KRAS G12D modulating compounds

Abstract

Provided herein are compounds useful as KRAS G12D inhibitors and / or KRAS G12C inhibitors, and pharmaceutically acceptable salts thereof, methods of making and using the same (alone or in combination with additional drugs), and pharmaceutical compositions thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 333,347 filed on April 21, 2022, U.S. Provisional Application No. 63 / 353,726 filed on June 20, 2022, and U.S. Provisional Application No. 63 / 386,651 filed on December 8, 2022, which are incorporated herein in their entirety for all purposes. Background Art

[0003] The KRAS protein, Kirsten rat sarcoma 2 viral oncogene homolog ("KRAS"), is a GTPase. KRAS gene mutations have been observed in many conditions, including, for example, pancreatic cancer, endometrial cancer, lung adenocarcinoma, colorectal cancer, rectal cancer, gallbladder cancer, thyroid cancer, bile duct cancer, small cell lung cancer, and non-small cell lung cancer (NSCLC). Therefore, there is a need for compounds, pharmaceutical compositions, and methods for inhibiting KRAS (e.g., KRAS G12C and / or KRAS G12D) and treating related cancers. Summary of the Invention

[0004] In one embodiment, the present disclosure provides a compound of Formula I:

[0005]

[0006] or a pharmaceutically acceptable salt thereof,

[0007] in

[0008] X is N, CH or CR x ;

[0009] R x (CH2) m CN or halide;

[0010] m is 0, 1, 2, or 3;

[0011] R 1 、R 2 、R 3 and R 4 Each independently is H or C1-C3 alkyl;

[0012] L 1 O, S or CR 1a R 1b ;

[0013] R 1a and R 1bEach is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, C1-C3 cyanoalkyl or C3-C6 cycloalkyl;

[0014] Alternatively, R 1a and R 1b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0015] L 2 CR 2a R 2b ;

[0016] Alternatively, L 2 is O or S, and L 1 CR 1a R 1b ;

[0017] R 2a and R 2b Each is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, C1-C3 cyanoalkyl or C3-C6 cycloalkyl;

[0018] Alternatively, R 2a and R 2b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0019] Alternatively, R 1b and R 2b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0020] L 3 key or CR 3a R 3b ;

[0021] R 3a and R 3b Each is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, C1-C3 cyanoalkyl or C3-C6 cycloalkyl;

[0022] Alternatively, R 3a and R 3b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0023] Alternatively, R 2b and R 3b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0024] R A is phenyl or naphthyl, wherein R A 0, 1, 2, 3, 4 or 5 R A2 replace;

[0025] Each R A2 are independently -OH, C1-C 10 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C 10 Alkoxy, C1-C 10 Hydroxyalkyl, C2-C 10 Alkoxyalkyl, C1-C6 alkyl-N(R A2a )(R A2b ), C1-C 10 Thioalkyl, halogen, C1-C6 haloalkyl, -CN, -C(O)R A2a 、-C(O)OR A2a 、-OC(O)R A2a 、-OC(O)OR A2a 、-C(O)N(R A2a )(R A2b )、-N(R A2a )C(O)(R A2b )、-OC(O)N(R A2a )(R A2b )、-N(R A2a )C(O)(OR A2b ), oxo, -OR A2a 、-SR A2a 、-S(O)2R A2a 、-S(O)2OR A2a 、-N(R A2a )(R A2b )、-(C0-C3 alkyl)-SF5、-OP(O)(OR A2a )(OR A2b ), C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C3-C8 cycloalkyl), 3- to 14-membered heterocyclic group, -(C1-C6 alkyl)-(3- to 14-membered heterocyclic group), C6-C 14 Aryl, -(C1-C6 alkyl)-(C6-C 14 aryl), 5- to 14-membered heteroaryl, or -(C1-C6 alkyl)-(5- to 14-membered heteroaryl), wherein each alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, and haloalkyl group is replaced by 0, 1, 2, or 3 R A3 substituted, and wherein each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl and alkyl-heteroaryl is replaced by 0, 1, 2 or 3 R A4 replace;

