y / ^ / V\zN

[2394] N-((4r,6s)-1-(2,2-Difluoroethyl)-1-azaspiro[3.3]heptan-6-yl)-5-fluoro-N- isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- / £ — tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspir o [3.3] heptan-2-y l)pyrimidin- 5 - yl) oxy) benzamide

[2395] N-((2S,3R)-1,2-Dimethylazetidin-3-yl)-5-fluoro-N-isopropyl-2-((4-(6-((6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide

[2396]

[2397] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2398] N-((2R,3R)-1,2-dimethylazetidin-3-yl)-5-fluoro-N-isopropyl-2-((4-(6-((6- N

[2399] methyl-5,6,7,8-tetrahydro-L6- / 1 “fl - I O' XJ naphthyridin-4-yl)oxy)-2- Xx j \ z\ N (R) azaspiro [3.3 j hep tan-2-y 1 )py rimidi n- 5 - ) < JLX z»—=\

[2400] (R)X s? yl)oxy)benzamide

[2401] (H Qi ' < o — KI

[2402] o o

[2403] 7X°Xx / / / / \\

[2404] } X) > o z z z) O Z Z — Z• — —, — y —,

[2405] \z N \ / \ \ \ / \ \zz z z- — _

[2406] F - N

[2407] J / y

[2408] 5-Fluoro-N-isopropyl-N-((1r,3r)-3-

[2409] methyl-3-(pyrrolidin-1-yl)cyclobutyl)-2-((4-(6-((6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide

[2410] ) _ / / X

[2411] N-((1r,3r)-3-(Dimethylamino)-3-methylcyclobutyl)-5-fluoro-N-

[2412] isopropyl-2-((4-(6-((5,6,7,8-tetrahydro-

[2413] ) 1 - 1,7-naphthyridin-4-yl)oxy)-2- azaspiro [3.3 ] heptan-2-y l)py rimid in- 5 - yl) oxy) benzamide

[2414] 2-((4-(6-((6,7-Dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-N-((1r,3r)-3-(dimethylamino)-3-methylcyclobutyl)-5-fluoro-N-isopropylbenzamide

[2415]

[2416] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2417] 5-Fluoro-N-isopropyl-N-((1r,3r)-3-methyl-3-(pyrrolidin-1-yl)cyclobutyl)-2-((4-(6-((5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide

[2418] <^>

[2419] j y N

[2420] .xL ^0.

[2421] Xj u

[2422] N-((1r,3r)-3-(Azetidin-1-yl)-3-methylcyclobutyl)-2-((4-(6-((6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-

[2423] yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

[2424] y y N

[2425] As. ^.0. A

[2426] ]fN

[2427] pA^X < JM I

[2428] <v o X zNz T— ---<sJ

[2429] / 2-((4-(6-((6,7-Dihydro-577-pyrrolo[3,4- d

[2430] \ V? O" b] pyridin-4-yl) oxy)-2-azaspiro [3,3]

[2431] \ Wxheptan-2-yl) pyrimidin-5-yl) oxy)-5- _ / ZAA'^AZ’ / \,^ S _ / X '

[2432] fluoro-N-isopropyl-N-((1r,3r)-3-methyl-3-(pyrrolidin-1-yl)cyclobutyl)benzamide

[2433] 5-Fluoro-N-isopropyl-2-((4-(6-((6-

[2434] AA'-'N methy 1 - 5,6, 7, 8-tetrahy dr o- 1,6- naphthyridin-4-yl)oxy)-2- azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)-Ar-((2.s\4r)-5-azaspiro[3.4]octan- 1 X 2-yl)benzamide

[2435] vv v

[2436] ' A / O.

[2437] CA I J

[2438]

[2439] F N" Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2440] (D1)-N-((1r,3r)-3-(Azetidin-1-yl)-3-methylcyclobutyl)-5-fluoro-2-((4-(6-((5,6,8,9,10,10a-hexahydropyrrolo[2,1-f][1,6]naphthyridin-1-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide

[2441] \, X)

[2442] Y Y N

[2443] F JU I N

[2444] (D2)-N-((1r,3r)-3-(Azetidin-1-yl)-3-methylcyclobutyl)-5-fluoro-2-((4-(6-((5,6,8,9,10,10a-hexahydropyrrolo[2,1-f][1,6]naphthyridin-1-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide

[2445] 5 U "

[2446] (f b z zz N — — — " ) Z Z\s\ / \{7Z=”

[2447] X f / \

[2448] \ Q S d d' 5-Fluoro-2-((4-(6-(((5’)-5,6,8,9, 10, 10a- O \A-- _ / \ \ / hexahydropyrrolo[2, 1 - >. ° ~

[2449] X ( >?z«- — ' f] [ 1,6]naphthyridin- 1 -yl)oxy)-2- ^yy <___U _\ \Z r z \ \~ '~''

[2450] r o~ azaspiro [3.3 ] heptan-2-y 1 )py rimidin- 5 - yl)oxy)-N-isopropyl-N-((1r,3r)-3-methyl-3-(pyrrolidin-1-yl)cyclobutyl)benzamide

[2451] or

[2452] (S)-5-Fluoro-2-((4-(6-(( 5,6,8,9,10, 10a- hexahydropyrrolo[2, 1 - f] [ 1,6]naphthyridin- 1 -yl)oxy)-2- azaspiro [3.3 ] heptan-2-yl)py rimidin- 5 - yl)oxy)-A7-isopropyl-A7-((lr,3r)-3- methy 1-3 -(pyrrolidin- 1 - yl)cyclobutyl)benzamide

[2453] 5-Fluoro-2-((4-(6-(((7?)-5,6,8,9, 10, 10a- hexahydropyrrolo[2, 1 - f] [ 1,6]naphthyridin- 1 -yl)oxy)-2- azaspiro [3.3 j hep tan-2-y 1 )py rimidi n- 5 - yl)oxy)-N-isopropyl-N-((1r,3r)-3-methyl-3-(pyrrolidin-1-yl)cyclobutyl)benzamide

[2454] or

[2455] (A)-5-Fluoro-2-((4-(6-((5,6,8,9, 10, 10a-

[2456]

[2457] hexahydropyrrolo[2, 1 - Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2458] f] [ 1,6]naphthyridin- 1 -yl)oxy)-2- CO azaspiro [3.3 j hep tan-2-y 1 )py rimidi n- 5 - yl)oxy)-N-isopropyl-N-((1r,3r)-3-

[2459] U-N / methy 1-3 -(pyrrolidin- 1 - $ yl)cyclobutyl)benzamide

[2460] X

[2461] v y N

[2462] (i 7 f, T

[2463] F"'X^

[2464] (D1)-5-Fluoro-2-((4-(6-((5,6,8,9,10,10a-hexahydropyrrolo[2,1-f][1,6]naphthyridin-1-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-N-isopropyl-N-((2s,4r)-5-azaspiro[3.4]octan-2-yl)benzamide

[2465] X \ Q Z < — — — / / / ' \M / ^

[2466] y t\= / / X / x

[2467] o E

[2468] (D2)-5-Fluoro-2-((4-(6-((5,6,8,9,10,10a-hexahydropyrrolo[2,1-

[2469] (D2) 1 Jj f] [ 1,6]naphthyridin- 1 -yl)oxy)-2- / X

[2470] azaspiro [3.3 ] heptan-2-y 1 )py rimidin- 5 - yl)oxy)-N-isopropyl-N-((2s,4r)-5-azaspiro[3.4]octan-2-yl)benzamide

[2471] Nx,0 k >

[2472] > y N

[2473] ! A.,o. X

[2474] < Y yN

[2475] " N"

[2476] (D7)-5-Fluoro-2-((4-(6-((5,6, 8,9, 10, 10a- hexahydropyrrolo[2, 1 - f] [ 1,6]naphthyridin- 1 -yl)oxy)-2- f—x <D1> X j

[2477] azaspiro [3.3 j hep tan-2-y l)pyrimidin-5- yl)oxy)-A7-isopropyl-7V-((2s,4r)-5- methy 1-5 -azaspiro [3.4] octan-2- yl)benzamide

[2478] YNY° N

[2479] rY°Y^N

[2480]

[2481] FU u Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2482] (D2)-5-Fluoro-2-((4-(6-((5,6,8,9,10,10a-hexahydropyrrolo[2,1-f][1,6]naphthyridin-1-yl)oxy)-2-

[2483] 7 ( n ' — — azaspiro [3.3 j hep tan-2-y l)pyrimidin-5- X Z\ \

[2484] f 'XL z:»s— yl)oxy)-N-isopropyl-N-((2s,4r)-5-methyl-5-azaspiro[3.4]octan-2-yl)benzamide

[2485] Y Y 5 ° / N

[2486] 1 X. JX \\\ / T X x

[2487] ) ) O z Z z X 2 — — / —

[2488] (D1)-N-((1r,3r)-3-(Dimethylamino)-3-methylcyclobutyl)-2-((4-(6-((5-ethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-4-

[2489] — 0 yl)oxy)-2-azaspiro [3.3 ]heptan-2- yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

[2490] \x-N^0 <*>

[2491] Y Y N I X. X

[2492] FX [TXJT T kINAN

[2493] (D2)-N-((1r,3r)-3-(Dimethylamino)-3-methylcyclobutyl)-2-((4-(6-((5-ethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

[2494] y yN

[2495] I X.,-<x X

[2496] yy XN

[2497] FXX ^-NA

[2498] (D1)-N-((1r,3r)-3-(Azetidin-1-yl)-3-methylcyclobutyl)-2-((4-(6-((5-ethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide

[2499]

[2500] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2501] (D2)-?7-((lr,3r / )-3-(Azetidin-l-yl)-3- methylcyclobutyl)-2-((4-(6-((5-ethyl- 5,6,7,8-tetrahydro-l,6-naphthyridin-4- yl)oxy )-2-azaspiro [3.3 ]heptan-2- y^pynmidm-S-y^oxy^-S-fluoro-A7- isopropylbenzamide

[2502] (D1)-2-((4-(6-((5-Ethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-((1r,3r)-3-methyl-3-(pyrrolidin-1-yl)cyclobutyl)benzamide

[2503] 2

[2504] / / X\ <

[2505] < X X X \ o z o <z( ox z < z z zA z: J^ —^ — — / xW \

[2506] z — —

[2507] \ / \ X \ xz / z z \\z

[2508] H )X

[2509] a H £ o o oS /

[2510] \ Q a X / / '" (D2)-2-((4-(6-((5-Ethyl-5, 6,7,8- O tetrahydro- 1,6-naphthyridin-4-yl)oxy)- h>x w. ° ~ - < > z 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-—v= y.

[2511] \ / z \zxy k? r_ yl)oxy)-5-fluoro< V-isopropyl-A’- V— ' V? J “•. (( 1 r,3 r)-3 -methyl-3 -(pyrrolidin- 1 - yl)cyclobutyl)benzamide

[2512] (D1)-2-((4-(6-((5-Ethyl-5,6,7,8-

[2513] tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-((2s,4r)-5-methyl-5-azaspiro[3.4]octan-2-yl)benzamide

[2514] -,-NtzoO

[2515] * Us< A ^X.