[0026] Each R A2a and R A2b are independently H, C1-C 10 Alkyl, C1-C6 haloalkyl or C3-C8 cycloalkyl;

[0027] Each R A3 are independently halogen, -CN, -OR A3a 、-SR A3a 、-N(R A3a )(R A3b ), C3-C8 cycloalkyl or 5- to 14-membered heteroaryl;

[0028] Each R A3a and R A3b are independently H, C1-C 10 Alkyl, C1-C6 haloalkyl or C3-C8 cycloalkyl;

[0029] Each R A4 C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkylthio, C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C6-C 10 aryl), halogen, -CN, -OH or -N(R A4a )(R A4b );

[0030] Each R A4a and R A4b are independently H or C1-C6 alkyl;

[0031] Alternatively, in R A On two adjacent atoms, two R A2 Can combine to form C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocyclyl, or 5- to 14-membered heteroaryl;

[0032] R B H, -C(O)R B1 or-C(O)OR B2 ;

[0033] R B1 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl, wherein C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl is substituted with 0, 1, 2 or 3 R B1a replace;

[0034] R B2 C1-C6 alkyl, C1-C6 haloalkyl, (C1-C6 alkyl)-OC(O)R B3 , C3-C8 cycloalkyl, C6-C 14 aryl, 5- to 14-membered heteroaryl, or

[0035]

[0036] wherein the C3-C8 cycloalkyl, the C6-C 14 The aryl group or the 5- to 14-membered heteroaryl group is replaced by 0, 1, 2 or 3 R B2a replace;

[0037] R B3 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl, wherein C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl is substituted with 0, 1, 2 or 3 R B3a replace;

[0038] Each R B1a 、R B2a and R B3a C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkoxyalkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, oxo, -OH, -CN or C3-C 10 Cycloalkyl;

[0039] L C For key or

[0040]

[0041] Y is C or Si;

[0042] n is 0, 1, 2, or 3;

[0043] q is 0, 1, 2, or 3;

[0044] R Y1 is H or C1-C3 alkyl;

[0045] R Y2 is H or C1-C3 alkyl;

[0046] Alternatively, R Y1 and R Y2 Combined to form C3-C 10 a cycloalkyl group or a 3- to 10-membered heterocyclic group;

[0047] RC H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, -NH2, -NHR C1 、-N(R C1 )2, C3-C8 cycloalkyl, 3- to 14-membered heterocyclic group, C6-C 14 aryl or 5- to 14-membered heteroaryl, wherein each C3-C8 cycloalkyl, 3- to 14-membered heterocyclyl, C6-C 14 Aryl and 3- to 14-membered heteroaryl groups are substituted with 0, 1, 2, 3, or 4 R C3 replace;

[0048] Each R C1 Independently selected from C1-C6 alkyl;

[0049] Each R C3 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C8 alkynyl, C1-C6 alkoxyalkyl, C1-C6 hydroxyalkyl, halo, C1-C6 haloalkyl, C1-C6 heteroalkyl, -(C1-C6 alkyl)-N(R C3a )(R C3b )、-CN、-C(O)R C3a 、-C(O)OR C3a 、-C(O)N(R C3a )(R C3b )、-N(R C3a )C(O)(R C3b )、-OC(O)N(R C3a )(R C3b )、-N(R C3a )C(O)(OR C3b ), =CH2, =CF2, oxo, -OR C3a 、-SR C3a 、-N(R C3a )(R C3b ), -N3, SF5, C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C3-C8 cycloalkyl), 3- to 10-membered heterocyclic group, -(C1-C6 alkyl)-(3- to 10-membered heterocyclic group), C6-C 10 Aryl, -(C1-C6 alkyl)-(C6-C 10 aryl), 5- to 10-membered heteroaryl, or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), wherein each alkyl is replaced by 0, 1, 2, or 3 -CN, -C(O)OR C3a1 、-C(O)N(R C3a1 )(R C3a2 )、-N(R C3a1)C(O)(R C3a2 )、-OC(O)N(R C3a1 )(R C3a2 ),-OR C3a1 、-SR C3a1 , N3, SF5 or 0, 1, 2 or 3 3R C3a2 substituted 3- to 10-membered heterocyclyl, each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl and alkyl-heteroaryl being replaced by 0, 1, 2 or 3 halo, -CN or R C3a2 substituted, each alkenyl group is substituted by 0, 1, 2 or 3 halo groups, and each alkoxyalkyl and alkynyl group is substituted by 0, 1, 2 or 3 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl substituted by 0 or 1 C1-C6 haloalkyl, C6-C 10 substituted with aryl or 5- to 10-membered heteroaryl;