[2516] kN-^

[2517]

[2518] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2519] (D2)-2-((4-(6-((5-Ethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-((2s,4r)-5-methyl-5-azaspiro[3.4]octan-2-yl)benzamide

[2520] Y

[2521] w V

[2522] / K x-CK A

[2523] ii T O

[2524] (D1)-N-((1r,3r)-3-(Azetidin-1-yl)-3-methylcyclobutyl)-5-fluoro-N-

[2525] isopropyl-2-((4-(6-((5-methyl-5, 6,7,8- Q, <D1> tetrahydro- 1,6-naphthyridin-4-yI)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- y 1) oxy jbenzami de

[2526] V

[2527] A / OA

[2528] A l l

[2529] F' N

[2530] (D2)-N-((1r,3r)-3-(Azetidin-1-yl)-3-methylcyclobutyl)-5-fluoro-N-isopropyl-2-((4-(6-((5-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide

[2531] \ -x<° '0

[2532] r T o Y

[2533] F (A N'

[2534] (D1)-5-Fluoro-N-isopropyl-N-((1r,3r)-3-methyl-3-(pyrrolidin-1-yl)cyclobutyl)-2-((4-(6-((5-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide

[2535] VY°

[2536] O U

[2537]

[2538] F N Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2539] (D2)-5-Fluoro-N-isopropyl-N-((1r,3r)-3-methyl-3-(pyrrolidin-1-yl)cyclobutyl)-2-((4-(6-((5-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide

[2540] (D1)-5-Fluoro-N-isopropyl-2-((4-(6-((5-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-N-((2s,4r)-5-methyl-5-azaspiro[3.4]octan-2-yl)benzamide

[2541] \ Z“-\ Z= A Z—

[2542] \ / \ O\ 2£ 2^ Z\ / z \ \ kky / / - /

[2543] < >< / ( b z z Z ( ( —~ — —' k / \

[2544] — —

[2545] \ \ / \ \zZ \ / Tz \ \ x \

[2546] /

[2547] O 0 o a S O (£>2)-5-fluoro-A’-isopropyl-2-((4-(6-((5- A O \-- ~ q\ k--x kN ° ~ methyl-5,6,7,8-tetrahydro-l,6- / _ \X / \ '

[2548] naphthyridin-4-yl)oxy)-2- ^ Qcw- azaspiro [3.3] hep tan-2-y 1 )py rimidi n- 5 - / \ / C kl yl)oxy)-Ar-((2s,4r)-5-methyl-5- azaspiro[3.4]octan-2-yl)benzamide

[2549] (D1)-N-((1r,3r)-3-(Dimethylamino)-3-

[2550] methylcyclobutyl)-5-fluoro-2-((5-(6-((5,6,8,9,10,10a-hexahydropyrrolo[2,1-

[2551] f] [ 1,6]naphthyri din- 1 -yl)oxy)-2- azaspiro[3, 3 ]heptan-2-yl)- 1,2,4-triazin- 6-yl)oxy)-AM sopropylbenzami de

[2552] O °^ _A^ N > F N

[2553]

[2554] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2555] (D2)-7V-((b',3 / ')-3-(Dimethylaniino)-3- methylcyclobutyl)-5-fluoro-2-((5-(6- ((5,6,8,9,10,10a-hexahydropyrrolo[2, 1 - / (D2) A. J

[2556] — 0 f] [ 1,6]naphthyridin- 1 -yl)oxy)-2- azaspiro [3.3 ]heptan-2-yl)- 1,2,4-triazin- 6-yl)oxy)-7V-isopropylbenzamide

[2557] p y N

[2558] * / L JX A

[2559] PYNN J

[2560] F " N

[2561] HN^’N N-((lr,3r)-3-(Dimethylamino)-3- methylcyclobutyl)-5-fluoro-A- isopropyl-2-((5-(6-(( 1,2,3,4- / jp

[2562] — 0 tetrahydroisoquinolin-8-yl)oxy)-2- azaspiro [3.3 ]heptan-2-yl)- 1,2,4-triazin- 6-yl)oxy)benzamide

[2563] Y yN

[2564] ' ri A^. Y.-0,. A N

[2565] Jl J N_ J

[2566] 'N

[2567] HN" A 5-Fluoro-N-isopropyl-N-((lr,3r)-3- methyl-3-(pyrrolidin-l-yl)cyclobutyl)-2- N O Aj ((5-(6-((5,6,7,8-tetrahydro-l,6- naphthyridin-4-yl)oxy)-2- azaspiro[3.3 ] heptan-2-y 1)- 1,2,4-triazin- 6-yl)oxy)benzamide

[2568] r 1 x

[2569] P J. N

[2570] Y,0. y XA

[2571] N'N^

[2572] pN'A (D7)-5-Fluoro-2-( (5-(6-((5,6, 8,9, 10, 10a- hexahydropyrrolo[2, 1 - f] [ 1,6]naphthyridin- 1 -yl)oxy)-2- Q <D,) ^XJNazaspiro [3.3 ]heptan-2-yl)- 1,2,4-triazin- 6-yl)oxy)-A / -isopropyl-A / -(( 1 r,3r)-3- methy 1-3 -(pyrrolidin- 1 - yl)cyclobutyl)benzamide

[2573] Y N

[2574] ' A. NK A

[2575] fl J'lN

[2576] JL xj N. J

[2577]

[2578] F N Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2579] (D2)-5-Fluoro-2-( (5-(6-((5,6, 8,9, 10, 10a- hexahydropyrrolo[2, 1 - f] [ 1,6]naphthyridin- 1 -yl)oxy)-2- azaspiro [3.3 ]heptan-2-yl)- 1,2,4-triazin- 6-yl)oxy)-AMsopropyl-A"-((lr,3 / ')-3- methy 1-3 -(pyrrolidin- 1 - yl)cyclobutyl)benzamide

[2580] Ar-((lr,3r)-3-(Dimethylamino)-3- / 56 methy lcyclobutyl)-5 -fluoro-A7- isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyridazin-3- YV° yl) oxy) benzamide

[2581] _ / / A

[2582] F__ / \

[2583] jj / / y\ \\ \

[2584] I^^

[2585] X <, o z< 2? 2:<

[2586] O 'N-- --- / \? / ZZA < X\ 0 \ zz — — ' —

[2587] > -* J“

[2588] 0 7V-((lr,3r)-3-(Azetidin-l-yl)-3- ^ 0, 80

[2589] methylcyclobutyl)-5-fluoro-A’- 7K >2:— isopropyi-2-((4-(6-((6-methyl-5, 6,7,8- po) \> Ix LL< / \ \ HZ \- tetrahydro- 1,6-naphthyridin-4-yI)oxy)- / V 2-azaspir 0 [3, 3 ] heptan -2-y l)pynmi din- 5 - y 1) oxy jbenzami de

[2590] X'N'^> (D2)-2-((4-(6-((5,6-Dimethyl-5, 6,7,8- (D2) AA tetrahydro- 1,6-naphthyridin-4-yl)oxy)-z2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)-A'r-((lr,3r)-3-(dimethylamino)- 3-methylcyclobutyl)-5-fluoro-A'r- isopropylbenzamide

[2591] Xo?

[2592]

[2593] F IJ N Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2594] 5-F! uoro-A-isopropy l-7V-(( 1 / ’..j / j-j - methyl-3-(pyrrolidin- 1 -yl)cyclobutyl)-2- ((4-(6-((6-methyl-6,7-dihydro-5H- pyrrolo[3,4-bjpyridin-4-yl)oxy)-2- 1 J! 1! ”H

[2595] ( ( >. Tl ' - -n -. \

[2596] } JLX azaspiro [3.3 j hep tan-2-y 1 )py rimidi n- 5 - XL< V? ^Z> —“ z.»~•=\ \ y yl)oxy)benzamide i tp° o

[2597] o o o

[2598] Z) A > > O) z z x O z z—— — — ~

[2599] / / \z ><> Z \Z V \ > O Z Z Z \ \'Z — 7 —.

[2600] ZJy

[2601] V ( ^ \=z=z A-((lr,3^)-3-(Azetidin-l-yl)-3- methylcyclobutyl)-5-fluoro-A- isopropyl-2-((4-(6-((6-methyl-6,7- dihydro-5 / / -pyrrolo[3,4-b] pyridin-4-yl) oxy)-2-azaspiro [3.3] heptan-2-yl) pyrimidin-5-yl) oxy) benzamide

[2602] A'-(( 1 r,3 r)-3 -(Dimethylamino)- 3 - methylcyclobutyl)-5-fluoro-7V- isopropyl-2-((4-(6-((6-methyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-4- yl)oxy)-2-azaspiro[3.3]heptan-2- yl)pyrimidin-5-yl)oxy)benzamide

[2603] x'N'xy 5-Fluoro-A'-isopropyl-2-((4-(6-((6- methy 1- 5,6, 7, 8-tetrahy dr o- 1,6- naphthyridin-4-yl)oxy)-2- azaspiro [3.3] heptan-2-y 1 )py rimidin- 5 - yl)oxy)-A'r-((25,4r)-5-methyl-5- azaspiro[3.4]octan-2-yl)benzamide

[2604] ^N?

[2605] YNY° N

[2606] jf j °Y^N

[2607]

[2608] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2609] 5-Fluoro-N-isopropyl-N-((1r,3r)-3- methyl-3-(pyrrolidin- 1 -yl)cyclobutyl)-2- ((5-(6-((6-methyl-5,6,7,8-tetrahydro- 1,6-naphthyridin-4-yl)oxy)-2- / \' r ( \ ’T] l

[2610] \ Z / \ \ azaspiro [3.3 ]heptan-2-yl)- 1,2,4-triazin- 6-yl)oxy)benzamide

[2611] A Vf

[2612] o

[2613] / Z-- \ / \Z '\ ' > Xo ~zz- / --.

[2614] KJ (D2)-N-(Q r,3 r)-3-(Azetidin-l-yl)-3- methylcyclobutyl)-2-((4-(6-((5-ethyl-6- methy 1 - 5,6, 7, 8-tetrahy dr o- 1, 6- / G (D2) Al K

[2615] naphthyridin-4-y!)oxy)-2- azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)-5-fluoro-N-isopropylbenzamide

[2616] 'K-N'Y>0

[2617] F' N

[2618] (D2)-2-((4-(6-((5-Ethyl-6-methyl- CG 5,6,7,8-tetrahydro-l,6-naphthyridin-4- K\> Y j yl)oxy)-2-azaspiro [3, 3 ]heptan-2- (D2)O> G

[2619] yl)pyrimidin-5-yl)oxy)-5-fluoro-N- isopropyl-N-((1r,3r)-3-methyl-3- (pyrrolidin-1 -yl)cyclobutyl)benzamide yY

[2620] FG P

[2621] (D2)-2-((4-(6-((5-Ethyl-6-methyl- G1 5,6,7,8-tetrahydro-l,6-naphthyridin-4- N

[2622] yl)oxy )-2-azaspiro [3.3 ]heptan-2-, NQ< D2)- yl)pyrimidin-5-yl)oxy)-5-fluoro-N- isopropyl-N-((25,4r)-5-methyl-5- azaspiro[3.4]octan-2-yl)benzamide \^. N^O <f>

[2623] y Y N

[2624] xy°i5

[2625]

[2626] F N Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2627] "' N'O (D2)-2-((4-(6-((5,6-Dimethyl-5, 6,7,8- tetrahydro-1,6-naphthyridin-4-yl)oxy)- (D2) N 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)-5-fluoro-A7-isopropyl-7V- ( 1 \ -\ y ((lr,3r)-3-methyl-3-(pyrrolidin-l- v JLX= yl)cyclobutyl)benzamide

[2628] Qi

[2629] VV° o N

[2630] KZ / =' T^1 / ■■■■■■■■ / """"? / v x

[2631] F V O N

[2632] (£^2)-jV-((lr,3r)-3-(Azetidin-l-yl)-3- methylcyclobutyl)-2-((4-(6-((5,6- N dimethyl-5,6,7,8-tetrahydro-l,6- £"7 (D2)

[2633] naphthyridin-4-yl)oxy)-2- azaspiro [3.3] heptan-2-y l)py rimid in- 5 - yl)oxy)-5-fluoro-7V-isopropylbenzamide

[2634] \. N^O \ /

[2635] V y N

[2636] F" N

[2637] (D2)-AL((lr,3r)-3-(Dimethylamino)-3- JO methylcyclobutyl)-2-((4-(6-((5-ethyl-6- / (D2) J J methy 1 - 5,6, 7, 8-tetrahy dr o- 1,6- naphthyridin-4-yl)oxy)-2- azaspiro [3.3] heptan-2-y l)py rimi din- 5 - yl)oxy)-5-fluoro-JV-isopropylbenzamide w v

[2638] ' X -o. O.

[2639] ij o

[2640] F N

[2641] N-(( 1 r, 3 r)-3 -(Dimethylamino)-3 - methylcyclobutyl)-5-fluoro-A’- isopropyi-2-((5-(6-((2-methyl-l,2,3,4- tetrahydroisoquinolin-8-yl)oxy)-2- azaspiro[3, 3 ]heptan-2-yl)- 1,2,4-triazin- 6-yl)oxy)benzamide

[2642]

[2643] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2644] N-((1r,3r)-3-(Ethyl(methyl)amino)-3- methy lcyclobutyl)-5 -fluoro-A7- isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- — O' tetrahydro- 1,6-naphthyridin-4-yl)oxy)-12-azaspiro[3.3]heptan-2-yl)pyrimidin-5- O )V F'-=\N yl)oxy)benzamide

[2645] HVLO< A A) O

[2646] O / A

[2647] \ / / \ / \-- z

[2648] 1J I ) X o z-z z>——— / ,. J

[2649] F N A4 \' )- >7K”=5-Fluoro-N-isopropyl-N-((lr,3r)-3-((2- methoxyethyl)(methyl)amino)-3- methylcyclobuty1)-2-((4-(6-((6-methyl- 5,6,7,8-tetrahydro- 1,6-naphthyridin-4- yl)oxy)-2-azaspiro[3, 3]heptan-2- y l)pyri midin- 5-y 1 )oxy)benzam ide

[2650] \ z^- W / “

[2651] — / Z\ / / \\ Zx / \x \V / / ~ “

[2652] / \ \ O x Z. Z. Z O Z — — — '

[2653] w /

[2654] o o 5 -Fluoro-A’-isopropy l-AT-(( 1 r,3r)-3 - methyl-3 -(methyl(oxetan- 3 - yl)amino)cyclobutyl)-2-((4-(6-((6- v)Hx

[2655] \ \ Y z:z \* methy 1- 5,6, 7, 8-tetrahy dr o- 1,6- / 1 u- '! ) i U" -SJ- — naphthyridin-4-yl)oxy)-2- azaspiro [3.3] heptan-2-y l)py rimid in- 5 - yl) oxy) benzamide

[2656] AT-((lr,3r)-3-((2,2- Difluoroethyl)(methyl)amino)-3- methylcyclobutyI)-5-fluoro-A^- isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yI)oxy)- 2-azaspir o [3.3 ] heptan-2-y l)py ri midi n- 5 - y I) oxy)benzam ide

[2657]

[2658] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2659] 5-Fluoro-N-((1r,3r)-3-(3-fluoroazetidin- F I l-yl)cyclobutyl)-A-isopropyl-2-((4-(6- A Y* ((6-methyl-5,6,7,8-tetrahydro-l,6- naphthyridin-4-yl)oxy)-2- azaspiro [3.3 j hep tan-2-y 1 )py rimidi n- 5 - yl)oxy)benzamide

[2660] \ A ^0 0>

[2661] y YN

[2662] ,ox_x"zL-.

[2663] IJ U F N"

[2664] / " N^Y (D7)-5-Fluoro-2-((4-(6-((5j6, 8,9, 10, 10a-H0\ XA hexahydropyrrolo[2,l - X(D1)I 4 f] [ 1,6]naphthyridm- 1 -yl)oxy)-2- azaspiro[3.3]heptan-2-yl)pyrimidin-5- y l)oxy)-N-(( 1 r,3 r)-3 -(3 - ^ z- hydroxyazetidin- 1 -y l)-3 - Y _ / / methylcyclobutyl)-7V- > x N

[2665] / A zO, A, / AX isopropylbenzamide

[2666] \ / \ / A / Y<. \ ( o x <, zz z— — —"

[2667] U uC X ( o z 2: z < — — — 'z

[2668] / \ / \—- \ Q O / ? Jz

[2669] (D2)-5-Fluoro-2-((4-(6-((5,6,8,9,10,10a- y _ / x / \ \J A A O - hexahydropyrrolo[2, 1 - _ > / \ / z T\ Z \ / — / \= f] [ 1,6]naphthyridin- 1 -yl)oxy)-2- y y / Lt- / \< \ O rzz z<> z \ --- -----~

[2670] k~~v' azaspiro[3.3]heptan-2-y1)pyrimidin-5- T i yl)oxy)-Ar-((l r,3r)-3-(3- hydroxyazetidin- 1 -yl)-3 - m ethy Icyclobuty 1)-Ar- isopropylbenzamide

[2671] 5-Fluoro-A-(3-(3-hydroxyazetidin-l - yl)bicy clo[ 1.1.1 ]pentan- 1 -y 1)-7V- isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspir 0 [3.3] heptan-2-y l)pyrimidin- 5 - yl) oxy) benzamide

[2672]

[2673] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2674] 5-F! uoro-A-isopropy l-7V-(( 1 / ’..j / j-j - <1 Sr 'N methyl-3-(5-azaspiro [2.3] hexan-5-yl)

[2675] 7^7 L h cyclobutyl)-2-((4-(6-((6-methyl-5,6,7,8- (y '"'

[2676] / / 7 “Y> _ tetrahydro-1,6-naphthyridin-4-yl) oxy)- / \ \ 'f X? Hw- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide

[2677] " f^H vf0< /

[2678] o

[2679] O l / ^ / \\ / bx) X O z z z? —, — — >

[2680] ^ \ \ (z~ _ 5-Fluoro-A-isopropyl-A-(( 1 r,3r)-3 - j ry

[2681] methyl-3 -(3 -methy lazetidin- 1 - Y=z

[2682] yl)cyclobutyl)-2-((4-(6-((6-methyl- b X)N5, 6, 7, 8-tetrahy dr o- 1, 6-naphthyridin-4- yl)oxy)-2-azaspiro [3.3 ]heptan-2- yl)pyrimidin-5-yl)oxy)benzamide

[2683] \ YxN^ V ° N

[2684] xL,-Ck X

[2685] n HN

[2686] 'X'N'^X1 5-Fluoro-N-isopropyl-JV-((l r,3r)-3 - £ 7 methyl-3-(2-azaspiro[3.3]heptan-2- / / JL JJ yl)cyclobutyl)-2-((4-(6-((6-methyl- 5,6,7, 8-tetrahy dro- 1, 6-naphthyridin-4- yl)oxy)-2-azaspiro[3.3]heptan-2- yl)pyrimidin-5-yl)oxy)benzamide

[2687] y r N

[2688] ' bts. A.

[2689] fl H

[2690] N-(( 1 r,3r)-3-(Azetidin- 1 -y l)-3 - methylcyclobutyl)-5-fluoro-tV- isopropyl-2-((4-(6-((5,6,7,8-tetrahydro- 1,6-naphthyridin-4-yl)oxy)-2- azaspiro [3.3 ] heptan-2-y l)py rimid in- 5 - yl) oxy) benzamide

[2691]

[2692] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2693] N-((1r,3r)-3-(3,3-Dimethylazetidin-1- yl)-3-methylcyclobutyl)-5-fluoro-jV- isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)- s: \ / z z\. 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide

[2694] ^T V / Axo; < —

[2695] p

[2696] y X O) Z Z Z 2 —, — / —

[2697] 'V- / ' Vi v \ \

[2698] OEt XX A'r-((l / ',3r)-3-(3-(Ethoxy methyl)

[2699] o7.xazetidm-l-yl)-3-methylcyclobutyl)-5- z—

[2700] L h fluoro-A-isopropyl-2-((4-(6-((6-methyl- 5,6, 7, 8-tetrahy dr o- 1, 6-naphthyridin-4- yl) oxy)-2-azaspiro [3.3] heptan-2-yl) pyrimidin-5-yl) oxy) benzamide \. N^O <*>

[2701] 1zkz°xA.

[2702] H 1 ll ™

[2703] 5-Fluoro-N-isopropyl-N-((1r,3r)-3-(3-(methoxymethyl)azetidin-1-yl)-3- \ O \

[2704] y_ / A methylcyclobutyl)-2-((4-(6-((6-methyl- 5,6,7,8-tetrahydro-1,6-naphthyridin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide

[2705] A'r-((lr,3r)-3-(2-Azaspiro[3.3]heptan-2- yl)cyclobutyl)-5-fluoro-A'-isopropyl-2- < C iiN((4-(6-((6-methyl-5,6,7,8-tetrahydro- 1,6-naphthyridin-4-yl)oxy)-2- azaspiro [3.3 ] heptan-2-y 1 )py rimidin- 5 - yl) oxy) benzamide

[2706] j N

[2707] Ju d1

[2708]

[2709] F N Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2710] N-((1r,3r)-3-(Dimethylamino)-3-methylcyclobutyl)-5-fluoro-N- isopropyl-2-((4-(6-((2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)oxy)-2- 1 ( n —

[2711] Z ^ '\ \ azaspiro[3.3]heptan-2-yl)pyrimidin-5- X■ J? <xxx z->—=\

[2712] yl)oxy)benzamide

[2713] OO X X X< O z Z—~

[2714] ZJy

[2715] N-(( 1 r,3 r)-3 -(Dim ethylamino)-3 - methylcyclobutyl)-5-fluoro-A?- isopropyl-2-((4-(6-((2-methylisoindolin- 4-yl)oxy)-2-azaspiro[3,3]heptan-2- yl)pyrimidin-5-yl)oxy)benzamide

[2716] A / _ / / A / AZ~

[2717] / y\x** 3? —

[2718] XC{ X. v O z < o z zyjA z z ( CKxA — ' — — — ' — ' —

[2719] / \ / —

[2720] o o

[2721] %h Ar-((lr,3r)-3-(Dimethylamino)-3- \ Xz— / \== methy lcyclobutyl)-5 -fluoro-A7- \X< >z— / \=== *

[2722] LL \ \Z z \ isopropy l-2-((4-(6-((7-methyl-5, 6,7,8- r i~ tetrahydro-l,7-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide

[2723] (D1)-5-Fluoro-2-((5-(6-((5,6,8,9,10,10a- \ I I hexahydropyrrolo[2, 1 - L h f] [ 1,6]naphthyridin- 1 -yl)oxy)-2- azaspiro [3.3 ]heptan-2-yl)- 1,2,4-triazin- 6-yl)oxy)-N-isopropyl-N-((2s,4r)-5-methyl-5-azaspiro[3.4]octan-2-yl)benzamide

[2724] \, N^O \, /

[2725] 1 Jx ^0^ Jx.

[2726] N.- JJ

[2727]

[2728] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2729] (£>2)-5-Fluoro-2-( (5-(6-((5,6, 8,9, 10, 10a- (Isomer 2) hexahydropyrrolo[2, 1 - f] [ 1,6]naphthyridin- 1 -yl)oxy)-2- azaspiro [3.3 ]heptan-2-yl)- 1,2,4-triazin- ( " 41 -n —=j - s-. \s&_. ) _ Q X _ 6-yl)oxy)-A7-isopropyl-A7-((25,4r)-5- "? methy 1-5 -azaspiro [3.4] octan-2-SY" So Y yl)benzamide

[2730] T

[2731] 1Y

[2732] A / ~ o N

[2733] j.( ( ) Y

[2734] FY V Y?-- N

[2735] X O zz z y / / — - FJxJ ■—.

[2736] N HJ (D / )-A?-((lr,3r)-3-(Azeti din-1 -yl)-3- methylcyclobutyl)-5-fluoro-2-((5-(6- ((5, 6, 8, 9, 10, 10a-hexahydropyrrolo[2, 1 - f] [ 1,6]naphthyridm- 1 -yl)oxy)-2- azaspiro[3.3]heptan-2-yl)- 1,2,4-triazin- 6-yl)oxy)-N-isopropylbenzamide

[2737] YNY (D2) -Ar-(( 1 r, 3 r) - 3 - ( Azetidin- 1 -y 1)- 3 - (Isomer 2) \ ■ |

[2738] AYN methylcyclobutyl)-5-fluoro-2-((5-(6- ((5, 6, 8, 9, 10, 10a-hexahydropyrrolo[2, 1 - A AJ

[2739] ~" N » 0 f] [ 1,6]naphthyridin- 1 -yl)oxy)-2- azaspiro [3.3 ]heptan-2-yl)- 1,2,4-triazin- 6-yl)oxy)-N-isopropylbenzamide

[2740] X IwX X

[2741] \ / N^. O < •>

[2742] 7 f N

[2743] ' A, CK A

[2744] YX A?