[0050] Each R C3a and R C3b are independently H, C1-C 10 Alkyl, C1-C6 haloalkyl, C6-C 10 Aryl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein each aryl and heteroaryl is substituted by 0, 1, 2 or 3 halogen, -CN or R C3a2 replace;

[0051] Alternatively, R C3a and R C3b Together with the nitrogen to which they are attached, they form a 3- to 8-membered heterocyclic ring;

[0052] Each R C3a1 and R C3a2 C1-C3 alkyl, halo, C1-C6 haloalkyl, C3-C8 cycloalkyl, -(C1-C3 alkyl)-(C3-C8 cycloalkyl), 3- to 10-membered heterocyclyl, -(C1-C3 alkyl)-(3- to 10-membered heterocyclyl), C6-C 10 Aryl, -(C1-C3 alkyl)-(C6-C 10 Aryl), -(C2-C4 alkynyl)-(C6-C 10 aryl), 5- to 10-membered heteroaryl, -(C1-C3 alkyl)-(5- to 10-membered heteroaryl), or SF5, wherein each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, alkynyl-aryl, heteroaryl and alkyl-heteroaryl is substituted with 0, 1, 2 or 3 halo, C1-C3 haloalkyl, C1-C3 haloalkoxy or SF5;

[0053] Alternatively, R C3a1and R C3a2 Together with the nitrogen to which they are attached, they form a 3- to 8-membered heterocyclic ring;

[0054] R D is a halogen group;

[0055] Each heterocyclyl group has 1, 2, 3 or 4 heteroatoms selected from N, O, S and Si; and

[0056] Each heteroaryl group has 1, 2, 3 or 4 heteroatoms selected from N, O and S.

[0057] In one embodiment, the present disclosure provides a compound of Formula IA:

[0058]

[0059] or a pharmaceutically acceptable salt thereof, wherein

[0060] X is N, CH or CR x ;

[0061] R x (CH2) m CN or halide;

[0062] m is 0, 1, 2, or 3;

[0063] L 1 O, S or CR 1a R 1b ;

[0064] R 1a and R 1b Each is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, C1-C3 cyanoalkyl or C3-C6 cycloalkyl;

[0065] Alternatively, R 1a and R 1b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0066] L 2 CR 2a R 2b ;

[0067] Alternatively, L 2 is O or S, and L 1 CR 1a R 1b ;

[0068] R 2a and R 2bEach is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, C1-C3 cyanoalkyl or C3-C6 cycloalkyl;

[0069] Alternatively, R 2a and R 2b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0070] Alternatively, R 1b and R 2b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0071] L 3 key or CR 3a R 3b ;

[0072] R 3a and R 3b Each is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, C1-C3 cyanoalkyl or C3-C6 cycloalkyl;

[0073] Alternatively, R 3a and R 3b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0074] Alternatively, R 2b and R 3b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0075] R A is phenyl or naphthyl, wherein R A 0, 1, 2, 3, 4 or 5 R A2 replace;