[2745] F AY N.' N /

[2746] X'N'X (D7)-5-Fluoro-A7-isopropyl-2-((5-(6-((6- methy 1- 5,6, 7, 8-tetrahy dr o- 1,6- (Isomer 1) AA'fsj

[2747] naphthyridin-4-yl)oxy)-2- azaspiro [3.3 ]heptan-2-yl)- 1,2,4-triazin- N N. Y J 0 i '^^

[2748] 6-yl)oxy)-Ar-(5-methyl-5- azaspiro[3.5]nonan-2-yl)benzamide

[2749] Y 7

[2750] 7X °A

[2751] AY hk 4

[2752]

[2753] F N Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2754] (D2)-5-Fluoro-Ar-isopropyl-2-((5-(6-((6- methyl-5,6,7,8-tetrahydro-L6- naphthyridin-4-yl)oxy)-2- azaspiro [3.3 ]heptan-2-yl)- 1,2,4-triazin-, O r° 6-yl)oxy)-7V-(5-methyl-5- azaspiro[3.5jnonan-2-yl)benzamide VY° N

[2755] F J' L ^ hk '-N J

[2756] HN'Y 5-Fluoro-2V-isopropyl-2V-((2s,4r)-5- methyl-5-azaspiro[3.4]octan-2-yl)-2-((5- (6-((5,6,7,8-tetrahydro-l,6- naphthyridin-4-yl)oxy)-2- 9

[2757] azaspiro [3.3 ]heptan-2-yl)- 1,2,4-triazin- 6-yl)oxy)benzamide

[2758] *X

[2759] YNY° V

[2760] AV *

[2761] J F U u N

[2762] (D7)-2-((5-(6-((5-Ethyl-5, 6,7,8- (Isomer 1) |

[2763] tetrahydro- 1,6-naphthyridin-4-yl)oxy)- \ 2-azaspiro [3.3 ]heptan-2-yl)- 1,2,4- '—N / / O^ k '-^ JJ tiazin-6-yl)oxy)-5-fluoro-A / -isopropyl- JV-((1 r,3r)-3 -methyl-3-(pyrrolidin- 1 - 6 I«

[2764] \. ^ z <

[2765] N \\> y l)cyclobutyl) benzamide | YO /

[2766] N

[2767] rv0^ N<- J

[2768] (D7)-2-((5-(6-((5-Ethyl-5, 6,7,8- (Isomer 1)n7 ]

[2769] tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro [3.3 ]heptan-2-yl)- 1,2,4- triazin-6-yl)oxy)-5-fluoro-A’-isopropyl- 7V-((2s,4r)-5-methyl-5- azaspiro[3.4]octan-2-yl)benzamide

[2770] \, N u_s),0 \ X>

[2771] Np N

[2772]

[2773] FXYNXX Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2774] 5-Fluoro-7V-isopropyl-2-((4-(6-((6- methyl-5,6,7,8-tetrahydro-L6- ^Y naphthyridin-4-yl)oxy)-2- N OJ's)., J i azaspiro [3.3 j hep tan-2-y I )py rimidi n- 5 - yl)oxy)-A7-((2r,45)-5-methyl-5- 2 2 azaspiro[3.5jnonan-2-yl)benzamide

[2775] ] f N

[2776] 1 / Lx.oxA

[2777] j! J 1; J

[2778] F" N'

[2779] 5-Fluoro-A-isopropyl-2-((4-(6-((6- methy 1- 5,6, 7, 8-tetrahy dr o- 1,6- naphthyridin-4-yl)oxy)-2- azaspiro [3.3] heptan-2 -y l)py nniidin- 5 - yl)oxy)-A’-((2?,4r)-5-methyl-5- azaspiro [3.5 ]nonan-2-yl)benzamide

[2780] _ / /

[2781] p; YCHozzz^

[2782] o

[2783] HN'Y 6D / )-5-Fluoro-A?-isopropyl-A-(5- VZA.___ methyl-5-azaspiro[3.5]nonan-2-yl)-2- / ( sYZ / "-= ^ \ / \ / 1- / zx (Isomer 1)

[2784] z u. ' — —v((4-(6-((5,6,7,8-tetrahydro-I,6- \ / JT I o' naphthyridin-4-yl)oxy)-2- azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzainide

[2785] \ „xN,.0 2 \ /

[2786] N Y N

[2787] HN'Y (D2)-5-Fluoro-? / -isopropyl-Ar-(5- (Isomer 2) methyl-5-azaspiro[3.5]nonan-2-yl)-2- ((4-(6-((5,6,7,8-tetrahydro-l,6- naphthyridin-4-yl)oxy)-2- azaspiro[3.3]heptan-2-yl)pyrimidin-5- y I) oxy)benzam ide

[2788] y N

[2789] ' f / Ly, Y Y. U^sN

[2790] FYY LNU

[2791]

[2792] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2793] ( / ?7)-2-((4-(6-((5-Ethyl-5, 6,7,8- (Isomer 1) |

[2794] tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspir o [3.3 ] heptan -2-y l)pynmi din- 5- yl)oxy)-5-fluoro-7V-isopropyl-. V-(5- methyl-5-azaspiro[3.5]nonan-2- yl)benzamide

[2795] V Y° v

[2796] XJ °X^

[2797] F NN

[2798] (D2)-2-((4-(6-((5-Ethyl-5, 6,7,8- (Isomer 2)

[2799] tetrahydro- 1,6-naphthyridin-4-yl)oxy)- 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- o uo

[2800] Ji J 0 ^ yl)oxy)-5-fluoro-Az-isopropyl-JV-(5- methy 1-5 -azaspiro [3.5] nonan-2- yl)benzamide

[2801] Y^°

[2802] Ij °Y\N

[2803] (DJ)-5-Fluoro-A7-isopropyl-2-((4-(6-((6- Y Y methy 1 - 5,6, 7, 8-tetrahy dr o- 1, 6- (Isomer 1) Y

[2804] 7j N naphthyridin-4-yl)oxy)-2- Y~9 ULY azaspiro [3.3] heptan -2-y l)py rimi din- 5 - ^N, A? yl)oxy)-A’-(5-methyl-8-oxa-5- azaspiro [3.5 ]nonan-2-yl) benzamide \, N^O

[2805] | i N

[2806] * / k JD. U

[2807] JU O F N

[2808] "‘'N'Y (£)2)-5-Fluoro-Ar-isopropyl-2-((4-(6-((6- (Isomer 2) L U methy 1 - 5,6, 7, 8-tetrahy dr o- 1, 6- naphthyridin-4-yl)oxy)-2- Y ulY azaspiro [3.3] heptan -2-y l)py rimi din- 5 - yl)oxy)--V-(5-methyl-8-oxa-5- azaspiro[3.5]nonan-2-yl)benzamide ' < >0

[2809] N Y N

[2810] rrN"°Y^N

[2811] JU J 4 F N

[2812]

[2813] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2814] (D7)-5-Fluoro-2-( (4-(6-((5,6, 8,9, 10, 10a- (isomer 1) \ J, JI hexahydropyrrolo[2, 1 - f] [ 1,6]naphthyridin- 1 -yl)oxy)-2- o U

[2815] ( J z -j-j - « —, azaspiro [3.3 j hep tan-2-y 1 )py rimidi n- 5 - / i yl)oxy)-7V-isopropyl-7V-(5-methyl-5- Y / AAZN 3- / „ azaspiro[3.5jnonan-2-yl)benzamide

[2816] < >

[2817] y > o N

[2818] ' Us.,-Ck / U Z / \\s

[2819] ) XO z z ~z z— / — / —.

[2820] FUs^U ^N / / JU V A N \ \_

[2821] / j y

[2822] / '''N''Y i ' z— (D2)-5-Fhioro-2-((4-(6-((5,6, 8,9, 10, 10a- (Isomer 2) \ 1 hexahydropyrrolo[2, 1 - '"" >| N

[2823] f] [ 1,6]naphthyridin- 1 -yl)oxy)-2- Ji ] 0x'" azaspiro [3.3] heptan-2 -y l)py nniidin- 5 - yl)oxy)-A'r-isopropyl-A'r-(5-methyl-5- Z A“

[2824] _ / / A azaspiro [3.5 ]nonan -2-yl)benzamide V" Y° N Q ZZz — — / / \ / _ / \Z_Z A / AA \"

[2825] : Js 0 y / = / U N\ / / .

[2826] Y o

[2827] F u N

[2828] 5-Fluoro-? V-isopropyl-2-((4-(6-((6- methy 1 - 5,6, 7, 8-tetrahy dr o- 1,6- ) Z U- —IYY CU naphthyridin-4-yl)oxy)-2- / / azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)- / V-((25,4r)-6-methyl-6- azaspiro[3.5]nonan-2-yl)benzamide

[2829] 5-Fluoro-AMsopropyl-2-((4-(6-((6- methy 1 - 5,6, 7, 8-tetrahy dr o- 1,6- naphthyridin-4-yl)oxy)-2- azaspiro[3.3]heptan-2-yl)pyrimidin-5- yI)oxy)-Ar-((2r,4s)-6-methyl-6- azaspiro[3.5]nonan-2-yl)benzamide

[2830]

[2831] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2832] 5-Fluoro-A-isopropyl-Ar-(7-methyl-7- azaspiro[3.5]nonan-2-yl)-2-((4-(6- ((5,6,7,8-tetrahydro-l,6-naphthyridin-4- / hL Jt j

[2833] r j yl)oxy )-2-azaspiro [3.3 ]heptan-2- ( ( 11 Z / \ - / \ yx-,

[2834] \ 1 } / yS Z\ / — — —s>-z222LX yl)pyrimidin-5-yl)oxy)benzamide

[2835] Ql

[2836] ip o o N

[2837] {X?- / / / z^\ Z\ z\

[2838] [| i! X O H z H O > x z> z z? x — — / — / — — —:

[2839] v- / - V y v ™

[2840] > n.

[2841] v-z--- 5-Fluoro-AT-isopropyl-2-((4-(6-((6- methy 1- 5, 6, 7, 8-tetrahy dr o- 1, 6- naphthyridin-4-yl)oxy)-2- azaspiro [3.3] heptan-2 -y l)py nniidin- 5 - yl)oxy)-A’-((2r,4i,)" S-methyl-5- \ Z= azaspiro[ 3.4] octan-2-y l)benzamide

[2842] / / / —

[2843] / / / \ / \ \ \ \ / x ( \ / X Zx=

[2844] X (\ o < zz z— —1—

[2845] y / xv \- o

[2846] 5-Fluoro-A-isopropyl-2-((5-(6-((6- methy 1- 5,6, 7, 8-tetrahy dr o- 1,6- L \ x. < ’

[2847] LLZ \--' " ' naphthyridin-4-yl)oxy)-2- \ / azaspiro [3.3 ]heptan-2-yl)- 1,2,4-triazin- 6-yl)oxy)-A'r-((25,4r)-5-methyl-5- azaspiro[3.4]octan-2-yl)benzamide

[2848] 5-Fluoro-Ar-isopropyl-2-((4-(6-((6- methy 1- 5,6, 7, 8-tetrahy dr o- 1,6- naphthyridin-4-yl)oxy)-2- azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)-A'-(7-methyl-7- azaspiro[3.5]nonan-2-yl)benzamide

[2849]

[2850] Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2851] 0 2-((4-(6-((6-Acetyl-5?6,7, S-tetrahydro- 1,6-naphthyridin-4-yl)oxy)-2- azaspiro [3.3 j hep tan-2-y 1 )py rimidi n- 5 - X'Nyl)oxy)-5-fl uoro-TV-isopropy 1 -N- / — \, X /

[2852] Z-NA ((25,4'r)-5-methyl-5-azaspiro[3.4]octan- 9

[2853] 2-yl)benzamide

[2854] 7

[2855] A A N

[2856] *. A A.. A

[2857] py N

[2858] FX^ SS

[2859] '" N'X / V-(3-(Dimethylamino)azetidin-l-yl)-5- fluoro- / V-isopropyl-2-((4-(6-((6-methyl- \A

[2860] L j 5,6, 7, 8-tetrahy dr o- 1, 6-naphthy ri din -4- N yI)oxy)-2-azaspiro [3.3 ]heptan-2- yl)pyrimidin-5-yl)oxy)benzamide

[2861] hi \Z

[2862] \ Y, N^;. O O

[2863] AN

[2864] . A zO. A

[2865] Ay Y |

[2866] FXY kNJ

[2867] O | 0 1 -Acetoxyethyl 4-((2-(5-(4-fluoro-2- JA 0 OA N / A\ (isopropyl((2s,4r)-5-methyl-5- azaspiro [3, 4] octan-2- yl)carbamoyl)phenoxy)pyrimidin-4-yI)- 1 J

[2868] 9 2-azaspiro[3.3]heptan-6-yI)oxy)-7,8- di hydro- 1, 6-naphthy ri din e- 6(5H) - carboxylate

[2869] £

[2870] xA-A \, Z

[2871] Y A N

[2872] ' A AzY A^N

[2873] FA^ kN^

[2874] ■ O 1 0 1 -((L-Valyl)oxy)ethyl 4-((2-(5-(4- A YrsA o A o A NA fluoro-2-(isopropyl((2v,4r)-5-methyl-5- SA azaspiro [3.4] octan-2- •2HCir-A A J yl)carbamoyl)phenoxy)pyrimidin-4-yl)- 2-azaspiro[3.3]heptan-6-yl)oxy)-7,8- "' x A dihy dro- 1, 6-naphthy ndine-6( 5H)- carboxylate dihydrochloride

[2875] \. N i ®xA X \ /

[2876] AoJt

[2877]

[2878] FA U Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2879] 1 -(Pivaloyloxy )ethyl 4-((2-(5-(4-fluoro- 2-(isopropyl((25,4;')-5-methyl-5- azaspiro [3.4] octan-2- yl)carbamoyl)phenoxy)pynmidin-4-yl)- \ / V ( X m - — * 2-azaspiro[3.3]heptan-6-yl)oxy)-7,8- \O 2:J - X"

[2880] dihydro- 1?6-naphthyridine-6(5H)- ®l °f V / y carboxylate

[2881] \ O O

[2882] AA° / =v / y...

[2883] > > / c o z z ^z — — — / .

[2884] / A / V V \ \

[2885] o "'A p 1 -Acetoxy-2-methylpropyl 4-((2-(5-(4- X" 'Q' '^''QX- N "’" A fluoro-2-(isopropyl((25,4;')-5“methyl-5- azaspiro [3.4] octan-2- ''V A yl)carbamoyl)phenoxy)pyrimidin-4-yl)- 2-azaspiro[3.3]heptan-6-yl)oxy)-7,8- dihy dro- 1,6-naphthyndme-6( 5H)- _ / / carboxylate

[2886] 7 Qyy _ f _ / / • •

[2887] AV ^ y 0== / V

[2888] o o

[2889] A... x CK

[2890] X y y ( o —v_Az)A ° ”~

[2891] F [AA| o / XX=

[2892] / r 2 L T A N

[2893] L. \

[2894] \ A / 2 -Methyl- 1 -(pivaloyloxy) propyl 4-((2- (5-(4-fluoro-2-(isopropyl((2s,4r)-5- methyl-5-azaspiro[3.4]octan-2- yl)carbamoyl)phenoxy)pyrimidin-4-yl)- 2-azaspir o [3.3] heptan-6-y 1) oxy) -7,8- dihydro- 1,6-naphthyridine-6(5H)- carboxylate

[2895] A ''A 5-Fluoro-N-isopropyl-2-((4-(6-((6- k A^ X" methy 1- 5,6, 7, 8-tetrahy dr o- 1,6- N

[2896] O0Xx naphthyridin-4-yl)oxy)-2- azaspiro [3.3] heptan-2-y 1 )py rimidin- 5 - HN«A Y

[2897] yl)oxy)-N-((2s,4r)-5- azaspiro [3.5 ]nonan-2-yl)benzamide

[2898] A; / A

[2899] \ N ^0 < >

[2900] Y p N

[2901] V A.

[2902]

[2903] F AT A N Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2904] 235 N-((1 r,3r)-3-Acetamido-3- methylcyclobutyl)-5-fluoro-N- isopropyl-2-((4-(6-((6-methyl-5, 6,7,8- tetrahydro- 1,6-naphthyridin-4-yl)oxy)- o - / Z\ \ ' 2-azaspiro[3.3]heptan-2-yl)pyrimidin-5- yl)oxy)benzamide

[2905] b

[2906] o

[2907] ^ / \ / 77'\\ \ z o> / — / — / —\

[2908] 236 - 5-fhioro-N-isopropyl-N-((lr,3r)-3- methyl-3-(pyrrolidin-l -yl)cyclobutyl)-2- ((4-(6-((l,2,3,4-tetrahydroisoquinolin-8- yl)oxy)-2-azaspiro [3.3 ]heptan-2- yl)pyrimidin-5-yl)oxy)benzamide

[2909] / CJ

[2910] \ / \ / ( \ —7

[2911] ( z z / ■

[2912] 6 o

[2913] 237 O 5-Fhioro-rV-isopropyl-2-((4-(6-((2- o >. methyl-l,2,3,4-tetrahydroisoquinolin-8- / U_ < > 1LL- / \Z —£. \ X ■ yl)oxy)-2-azaspiro [3.3 ]heptan-2- / o _ \ 1 y l)py rimid in- 5 -y 1) oxy) -N- (( 1 r, 3 r)- 3 - methyl-3 -(pyrrolidin- 1 - yl)cyclobutyl)benzamide

[2914]

[2915] In some embodiments, the present disclosure is directed to a compound as shown in Table 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[2916] In some embodiments, the present disclosure is directed to a compound as shown in Table 1 or a pharmaceutically acceptable salt thereof

[2917] In some embodiments, the present disclosure is directed to a compound as shown in Table 1.

[2918] In some embodiments, the present disclosure is directed to a compound as shown in Table 1 or a pharmaceutically acceptable salt thereof, wherein the salt is hydrochloride. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2919] In some embodiments, a compound according to any embodiments herein (e.g., Formulae I’, I, I-a, I-b, and I-c, and Table 1) exhibits an inhibition activity against the binding of menin and MLL. In some embodiments, a compound according to any embodiments herein (e.g., Formulae I’, I, I-a, I-b, and I-c, and Table 1) exhibits an inhibition activity against the binding of menin and MLL. In some embodiments, a compound according to any embodiments herein e.g., Formulae F, I, I-a, I-b, and I-c, and Table 1) exhibits an inhibition activity against the binding of menin and MLL which is useful in the treatment and / or prevention of one or more diseases in which menm and MLL play a role.

[2920] In some embodiments, a compound according to any embodiments herein (e.g.. Formulae I’, I, I-a, I-b, and I-c, and Table 1) exhibits low hERG binding. In some embodiments, a compound according to any embodiments herein (e g., Formulae I’, I, I-a, I-b, and I-c, and Table 1) minimizes hERG binding and is useful for the treatment of one or more diseases in which menm and MLL play a role. Without being bound to any theory, one of the primary causes of QT prolongation is thought to be blockage of the hERG potassium channel in cardiac myocytes. In some embodiments, the compounds of the present disclosure (e.g., Formulae I’, I, La, Lb, and I-c, and Table 1) do not significantly block the hERG potassium channel.

[2921] In some embodiments, the compounds of the present disclosure (e.g.. Formulae I’, I, La, I-b, and Lc, and Table 1) do not significantly block the hERG potassium channel (e.g., an IC50 greater than 1 pM, 5 pM, 10 pM, 15 pM, 20 pM, 25 pM, 30 pM, 35 pM, 40 pM, or 50 pM) as measured by a standard patch clamp hERG assay.

[2922] In some embodiments, the compounds of the present disclosure (e.g., Formulae 1’, I, La, I-b, and Lc, and Table 1) do not significantly block the hERG potassium channel (e.g., a compound of the invention has an IC50 greater than 1 pM, 5 pM, 10 pM, 15 pM, 20 pM, 25 pM, 30 pM, 35 μM, 40 μM, or 50 μM for the hERG potassium channel).

[2923] In some embodiments and without wishing to be bound to any theory, the present disclosure is directed to inhibitors of the menin-MLL interaction comprising a pyrrolidine moiety (e.g., Formulae I’, I, La, Lb, and Lc, and Table 1) where the pyrrolidine moiety has been found to reduce hERG inhibition.

[2924] In some embodiments and without wishing to be bound to any theory', the present disclosure is directed to inhibitors of the menin-MLL interaction comprising a piperidine moiety Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2925] (e.g., Formulae I’, I, I-a, I-b, and I-c, and Table 1) where the piperidine moiety has been found to reduce hERG inhibition.

[2926] In some embodiments and without wishing to be bound to any theory, the present disclosure is directed to inhibitors of the menin-MLL interaction (e.g., Formulae F, I, I-a, I-b, and I-c, and Table 1) which are resistant to metabolism. In some embodiments and without wishing to be bound to any theory, the present disclosure is directed to inhibitors of the menin-MLL interaction (e g., Formulae I’, I, I-a, I-b, and I-c, and Table 1) which are resistant to metabolism, where the metabolites are inhibitors of the hERG potassium channel. In some embodiments and without wishing to be bound to any theory, the present disclosure is directed to inhibitors of the menin-MLL interaction (e.g., Formulae L, I, I-a, I-b, and I-c, and Table 1) which are resistant to metabolism, where the metabolism decreases the bioavailability of the inhibitor. In some embodiments and without wishing to be bound to any theory, the present disclosure is directed to inhibitors of the menin-MLL interaction (e.g., Formulae F, I, I-a, I-b, and I-c, and Table 1) which are resistant to metabolism, where the metabolism decreases the bioavailability of the inhibitor and the corresponding metabolites are more effective (e.g., by IC50, etc.) at binding the hERG potassium channel.

[2927] In some embodiments, one or more hydrogen atoms in any of the compounds of Formula L, I, I-a, I-b, or I-c may be replaced with one or more deuterium atoms.

[2928] Another aspect is an isotopically labeled compound of any of the formulae delineated herein. Such compounds have one or more isotopic atoms (e.g.,3H,2H,14C,13C,18F,35S,32P,125I, and131I) introduced into the compound. Such compounds are useful for drug metabolism studies and diagnostics, as well as therapeutic applications. In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[2929] It is understood that the deuterium labeled compound comprises a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%.

[2930] In some embodiments, the deuterium labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2931] deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term “deuterium enrichment factor” means the ratio between the deuterium abundance and the natural abundance of a deuterium.

[2932] It is understood that the deuterium labeled compound can be prepared using any of a variety of art-recognized techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a deuterium labeled reagent for a non-deuterium labeled reagent.

[2933] A compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the disclosure. Further, substitution with deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[2934] For the avoidance of doubt, it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.

[2935] Potency can also be determined by IC50 value. A compound with a lower IC50 value, as determined under substantially similar conditions, is more potent relative to a compound with a higher IC50 value.

[2936] Potency can also be determined by EC50 value. A compound with a lower EC50 value, as determined under substantially similar conditions, is more potent relative to a compound with a higher EC50 value.

[2937] In some embodiments, a pair of enantiomers have similar potency.

[2938] In some embodiments, a pair of enantiomers have different potency. In specific embodiments, the enantiomer with (R) configuration is more potent than the enantiomer with (S) configuration. In other specific embodiments, the enantiomer with (S ) configuration is more potent than the enantiomer with (R) configuration.

[2939] In some embodiments, a pair of isomers have similar potency.

[2940] In some embodiments, a pair of isomers have different potency. In specific embodiments, the trans isomer is more potent than the cis isomer. In specific embodiments, the cis isomer is more potent than the trans isomer.

[2941] In some embodiments, a group of diastereomers have similar potency. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2942] In some embodiments, a group of diastereomers have different potency.

[2943] In specific embodiments, the diastereomer with (R)(R) configuration is the most potent among the group of diastereomers.

[2944] In specific embodiments, the diastereomer with (S)(S) configuration is the most potent among the group of diastereomers.

[2945] In specific embodiments, the diastereomer with (S)(R) configuration is the most potent among the group of diastereomers.

[2946] In specific embodiments, the diastereomer with (R)(S) configuration is the most potent among the group of diastereomers.

[2947] In specific embodiments, the diastereomer with (R)(R) configuration is more potent than the diastereomer with (S)(S) configuration.