[0076] Each R A2 are independently -OH, C1-C 10 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C 10 Alkoxy, C1-C 10 Hydroxyalkyl, C2-C 10 Alkoxyalkyl, C1-C6 alkyl-N(R A2a )(R A2b ), C1-C 10 Thioalkyl, halogen, C1-C6 haloalkyl, -CN, -C(O)R A2a 、-C(O)OR A2a 、-OC(O)R A2a 、-OC(O)ORA2a 、-C(O)N(R A2a )(R A2b )、-N(R A2a )C(O)(R A2b )、-OC(O)N(R A2a )(R A2b )、-N(R A2a )C(O)(OR A2b ), oxo, -OR A2a 、-SR A2a 、-S(O)2R A2a 、-S(O)2OR A2a 、-N(R A2a )(R A2b )、-(C0-C3 alkyl)-SF5、-OP(O)(OR A2a )(OR A2b ), C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C3-C8 cycloalkyl), 3- to 14-membered heterocyclic group, -(C1-C6 alkyl)-(3- to 14-membered heterocyclic group), C6-C 14 Aryl, -(C1-C6 alkyl)-(C6-C 14 aryl), 5- to 14-membered heteroaryl, or -(C1-C6 alkyl)-(5- to 14-membered heteroaryl), wherein each alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, and haloalkyl group is replaced by 0, 1, 2, or 3 R A3 substituted, and wherein each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl and alkyl-heteroaryl is replaced by 0, 1, 2 or 3 R A4 replace;

[0077] Each R A2a and R A2b are independently H, C1-C 10 Alkyl, C1-C6 haloalkyl or C3-C8 cycloalkyl;

[0078] Each R A3 are independently halogen, -CN, -OR A3a 、-SR A3a 、-N(R A3a )(R A3b ), C3-C8 cycloalkyl or 5- to 14-membered heteroaryl;

[0079] Each R A3a and R A3b are independently H, C1-C 10 Alkyl, C1-C6 haloalkyl or C3-C8 cycloalkyl;

[0080] Each RA4 C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkylthio, C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C6-C 10 aryl), halogen, -CN, -OH or -N(R A4a )(R A4b );

[0081] Each R A4a and R A4b are independently H or C1-C6 alkyl;

[0082] Alternatively, in R A On two adjacent atoms, two R A2 Can combine to form C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocyclyl, or 5- to 14-membered heteroaryl;

[0083] R B H, -C(O)R B1 or-C(O)OR B2 ;

[0084] R B1 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl, wherein C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl is substituted with 0, 1, 2 or 3 R B1a replace;

[0085] R B2 C1-C6 alkyl, C1-C6 haloalkyl, (C1-C6 alkyl)-OC(O)R B3 , C3-C8 cycloalkyl, C6-C 14 aryl, 5- to 14-membered heteroaryl, or

[0086]

[0087] wherein the C3-C8 cycloalkyl, the C6-C 14 The aryl group or the 5- to 14-membered heteroaryl group is replaced by 0, 1, 2 or 3 R B2a replace;

[0088] R B3 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl, wherein C3-C8 cycloalkyl, C6-C14 Aryl or 5- to 14-membered heteroaryl is substituted with 0, 1, 2 or 3 R B3a replace;

[0089] Each R B1a 、R B2a and R B3a C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkoxyalkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, oxo, -OH, -CN or C3-C 10 Cycloalkyl;

[0090] L C For key or

[0091]

[0092] Y is C or Si;

[0093] n is 0, 1, 2, or 3;

[0094] q is 0, 1, 2, or 3;

[0095] R Y1 is H or C1-C3 alkyl;

[0096] R Y2 is H or C1-C3 alkyl;

[0097] Alternatively, R Y1 and R Y2 Combined to form C3-C 10 a cycloalkyl group or a 3- to 10-membered heterocyclic group;

[0098] R C H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, -NH2, -NHR C1 、-N(R C1 )2, C3-C8 cycloalkyl, 3- to 14-membered heterocyclic group, C6-C 14 aryl or 5- to 14-membered heteroaryl, wherein each C3-C8 cycloalkyl, 3- to 14-membered heterocyclyl, C6-C 14 Aryl and 3- to 14-membered heteroaryl groups are substituted with 0, 1, 2, or 3 R C3 replace;

[0099] Each R C1 Independently selected from C1-C6 alkyl;