[2948] In specific embodiments, the diastereomer with (S)(S) configuration is more potent than the diastereomer with (R)(R) configuration.

[2949] In specific embodiments, the diastereomer with (R)(S) configuration is more potent than the diastereomer with (S)(R) configuration.

[2950] In specific embodiments, the diastereomer with (S)(R) configuration is more potent than the diastereomer with (R)(S) configuration.

[2951] The compounds of the application are defined herein by their chemical structures and / or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[2952] In another aspect, the application provides a method of synthesizing a compound disclosed herein. The synthesis of the compounds of the application can be found herein and in the Examples below. Other embodiments are a method of making a compound of any of the formulae herein using any one, or combination of, reactions delineated herein. The method can include the use of one or more intermediates or chemical reagents delineated herein.

[2953] In some embodiments, each of the intermediates prepared in the Schemes herein are considered embodiments of the present disclosure. In some embodiments, each of the intermediates prepared in the Examples herein are considered embodiments of the present disclosure. In some embodiments, each synthetic step as disclosed in the Schemes herein is separately considered as part of the present disclosure. In some embodiments, each synthetic step Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2954] as disclosed in the Examples herein is separately considered as part of the present disclosure. It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the disclosure which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[2955] At various places in the present specification, substituents of compounds of the disclosure are disclosed in groups or in ranges. It is specifically intended that the disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term “Ct-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and Ce alkyl.

[2956] At various places in the present specification various cycloalkyl, and heterocyclyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term “a pyridine ring” or “pyndinyl” may refer to a pyndin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

[2957] For compounds of the disclosure in which a variable appears more than once, each variable can be a different moiety independently selected from the group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound, the two R groups can represent different moieties independently selected from the group defined for R

[2958] As used herein, “alkyl”, “Ci, C2, C3, C4, C5 or Ce alkyl” or “Ci-Ce alkyl” is intended to include Ci, C2, C3, C4, Cs or Ce straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, Cs or Ce branched saturated aliphatic hydrocarbon groups. For example, C1-C6alkyl is intends to include C1, C2, C3, C4, C5and C6alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., Ci-Ce for straight chain, C3-C6 for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.

[2959] As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2960] halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[2961] As used herein, the term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxy carbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

[2962] As used herein, the term "amino," employed alone or in combination with other terms, refers to a group of formula -NEE. In some embodiments, an amine can be substituted by one or more groups, e.g., -N-(CI-C6 alkyl)2. In some embodiments, when two groups are attached to an amine they can be the same or different. Each group is selected independently of each other and can be each independently optionally substituted.

[2963] As used herein, the term “halogen” or "halo," employed alone or in combination with other terms, refers to a halogen atom selected from F, Cl, I or Br. In some embodiments, "halo" refers to a halogen atom selected from F, Cl, or Br. In some embodiments, the halo substituent is F. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2964] The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms. In some embodiments, the haloalkyl group is fluorinated. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the haloalkyl group is fluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments, the haloalkyl group is trifluoromethyl. In some embodiments, the haloalkyl group is 2,2,2-trifluoroethyl. In some embodiments, the haloalkyl group is 2,2-difluoroethyl. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms.

[2965] As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkenyl groups containing two to six carbon atoms. The term “Cb-Ce” includes alkenyl groups containing three to six carbon atoms.

[2966] As used herein, the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[2967] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2968] in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C6” includes alkynyl groups containing two to six carbon atoms. The term “C3-C6” includes alkynyl groups containing three to six carbon atoms. As used herein, “C2-C6 alkenylene linker” or “C2-C6 alkynylene linker” is intended to include C2, C3, C4, C5 or Co chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C2-C6alkenylene linker is intended to include C2, C3, C4, C5 and C6alkenylene linker groups.

[2969] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl- 1,2,3,6-tetrahydropyridinyl.

[2970] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be non-aromatic. In some embodiments, cycloalkyl may optionally contain one or more alkenylene groups as part of the ring structure. Cycloalkyl groups can include mono- or polycyclic ring systems. Polycyclic ring systems can include fused ring systems and spirocycles. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (z.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or pyrido derivatives of cyclopentane, cyclopentene, cyclohexane, and the like. A heterocyclyl group that includes a fused aromatic (e.g., aryl or heteroaryl) moiety can be attached to the molecule through an atom from either the aromatic or non-aromatic portion. One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized to form carbonyl linkages. In some embodiments, cycloalkyl is C3-10 cycloalkyl, C3-7 cycloalkyl, or C5-6 cycloalkyl. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and the like. Further exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Additional example cycloalkyl groups, where the cycloalkyl group has a fused aryl or heteroaryl moiety, include Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2971] tetrahydronaphthalen-2-yl, 2,3-dihydro-lH-inden-2-yl; 2,3,4,9-tetrahydro-lH-carbazol-7-yl; 2,6,7,8-tetrahydrobenzo[cd]indazol-4-yl; and 5,6,7,8,9,10-hexahydrocyclohepta[b]indol-3-yl.

[2972] Further exemplary cycloalkyl groups include

[2973]

[2974] As used herein, the term “aryl,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbon, such as, but not limited to, phenyl, 1 -naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, aryl is Ce-ioaryl. In some embodiments, aryl is Ce-uaryl. In some embodiments, the aryl group is a naphthalene ring or phenyl ring. In some embodiments, the aryl group is phenyl.

[2975] As used herein, the term “heteroaryl,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic heterocylic moiety, having one or more heteroatom ring members selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl group has 1, 2, 3, or 4 heteroatom ring members. In some embodiments, the heteroaryl group has 1, 2, or 3 heteroatom ring members. In some embodiments, the heteroaryl group has 1 or 2 heteroatom ring members. In some embodiments, the heteroaryl group has 1 heteroatom ring member. In some embodiments, the heteroaryl group is 5- to 10-membered or 5- to 6-membered. In some embodiments, the heteroaryl group is 5 -membered. In some embodiments, the heteroaryl group is 6-membered. In some embodiments, the heteroaryl group is 9- or 10-membered bicyclic. In some embodiments, the heteroaryl is 9-member bicyclic. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring(s) of the heteroaryl group can be oxidized to form N-oxides. Example heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, furanyl, thiophenyl, triazolyl, tetrazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzothiopheneyl, benzofuranyl, benzisoxazolyl, benzoimidazolyl, imidazo[l, 2-b]thiazolyl, purinyl, triazinyl, and the like. In some embodiments, the heteroaryl group is 9H-carbazol-2-yl; lH-benzo[d]imidazol-6-yl; lH-indol-6-yl; lH-indazol-6-yl; 2H-indazol-4-yl; lH-benzo[d][l,2,3]triazol-6-yl; benzo[d]oxazol-2-yl; quinolin-6-yl; or benzo[d]thiazol-2-yl. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2976] Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodi oxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, deazapurine, indolizine.

[2977] The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g,, the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, aryl carbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][l,3]dioxole-5-yl).

[2978] As used herein, the phrase "optionally substituted" means unsubstituted or substituted. As used herein, the term “substituted” or “substituted with one or more”, means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =0), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[2979] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2980] formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[2981] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[2982] As used herein, the term "heterocyclyl" or "heterocycloalkyl" employed alone or in combination with other terms, refers to a non-aromatic heterocyclic ring system, which may optionally contain one or more unsaturations as part of the ring structure, and which has at least one heteroatom ring member independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heterocyclyl group has 1, 2, 3, or 4 heteroatom ring members. In some embodiments, the heterocyclyl group has 1, 2, or 3 heteroatom ring members. In some embodiments, the heterocyclyl group has 1 or 2 heteroatom ring members. In some embodiments, the heterocyclyl group has I heteroatom ring member. When the heterocyclyl group contains more than one heteroatom in the ring, the heteroatoms may be the same or different. Example ring¬ forming members include CH, CII2, C(O), N, Nil, O, S, S(O), and S(=O)2. Heterocyclyl groups can include mono- or polycyclic (e.g, having 2, 3 or 4 fused rings) ring systems. Polycyclic rings can include both fused systems and spirocycles. Also included in the definition of heterocyclyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the non-aromatic ring, for example, 1, 2, 3, 4-tetrahydro-quinoline, dihydrobenzofuran and the like. A heterocyclyl group that includes a fused aromatic moiety can be attached to the molecule through an atom from either the aromatic or non-aromatic portion. The carbon atoms or heteroatoms in the ring(s) of the heterocyclyl group can be oxidized to form a carbonyl, sulfinyl, or sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quaternized. In some embodiments, heterocyclyl is 5- to 10-membered, 4- to 10-membered, 4- to 7-membered, 5-membered, or 6- membered. Examples of heterocyclyl groups include 1, 2, 3, 4-tetrahydro-quinolinyl, dihydrobenzofuranyl, azetidinyl, azepanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and pyranyl. Examples of heterocyclyl groups that include one or more fused Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2983] aromatic groups (e.g, aryl or heteroaryl) include N-(2'-oxospiro[cyclohexane-l,3'-indolin]-6'-yl; l,2,3,4-tetrahydroisoquinolin-6-yl; 2,3-dihydro-lH-benzo[d]imidazol-5-yl; 1,3-dihydrospiro[indene-2,3'-indolin]-6'-yl; 2,3-dihydrobenzo[d]oxazol-5-yl; l,2-dihydroquinolin-7-yl; indolin-6-yl; spiro[cyclopentane-l,3'-indolin]-6'-yl; spiro[cyclohexane-l,3'-indolin]-6'-yl; chroman-6-yl; 3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl; and benzo[d][l,3]dioxol-5-yl.

[2984] Examples of "heterocyclyl" or "heterocycloalkyl" groups include

[2985]

[2986]

[2987] As used herein, the term “alkylene” refers to a refers to a divalent radical derived from an alkane, as exemplified, by (-CH2-)n, wherein n may be 1 to about 24. By way of example only, such groups include, but are not limited to, groups having 10 or fewer carbon atoms such as the structures -CH2CH2- and -CH2CH2CH2CH2-. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[2988] As used herein, the terms “Cn-Cm” and “Cn-m”, where each of n and m is an integer, can be used interchangeably.

[2989] As used herein, the term “cycloalkylene” refers to a cycloalkyl group wherein two hydrogens are removed to provide a divalent radical. It is understood that the two hydrogens, prior to removal, can be attached to same or different atoms in the cycloalkyl group. Examples of

[2990] cycloalkylene groups include

[2991]

[2992] As used herein,

[2993]

[2994] ” represents a bond to the position indicated by the corresponding variable, for example Ring A, R1, R2, R3, Z, W, Y, X3, R1as, R1bs, R1cs, R3a, R4a, R4b, R3a’, R3b’, R3R4a’, or R4b\

[2995] As used in the embodiments describing Ring A, when Ring A is

[2996]

[2997] is intended that the position of the substituents can be at any position allowed by the available valences according to general formulae I’, I, I-a, I-b, and 1-c, or a stereoisomer, or a

[2998]

[2999] pharmaceutically acceptable salt thereof, e.g.

[3000]

[3001] wherein * indicates atachment to Z.

[3002] As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers, A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”

[3003] As used herein, the term “chiral center” refers to a carbon atom bonded to four nonidentical substituents. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[3004] As used herein, the term “chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents atached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al,, Angew, Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn etal., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem, Soc. 1951 (London), 612; Cahn et l., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116). As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[3005] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity.

[3006] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity.

[3007] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently m space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

[3008] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where Attorney Docket No.: SYND-063 / 001WO 43707-02984

[3009] tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

[3010] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all ta utomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

[3011] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R and S sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereoisomers, are intended unless otherwise indicated. Where a compound name or structure is silent with respect to the stereochemistry of a stereocenter, all possible configurations at the stereocenter are intended. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such Attorney Docket No.: SYND-063 / 001WO 43707-02984

[3012] as by resolution of racemic mixtures or by stereoselective synthesis. Geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms.

[3013] When the compounds of the disclosure contain a chiral center, the compounds can be any of the possible stereoisomers. In compounds with a single chiral center, the stereochemistry of the chiral center can be (R) or (S), In compounds with two chiral centers, the stereochemistry of the chiral centers can each be independently (R) or (S) so the configuration of the chiral centers can be (R) and (R), (R) and (S); (S) and (R), or (S) and (S). In compounds with three chiral centers, the stereochemistry / each of the three chiral centers can each be independently (R) or (S) so the configuration of the chiral centers can be (R), (R) and (R); (R), (R) and (S); (R), (S) and (R); (R), (S) and (S); (S), (R) and (R); (S), (R) and (S); (S), (S) and (R); or (S), (S) and (S).