[0100] Each R C3are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C8 alkynyl, C1-C6 alkoxyalkyl, C1-C6 hydroxyalkyl, halo, C1-C6 haloalkyl, C1-C6 heteroalkyl, -(C1-C6 alkyl)-N(R C3a )(R C3b )、-CN、-C(O)R C3a 、-C(O)OR C3a 、-C(O)N(R C3a )(R C3b )、-N(R C3a )C(O)(R C3b )、-OC(O)N(R C3a )(R C3b )、-N(R C3a )C(O)(OR C3b ), =CH2, =CF2, oxo, -OR C3a 、-SR C3a 、-N(R C3a )(R C3b ), -N3, SF5, C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C3-C8 cycloalkyl), 3- to 10-membered heterocyclic group, -(C1-C6 alkyl)-(3- to 10-membered heterocyclic group), C6-C 10 Aryl, -(C1-C6 alkyl)-(C6-C 10 aryl), 5- to 10-membered heteroaryl, or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), wherein each alkyl is replaced by 0, 1, 2, or 3 -CN, -C(O)OR C3a1 、-C(O)N(R C3a1 )(R C3a2 )、-N(R C3a1 )C(O)(R C3a2 )、-OC(O)N(R C3a1 )(R C3a2 ),-OR C3a1 、-SR C3a1 , N3, SF5 or 0, 1, 2 or 3 3R C3a2 substituted 3- to 10-membered heterocyclyl, each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl and alkyl-heteroaryl being replaced by 0, 1, 2 or 3 halo, -CN or R C3a2 substituted, each alkenyl group is substituted by 0, 1, 2 or 3 halo groups, and each alkoxyalkyl and alkynyl group is substituted by 0, 1, 2 or 3 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl substituted by 0 or 1 C1-C6 haloalkyl, C6-C 10 substituted with aryl or 5- to 10-membered heteroaryl;

[0101] Each R C3a and R C3b are independently H, C1-C 10 Alkyl, C1-C6 haloalkyl, C6-C 10 Aryl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein each aryl and heteroaryl is substituted by 0, 1, 2 or 3 halogen, -CN or R C3a2 replace;

[0102] Alternatively, R C3a and R C3b Together with the nitrogen to which they are attached, they form a 3- to 8-membered heterocyclic ring;

[0103] Each R C3a1 and R C3a2 C1-C3 alkyl, halo, C1-C6 haloalkyl, C3-C8 cycloalkyl, -(C1-C3 alkyl)-(C3-C8 cycloalkyl), 3- to 10-membered heterocyclyl, -(C1-C3 alkyl)-(3- to 10-membered heterocyclyl), C6-C 10 Aryl, -(C1-C3 alkyl)-(C6-C 10 Aryl), -(C2-C4 alkynyl)-(C6-C 10 aryl), 5- to 10-membered heteroaryl, -(C1-C3 alkyl)-(5- to 10-membered heteroaryl), or SF5, wherein each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, alkynyl-aryl, heteroaryl and alkyl-heteroaryl is substituted with 0, 1, 2, 3 or 4 halo, C1-C3 haloalkyl, C1-C3 haloalkoxy or SF5;

[0104] Alternatively, R C3a1 and R C3a2 Together with the nitrogen to which they are attached, they form a 3- to 8-membered heterocyclic ring;

[0105] R D is a halogen group;

[0106] Each heterocyclyl group has 1, 2, 3 or 4 heteroatoms selected from N, O, S and Si; and

[0107] Each heteroaryl group has 1, 2, 3 or 4 heteroatoms selected from N, O and S.

[0108] In one embodiment, the present disclosure provides a compound of Formula II:

[0109]

[0110] or a pharmaceutically acceptable salt thereof, wherein

[0111] X is N, CH or CR x ;

[0112] R x (CH2) m CN or halide;

[0113] m is 0, 1, 2, or 3;

[0114] L 1 O or CR 1a R 1b ;

[0115] R 1a and R 1b Each is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, C1-C3 cyanoalkyl or C3-C6 cycloalkyl;

[0116] Alternatively, R 1a and R 1b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0117] L 2 CR 2a R 2b ;

[0118] R 2a and R 2b Each is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, C1-C3 cyanoalkyl or C3-C6 cycloalkyl;

[0119] Alternatively, R 2a and R 2b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0120] Alternatively, R 1b and R 2b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0121] R A is phenyl or naphthyl, wherein R A 0, 1, 2, 3, 4 or 5 R A2 replace;

[0122] Each R A2 are independently -OH, C1-C 10 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C 10 Alkoxy, C1-C 10 Hydroxyalkyl, C2-C10 Alkoxyalkyl, C1-C6 alkyl-N(R A2a )(R A2b ), C1-C 10 Thioalkyl, halogen, C1-C6 haloalkyl, -CN, -C(O)R A2a 、-C(O)OR A2a 、-OC(O)R A2a 、-OC(O)OR A2a 、-C(O)N(R A2a )(R A2b )、-N(R A2a )C(O)(R A2b )、-OC(O)N(R A2a )(R A2b )、-N(R A2a )C(O)(OR A2b ), oxo, -OR A2a 、-SR A2a 、-S(O)2R A2a 、-S(O)2OR A2a 、-N(R A2a )(R A2b )、-(C0-C3 alkyl)-SF5、-OP(O)(OR A2a )(OR A2b ), C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C3-C8 cycloalkyl), 3- to 14-membered heterocyclic group, -(C1-C6 alkyl)-(3- to 14-membered heterocyclic group), C6-C 14 Aryl, -(C1-C6 alkyl)-(C6-C 14 aryl), 5- to 14-membered heteroaryl, or -(C1-C6 alkyl)-(5- to 14-membered heteroaryl), wherein each alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, and haloalkyl group is replaced by 0, 1, 2, or 3 R A3 substituted, and wherein each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl and alkyl-heteroaryl is replaced by 0, 1, 2 or 3 R A4 replace;

[0123] Each R A2a and R A2b are independently H, C1-C 10 Alkyl, C1-C6 haloalkyl or C3-C8 cycloalkyl;

[0124] Each R A3 are independently halogen, -CN, -OR A3a 、-SR A3a 、-N(R A3a )(RA3b ), C3-C8 cycloalkyl or 5- to 14-membered heteroaryl;

[0125] Each R A3a and R A3b are independently H, C1-C 10 Alkyl, C1-C6 haloalkyl or C3-C8 cycloalkyl;

[0126] Each R A4 C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkylthio, C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C6-C 10 aryl), halogen, -CN, -OH or -N(R A4a )(R A4b );

[0127] Each R A4a and R A4b are independently H or C1-C6 alkyl;

[0128] Alternatively, in R A On two adjacent atoms, two R A2 Can combine to form C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocyclyl, or 5- to 14-membered heteroaryl;

[0129] R B H, -C(O)R B1 or-C(O)OR B2 ;

[0130] R B1 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl, wherein C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl is substituted with 0, 1, 2 or 3 R B1a replace;

[0131] R B2 C1-C6 alkyl, C1-C6 haloalkyl, (C1-C6 alkyl)-OC(O)R B3 , C3-C8 cycloalkyl, C6-C 14 aryl, 5- to 14-membered heteroaryl, or

[0132]

[0133] wherein the C3-C8 cycloalkyl, the C6-C14 The aryl group or the 5- to 14-membered heteroaryl group is replaced by 0, 1, 2 or 3 R B2a replace;

[0134] R B3 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl, wherein C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl is substituted with 0, 1, 2 or 3 R B3a replace;

[0135] Each R B1a 、R B2a and R B3a C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkoxyalkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, oxo, -OH, -CN or C3-C 10 Cycloalkyl;

[0136] L C For key or

[0137]

[0138] Y is C or Si;

[0139] n is 0, 1, 2, or 3;

[0140] q is 0, 1, 2, or 3;

[0141] R Y1 is H or C1-C3 alkyl;

[0142] R Y2 is H or C1-C3 alkyl;

[0143] Alternatively, R Y1 and R Y2 Combined to form C3-C 10 a cycloalkyl group or a 3- to 10-membered heterocyclic group;

[0144] R C H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, -NH2, -NHR C1 、-N(R C1 )2, C3-C8 cycloalkyl, 3- to 14-membered heterocyclic group, C6-C 14 aryl or 5- to 14-membered heteroaryl, wherein each C3-C8 cycloalkyl, 3- to 14-membered heterocyclyl, C6-C 14Aryl and 3- to 14-membered heteroaryl groups are substituted with 0, 1, 2, or 3 R C3 replace;