[3014] Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as P-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereoisomencally pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1, 2-diaminocyclohexane, and the like.

[3015] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.

[3016] As used herein, the terms “El” and “E2” correspond to first and second enantiomers to elute from a chiral chromatography column as discussed in the Examples,

[3017] As used herein, the terms “DI” and “D2” correspond to first and second diastereomers to elute from a chiral chromatography column as discussed in the Examples, Attorney Docket No.: SYND-063 / 001WO 43707-02984

[3018] When a disclosed compound is named or depicted without indicating the stereochemistry of one or more stereocenters, each of the stereoisomers resulting from the possible stereochemistries at the undefined stereocenter(s) are intended to be encompassed. For example, if a stereocenter is not designated as R or S, then either or both are intended.

[3019] Compounds of the disclosure also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide -imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazo1e, 1H-, 2H- and 4H- 1, 2, 4-triazole, III- and 2H- isoindole, and HI- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

[3020] Compounds of the disclosure can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. Isotopes of constituent atoms of the compounds of the disclosure can be present in natural or non-natural abundance. Examples of isotopes of hydrogen include deuterium and tritium. In some embodiments, the compounds of the disclosure are deuterated, meaning at least one deuterium atom is present in the place of a hydrogen atom. In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogens in a compound of the disclosure are replaced by deuterium. Methods for replacing hydrogen with deuterium in a molecule are known in the art.

[3021] The term "compound" as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified (e.g., in the case of purine rings, unless otherwise indicated, when the compound name or structure has the 9H tautomer, it is understood that the 7H tautomer is also encompassed).

[3022] All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[3023] It will be understood that the compounds of the present disclosure and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds.

[3024] In some embodiments, the compounds of the disclosure, or salts thereof, or crystalline forms of any of the aforementioned, are purified or substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in a compound of the disclosure. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the disclosure, or salt thereof. In some embodiments, the compounds of the disclosure, or salts thereof, or crystalline forms of any of the aforementioned, can be prepared with a purity' of about 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more.

[3025] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[3026] The expressions, "ambient temperature" and "room temperature," as used herein, are understood m the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is earned out, for example, a temperature from about 20 °C to about 30 °C.

[3027] The present disclosure also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" or "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic Attorney Docket No.: SYND-063 / 001WO 43707-02984

[3028] inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (MeCN) are preferred.

[3029] The compounds disclosed herein include the compounds themselves, as well as their salts, their solvates, and their prodrugs, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., protonated amino) on a compound of this disclosure. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluroacetate). The term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a compound of this disclosure. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. The compounds of this disclosure also include those salts containing quaternary nitrogen atoms. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which, upon administration to a subject, are capable of providing active compounds of this disclosure.

[3030] Additionally, physiologically acceptable, i.e., pharmaceutically compatible, salts can be salts of the compounds disclosed herein with inorganic or organic acids. Preference is given to salts with inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or to salts with organic carboxylic or sulphonic acids, such as, for example, acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.

[3031] Other pharmaceutically compatible salts which may be mentioned are salts with customary bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts, derived from ammonia or organic amines, such as, for example, diethylamine, triethylamine, Attorney Docket No.: SYND-063 / 001WO 43707-02984

[3032] ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine or methylpiperidine.

[3033] As used herein, “pharmaceutically acceptable salts” can refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsamlic, hexyl resorcmic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[3034] Other examples of pharmaceutically acceptable salts can include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l-carboxylic acid, 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present m the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, or an alkaline earth metal ion, e.g., an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, diethylamine, diethylaminoethanol, ethylenediamine, imidazole, lysine, arginine, morpholine, 2-hydroxyethylmorpholine, dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine, tetramethylammonium hydroxide and the like. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[3035] It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

[3036] It is to be understood that, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to provide such treatment or prevention as is described herein. It is to be further understood, unless otherwise stated, any d escription of a method of treatment or prevention includes use of the compounds to prepare a medicament to treat or prevent such condition. The treatment or prevention includes treatment or prevention of human or non-human animals including rodents and other disease models.

[3037] It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment includes use of the compounds to prepare a medicament to treat such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models.

[3038] As used herein, the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In some embodiments, the subject is a human.

[3039] As used herein, the term “subject in need thereof’ refers to a subject having a disease or having an increased risk of developing the disease. A subject m need thereof can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy. Attorney Docket No.: SYND-063 / 001WO 43707-02984

[3040] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model. It is to be appreciated that references to “treating” or “treatment” include the alleviation of established symptoms of a condition. “Treating” or ...

Claims

Attorney Docket No.: SYND-063 / 001WO 43707-02984CLAIMSWhat is claimed is:

1. A compound of F ormula I ’,a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:denotes a single bond or a double bond, as valency permits;Bi, B2, D, and E are each independently selected from C(RA1)(RA2)-C(RA1)(RA2)-C(RA1)(RA2)-, -< RA1)(RA2)-- )--V--C(RA1)(RA2)-NA3--, C( O) -, -C(RA1)(RA2) -C(::::O) and --N:::C(Nf^) ’ wherein no more than one of Bi, B2, D, and E is --C(RA1)(RA2)-O-, -C(AI)(A2)--NRA3-, -C(RA1)(RA2)-C(===O)-, -C(=<))-, or -N===C(NH2)-;V is N or CRVwherein Rwis H, halo, CN, OH, C1-C4 alkyl, C1-C4 alkoxy, amino, C1-C4 alkyl ammo, or C2-C8 dialkylamino;X is N or CRX, wherein Rxis absent, H, halo, CN, OH, C1-C4 alkyl, C1-C4 alkoxy, amino, C1-C4 alkyl amino, or C2-C8 dialkylammo;each RAIis independently selected from absent, H, halo, C1-C4 alkyl, C1-C4 alkoxy, Ci-C4 haloalkyl, C1-C4 haloalkoxy, amino, C1-C4 alkylamino, C2-C8 dialkylamino, CN, NO2, and OH;each R'42is independently selected from H, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, amino, C1-C4 alkylamino, C2-C8 dialkylamino, CN, NO2, and OH;each R^ is independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C(O)RZ, and C(O)ORZ, wherein said C1-C4 alkyl is optionally substituted by phenyl, C1-C4 alkoxy, C1-C4 haloalkoxy, CN, NO2, or OH;Attorney Docket No.: SYND-063 / 001WO 43707-02984RZis H, C1-C4 alkyl, or phenyl;W is N or CH;Y is N or CH;R1is(a) -Ci-Cg alkylene-N(Rja’)(Rjb’) or -C3-C12 cycloalkylene-N(R3a’)(R3b’), wherein the Ci-Cg alkylene or C3-C12 cycloalkylene is optionally substituted with one or more R1as;each R1asis independently halo, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;(b) 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1bs;each R1bsis independently halo, oxo, OR3a’, Ci-Cg alkyl, Ci-Cg haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(:::O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’; or (c) C3-C12 cycloalkyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C12 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;each R1csis independently halo, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Cg alkoxy;R2is H, Ci-Cg alkyl, C2-C6 alkenyl, Cb-Cg alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-C10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Cg alkyl, C2-C6alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, C’g-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, or N(R4a’)(R4b’);Z is O, CH2, or NH;Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl or 6- to 10-membered heteroaryl is optionally substituted with one or more C1-C6 alkyl, halo, OH, CN, or C1-C6 alkoxy;X3is H or C1-C6alkyl, wherein the Ci-Cg alkyl is optionally substituted with one or more halo, OR43, oxo, CN, C(=O)N(R4a)(R4b), or N(R4a)(R4b);Attorney Docket No.: SYND-063 / 001WO 43707-02984R3is H, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-Cio aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, C(O)(R4a), or C(O)O-C(R4a)2-OC(O)(R4a), wherein the Ci-Cg alkyl, C2-C alkenyl, C2-Cg alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R3a; or R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected;each R3ais independently halo, OR4a, oxo, C(O)O(R4a), CN, C(=O)N(R4a)(R4b), OC(O)N(R4a)(R4b), S(=O)2R4b’, N(R4a)(R4b), Ci-Cg alkyl, C3-C12 cycloalkyl, Ci-C6alkoxy, Cg-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the Ci-Cg alkyl, C3-C12 cycloalkyl, Cg-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more substituent independently selected from halo, O(R4a’), oxo, CN, C(())OR4a’, OC(())N(R4a’)(R4b’), N(R4a’)(R4b’), N(R4a’)C(O)(R4b’), N(R4a’)C(O)O(R4b’), Ci-Cg alkyl that is optionally substituted with ()(R4a), and 3- to 12-membered heterocyclyl that is optionally substituted with oxo;each R4ais independently H, CN, or Ci-Cg alkyl optionally substituted with Cg-Cio aryl or N(R4a’)(R4b’);each R4bis independently H, S(===O)2R4b’, C(O)OR4b’, C(())R4b’, C(O)NR4a’R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-Cg alkyl, C3-C12 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Cg alkyl is optionally substituted with Ci-Cg alkoxy or C(O)N(R4a’)(R4b’);each R3a’ is independently H, Ci-Cg alkyl, Ci-Cg haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-C alkoxy;each R3b’ is independently H, Ci-Cg alkyl, Ci-Cg haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl;each R3C’ is independently H, Ci-Cg alkyl, Ci-Cg haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl;each R4a’ and R4b’ is independently H, Ci-Cg alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; andn is 1, 2, or 3.Attorney Docket No.: SYND-063 / 001WO 43707-029842. A compound of Formula I,a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:W is N or CH;Y is N or CH;R1is(a) -Ci-Ce alkylene-N(R'’a’)(R'’b’) or -C3-C12 cycloalkylene-N(R3a’)(R3b’), wherein the C1-C6 alkylene or C3-C12 cycloalkylene is optionally substituted with one or more R1as;each R1asis independently halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’;(b) 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1bs;each R1bsis independently halo, oxo, OR3a’, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’; or (c) C3-C12 cycloalkyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C12cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;each R1csis independently halo, oxo, Cj-Ce alkyl, C1-C6 haloalkyl, C( O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Cj-Ce alkoxy;Attorney Docket No.: SYND-063 / 001WO 43707-02984R2is H, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg-Cio aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, or N(R4a’)(R4b’);Z is O, CH2, or NH;Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl or 6- to 10-membered heteroaryl is optionally substituted with one or more C1-C6alkyl, halo, OH, CN, or C1-C6alkoxy;X3is H or C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with one or more halo, OR4a, oxo, CN, C(=O)N(R4a)(R4b), or N(R4a)(R4b);R3is H, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Cg alkoxy, C3-C12 cycloalkyl, Cg- Cio aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, C(O)(R4a), or C(O)O-C(R4a)2-OC(O)(R4a), wherein the Ci-C alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C12 cycloalkyl, Cg-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R3a; or R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected;each R3ais independently halo, OR4a, oxo, C(O)O(R4a), CN, C(=O)N(R4a)(R4b), ()C(O)N(R4a)(R4b), S(==O)2R4b’, N(R4a)(R4b), Ci-Cg alkyl, C3-C12 cycloalkyl, Ci-Cg alkoxy, Cg-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the Ci-C alkyl, C3-C12 cycloalkyl, Cg-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more substituent independently selected from halo, O(R4a’), oxo, CN, C(O)OR4a’, OC(O)N(R4a’)(R4b), N(R4a’)(R4b’), N(R4a’)C(O)(R4b’), N(R4a’)C(O)O(R4b’), Ci-Cg alkyl that is optionally substituted with O(R4a), and 3- to 12-membered heterocyclyl that is optionally substituted with oxo;each R4ais independently H, CN, or Ci-Cg alkyl optionally substituted with Cg-Cio aryl or N(R4a’)(R4b’);each R4bis independently H, S(=O)2R4b’, C(O)OR4b’, C(O)R4b’, C(O)NR4a’R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-Cg alkyl, C3-C12 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Ci-Cg alkyl is optionally substituted with Ci-Cg alkoxy or C(O)N(R4a’)(R4b’);Attorney Docket No.: SYND-063 / 001WO 43707-02984each R3a’ is independently H, Ci-Cg alkyl, Ci-Cg haloalkyl, C(O)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Cg alkoxy;each R3b’ is independently H, Ci-Cg alkyl, Ci-Cg haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl;each R3C’ is independently H, Ci-Cg alkyl, Ci-C haloalkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl;each R4a’ and R4b’ is independently H, Ci-Cg alkyl, Ci-Cn cycloalkyl, or 3- to 12-membered heterocyclyl; andn is 1, 2, or 3.A compound of Formula I -a,Formula I-a,a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:W is N or CH;Y is N or CH;R1is(a) -Ci-C6alkylene-N(R3a’)(R3b’) or -C3-C12 cycloalkylene-N(R3a’)(R3b’), wherein the Ci-Cg alkylene or C3-C12 cycloalkylene is optionally substituted with one or more R1as;each R1asis independently halo, oxo, Ci-Cg alkyl, Ci-Cg haloalkyl, C( O)(R3a’), N(R3a’)(R3b’), or S(==O)2R3a’;Attorney Docket No.: SYND-063 / 001WO 43707-02984(b) 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1bs;each R1bsis independently halo, oxo, OR3a’, Ci-C6 alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(=O)(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’; or (c) C3-C12 cycloalkyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C12 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;each R1csis independently halo, oxo, Cj-Cc, alkyl, Ci-Ce haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Cj-Ce alkoxy;R2is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, Cs-Cn cycloalkyl, Ce- C10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the Cj-Ce alkyl, C2-C.-. alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cw aryl, 5- to 10- membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more halo, OH, oxo, CN, or N(R4a’)(R4b’);Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl or 6- to 10-membered heteroaryl is optionally substituted with one or more C1-C6alkyl, halo, OH, CN, or C1-C6alkoxy;X3is H or C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with one or more halo, OR4a, oxo, CN, C(=O)N(R4a)(R4b), or N(R4a)(R4b);R3is H, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cw aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, C(O)(R4a), or C(O)O- C(R4a)2-OC(O)(R4a), wherein the Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, C3-C12 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl is optionally substituted with one or more R3a; or R3forms a 3- to 12-membered heterocyclyl with the carbon atom next to the nitrogen atom to which it is connected;each R3ais independently halo, OR4a, oxo, C(O)O(R4a), CN, C(=O)N(R4a)(R4b), OC(O)N(R4a)(R4b), S(=O)2R4b’, N(R4a)(R4b), Ci-C6alkyl, C3-C12 cycloalkyl, Ci-C6alkoxy, C6-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl,Attorney Docket No.: SYND-063 / 001WO 43707-02984C3-C12 cycloalkyl, Ce-Cio aryl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more substituent independently selected from halo, O(R4a’), oxo, CN, C(0)0R4a’, OC(O)N(R4a’)(R4b’), N(R4a’)(R4b’), N(R4a’)C(O)(R4b’), N(R4a’)C(O)O(R4b’), Ci-C6 alkyl that is optionally substituted with 0(R4a), and 3- to 12-membered heterocyclyl that is optionally substituted with oxo;each R4ais independently H, CN, or Ci-Ce alkyl optionally substituted with Ce-Cio aryl or N(R4a’)(R4b’);each R4bis independently H, S(=O)2R4b’, C(O)OR4b’, C(0)R4b’, C(O)NR4a’R4b’, C(O)CH2-N(R4a’)(R4b’), Ci-Cs alkyl, C3-C12 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein the C1-C6 alkyl is optionally substituted with C1-C6 alkoxy or C(O)N(R4a’)(R4b’);each R3a’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C(0)R3c’, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclyl are optionally substituted with Ci-Ce alkoxy;each R3b’ is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl;each3C’ IS independently H, Cj-Ce alkyl, Cj-Ce haloalkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl;each R4a’ and R4b’ is independently H, Ci-Ce alkyl, C3-C12 cycloalkyl, or 3- to 12- membered heterocyclyl; andn is 1, 2, or 3.