[0145] Each R C1 Independently selected from C1-C6 alkyl;

[0146] Each R C3 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C8 alkynyl, C1-C6 alkoxyalkyl, C1-C6 hydroxyalkyl, halo, C1-C6 haloalkyl, C1-C6 heteroalkyl, -(C1-C6 alkyl)-N(R C3a )(R C3b )、-CN、-C(O)R C3a 、-C(O)OR C3a 、-C(O)N(R C3a )(R C3b )、-N(R C3a )C(O)(R C3b )、-OC(O)N(R C3a )(R C3b )、-N(R C3a )C(O)(OR C3b ), =CH2, =CF2, oxo, -OR C3a 、-SR C3a 、-N(R C3a )(R C3b ), -N3, SF5, C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C3-C8 cycloalkyl), 3- to 10-membered heterocyclic group, -(C1-C6 alkyl)-(3- to 10-membered heterocyclic group), C6-C 10 Aryl, -(C1-C6 alkyl)-(C6-C 10 aryl), 5- to 10-membered heteroaryl, or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), wherein each alkyl is replaced by 0, 1, 2, or 3 -CN, -C(O)OR C3a1 、-C(O)N(R C3a1 )(R C3a2 )、-N(R C3a1 )C(O)(R C3a2 )、-OC(O)N(R C3a1 )(R C3a2 ),-OR C3a1 、-SR C3a1 , N3, SF5 or 0, 1, 2 or 3 3R C3a2 substituted 3- to 10-membered heterocyclyl, each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl and alkyl-heteroaryl being replaced by 0, 1, 2 or 3 halo, -CN or RC3a2 substituted, each alkenyl group is substituted by 0, 1, 2 or 3 halo groups, and each alkoxyalkyl and alkynyl group is substituted by 0, 1, 2 or 3 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl substituted by 0 or 1 C1-C6 haloalkyl, C6-C 10 substituted with aryl or 5- to 10-membered heteroaryl;

[0147] Each R C3a and R C3b are independently H, C1-C 10 Alkyl, C1-C6 haloalkyl, C6-C 10 Aryl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein each aryl and heteroaryl is substituted by 0, 1, 2 or 3 halogen, -CN or R C3a2 replace;

[0148] Alternatively, R C3a and R C3b Together with the nitrogen to which they are attached, they form a 3- to 8-membered heterocyclic ring;

[0149] Each R C3a1 and R C3a2 C1-C3 alkyl, halo, C1-C6 haloalkyl, C3-C8 cycloalkyl, -(C1-C3 alkyl)-(C3-C8 cycloalkyl), 3- to 10-membered heterocyclyl, -(C1-C3 alkyl)-(3- to 10-membered heterocyclyl), C6-C 10 Aryl, -(C1-C3 alkyl)-(C6-C 10 Aryl), -(C2-C4 alkynyl)-(C6-C 10 aryl), 5- to 10-membered heteroaryl, -(C1-C3 alkyl)-(5- to 10-membered heteroaryl), or SF5, wherein each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, alkynyl-aryl, heteroaryl and alkyl-heteroaryl is substituted with 0, 1, 2, 3 or 4 halo, C1-C3 haloalkyl, C1-C3 haloalkoxy or SF5;

[0150] Alternatively, R C3a1 and R C3a2 Together with the nitrogen to which they are attached, they form a 3- to 8-membered heterocyclic ring;

[0151] R D is a halogen group;

[0152] Each heterocyclyl group has 1, 2, 3 or 4 heteroatoms selected from N, O, S and Si; and

[0153] Each heteroaryl group has 1, 2, 3 or 4 heteroatoms selected from N, O and S.

[0154] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient.

[0155] In another embodiment, the present disclosure provides a method of inhibiting KRAS G12D protein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0156] In another embodiment, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0157] In another embodiment, the present disclosure provides a method for manufacturing a medicament for treating cancer in a subject in need thereof, characterized by using a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0158] In another embodiment, the present disclosure provides a method for manufacturing a medicament for inhibiting cancer metastasis in a subject in need thereof, characterized by using a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0159] In another embodiment, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.