4. The compound of any one of the preceding claims, wherein W is N.

5. The compound of any one of the preceding claims, wherein W is CH.

6. The compound of any one of the preceding claims, wherein Y is N.

7. The compound of any one of the preceding claims, wherein Y is CH.Attorney Docket No.: SYND-063 / 001WO 43707-029848. The compound of any one of the preceding claims, wherein R2is Ci-Ce alkyl optionally substituted with one or more halo, OH, oxo, CN, or N(R4a’)(R4b’).

9. The compound of any one of the preceding claims, wherein R2is isopropyl.

10. The compound of any one of the preceding claims, wherein Z is O.11, The compound of any one of claims 1-10, wherein R1is -Ci-Ce alkylene-N(R3a’)(R3b’) wherein the Ci-Cr, alkylene is optionally substituted with one or more R1as;each R1asis independently halo, oxo, Ci-Ce alkyl, Ci-G> haloalkyl, C(:::O)(R3a’), N(R3a’)(R3b’), or S(==O)2R3a.A12. The compound of claim 11, wherein R1is or13, The compound of any one of claims 1-10, wherein R1is -C3-C12 cycloalkylene-N(R3a’)(R3b’), wherein the C3-C12 cycloalkylene is optionally substituted with one or more R1as;each R!asis independently halo, oxo, Ci-Ce alkyl, Ci-Ce haloalkyl, C(:::O)(RJa’), N(R3a,)(R3b’), or S(=O)2R3aAttorney Docket No.: SYND-063 / 001WO 43707-0298415. The compound of any one of claims 1-10, wherein R1is 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members, wherein the 3- to 12-membered heterocyclyl is optionally substituted with one or more Ribs; each Ribsis independently halo, oxo, OR3a’, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C12 cycloalkyl, 3- to 12-membered heterocyclyl, C(:::())(R3a’), N(R3a’)(R3b’), or S(=O)2R3a’.Attorney Docket No.: SYND-063 / 001WO 43707-0298417. The compound of any one of claims 1-10, wherein R1is C3-C12 cycloalkyl substituted with one or more 3- to 12-membered heterocyclyl which has at least one nitrogen and optionally one or more other heteroatom ring members; and wherein each of the C3-C12 cycloalkyl and the 3- to 12-membered heterocyclyl is optionally substituted with one or more R1cs;each Ricsis independently halo, oxo, Ci-Ce alkyl, C1-C6 haloalkyl, C(=O)(R3a’), N(R3a’)(R3b’), OR3a’, or S(=O)2R3a’, wherein the alkyl or haloalkyl is optionally substituted by one or more Ci-Ce alkoxy.Attorney Docket No.: SYND-063 / 001WO 43707-0298419. The compound of any one of the preceding claims, wherein Ring A is 6- to 10-membered aryl or 6- to 10-membered heteroaryl.

20. The compound of any one of claims 1-19, wherein Ring A isAttorney Docket No.: SYND-063 / 001WO 43707-0298424. The compound of claim 21, whereinAttorney Docket No.: SYND-063 / 001WO 43707-0298425. The compound of any one of claims 1-22, wherein X3is H or C1-C6alkyl.

26. The compound of any one of the preceding claims, wherein R3is C1-C6alkyl optionally substituted with C6-C10aryl, 3- to 12-membered heterocyclyl, or OR4a, and R4ais H, CN, or C1-C6alkyl.

27. The compound of any one of the preceding claims, wherein R3is methyl, ethyl, isopropyl or tert-butyl.

28. The compound of any one of claims 1-25, wherein R3is29. The compound of any one of claims 1-25, wherein R3is C(O)(R4a) or C(O)O-C(R4a)2-OC(O)(R4a), wherein:each R4ais independently H, CN, or Ci-Cg alkyl optionally substituted with Cg-Cio aryl or N(R4a’)(R4b’); andeach R4a’ and R4b’ is independently H, Ci-Cg alkyl, C3-C12 cycloalkyl, or 3- to 12-membered heterocyclyl.

30. The compound of any one of claims 1-25 and 29, wherein R3isAttorney Docket No.: SYND-063 / 001WO 43707-0298431. The compound of any one of claims 1-25, wherein R3is H.

32. The compound of any one of the preceding claims, wherein n is 1.

33. The compound of any one of claims 1-31, wherein n is 2.

34. A compound as shown in Table 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

35. A compound as shown in Table 1 or a pharmaceutically acceptable salt thereof.

36. A compound as shown in Table 1.

37. A compound as shown in Table 1 or a pharmaceutically acceptable salt thereof, wherein the salt is hydrochloride.

38. The compound according to any one of the preceding claims, wherein the compound is useful for the treatment of cancer and wherein the compound minimizes hERG binding.

39. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

40. A pharmaceutical composition comprising a salt or crystalline form of the compound of any one of claims 1 -38, and at least one pharmaceutically acceptable carrier,41. A method of inhibiting the interaction between menin and MIT, comprising contacting the menin and MLL with a compound of any one of claims 1-38 or the pharmaceutical composition of claim 39 or claim 40.Attorney Docket No.: SYND-063 / 001WO 43707-0298442. A method of treating cancer in a patient comprising administering to the patient a compound of any one of claims 1-38 or the pharmaceutical composition of claim 39 or claim 40.

43. The method of claim 42, wherein the cancer is a hematological cancer.

44. The method of claim 42, wherein the cancer is a leukemia or a lymphoma.

45. The method of claim 42, wherein the cancer is mixed lineage leukemia (MLL), MLL-related leukemia, MLL-associated leukemia, MLL-positive leukemia, MLL -induced leukemia, rearranged mixed lineage (KMT2A-rearranged) leukemia (MLL-r), leukemia associated with a MLL rearrangement or a rearrangement of the MLL gene, acute leukemia, chronic leukemia, indolent leukemia, lymphoblastic leukemia, lymphocytic leukemia, myeloid leukemia, myelogenous leukemia, childhood leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute granulocytic leukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), therapy related leukemia, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), myeloproliferative neoplasia (MI’N), plasma cell neoplasm, multiple myeloma, myelodysplasia, cutaneous T-cell lymphoma, lymphoid neoplasm, AIDS-related lymphoma, thymoma, thymic carcinoma, mycosis fungoides, Alibert-Bazm syndrome, granuloma fungoides, Sezary Syndrome, hairy cell leukemia, T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, meningeal leukemia, leukemic leptomeningitis, leukemic meningitis, multiple myeloma, Hodgkin's lymphoma, non Hodgkin's lymphoma (malignant lymphoma), or Waldenstrom's macroglobulinemia.

46. The method of claim 42, wherein the cancer is an abstract nucleophosmin (NPM1 )-mutated acute myeloid leukemia (i.e., NPM1mutacute myloid leukemia) or a rearranged mixed lineage (KMT2A-rearranged) leukemia (MLL-r).Attorney Docket No.: SYND-063 / 001WO 43707-0298447. The compound of any one of claims 1-38 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 39 or claim 40, for use in treating or preventing a disease caused by, or associated with, menin expression, activity, and / or function.

48. The compound of any one of claims 1-38 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 39 or claim 40, for use in treating or preventing cancer.

49. Use of the compound of any one of claims 1-38 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 39 or claim 40, for treating or preventing a disease caused by, or associated with, menin expression, activity, and / or function.

50. Use of the compound of any one of claims 1-38 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 39 or claim 40, in the manufacture of a medicament for treating or preventing a disease caused by, or associated with, menin expression, activity, and / or function.

51. Use of a compound of any of claims 1 -38 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 39 or claim 40, for treating or preventing cancer.

52. Use of the compound of any one of claims 1-38 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 39 or claim 40, in the manufacture of a medicament for treating or preventing cancer.

53. A kit comprising the compound of any one of claims 1 -38 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 39 or claim 40 and instructions for its use.

54. A method of preparing a compound of any one of claims 1-38 or a pharmaceutically acceptable salt thereof, according to a scheme of the present disclosure or synthetic description in the Examples.Attorney Docket No.: SYND-063 / 001WO 43707-0298455. An intermediate useful in the preparation of a compound of any one of claims 1-38 or a pharmaceutically acceptable salt thereof.

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