[0160] In another embodiment, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting cancer metastasis in a subject.

[0161] In another embodiment, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof.

[0162] In another embodiment, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in inhibiting cancer metastasis in a subject in need thereof.

[0163] In another embodiment, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0164] Also disclosed herein are compounds of subformulas of Formula I, IA, and II, and pharmaceutically acceptable salts thereof, such as Formula (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2). DETAILED DESCRIPTION

[0165] I. Overview

[0166] The present disclosure generally relates to methods for inhibiting KRAS G12D and / or KRAS G12C The following description sets forth exemplary methods, parameters, etc. However, it should be recognized that such description is not intended to limit the scope of the present disclosure, but is provided as a description of exemplary embodiments.

[0167] II. Definitions

[0168] As used in this specification, the following words, phrases, and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0169] A dash ("-") that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -CONH2 is attached through a carbon atom. Dashes at the beginning or end of a chemical group are for convenience; a chemical group can be depicted without one or more dashes without losing its ordinary meaning. A wavy line drawn through a line in a structure indicates the point of attachment of a group. Unless required by chemistry or structure, directionality is not indicated or implied by the order in which chemical groups are written or named.

[0170] For example, the wavy lines on the chemical groups shown below, The point of attachment is indicated, ie, it shows the broken bond through which the group is connected to the other described group.

[0171] As used herein, "a compound of the present disclosure" may refer to a compound of any one of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), and (IIb-2), or a pharmaceutically acceptable salt thereof. Similarly, the phrase "a compound of formula (number)" means a compound of that formula and a pharmaceutically acceptable salt thereof.

[0172] The prefix "C u- C v " indicates that the following group has u to v carbon atoms. For example, "C 1-8 "Alkyl" indicates that the alkyl group has 1 to 8 carbon atoms.

[0173] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1-C 20Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH), ethyl (Et, -CHCH), 1-propyl (n-Pr, n-propyl, -CHCHCH), 2-propyl (i-Pr, isopropyl, -CH(CH)), 1-butyl (n-Bu, n-butyl, -CHCHCHCH), 2-methyl-1-propyl (i-Bu, isobutyl, -CHCH(CH)), 2-butyl (s-Bu, sec-butyl, -C H(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1 -butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (- )2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3). Other alkyl groups include, but are not limited to, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl.

[0174] "Alkenyl" refers to a straight or branched hydrocarbon chain containing at least two carbon atoms and at least one carbon-carbon double bond. As used herein, an alkenyl group can have from 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl) or 2 to 4 carbon atoms (ie, C 2-4Alkenyl). Alkenyl may include any number of carbon atoms, such as C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 、C 18 、C 19 、C 20 or any range therein. The alkenyl group may have any suitable number of double bonds, including but not limited to 1, 2, 3, 4, 5, or more. Examples of alkenyl groups include but are not limited to ethenyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl.

[0175] "Alkynyl" refers to a hydrocarbon chain containing at least one carbon-carbon triple bond, whether straight or branched. For example, an alkynyl group can have 2 to 20 carbon atoms (i.e., C 2-20 Alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 Alkynyl), 2 to 6 carbon atoms (ie, C 2-6 Alkynyl), or 2 to 4 carbon atoms (ie, C 2-4 The term "alkynyl" also includes those groups having one triple bond and one double bond. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-4-ynyl, and pent-1,4-diynyl.

[0176] "Alkoxy" means an alkyl group having the formula -O-, wherein the alkyl group as defined above is attached to the parent molecule via an oxygen atom. The alkyl portion of the alkoxy group may have from 1 to 20 carbon atoms (i.e., C1-C 20 alkoxy), 1 to 12 carbon atoms (i.e., C1-C 12 Suitable alkoxy groups include, but are not limited to, methoxy (-O-CH or -OMe), ethoxy (-OCHCH or -OEt), isopropoxy (-O-CH(CH)), tert-butoxy (-OC(CH) or -OtBu), and the like. Other examples of suitable alkoxy groups include, but are not limited to, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0177] "Alkoxyalkyl" refers to an alkoxy group attached to an alkyl group, which is attached to the rest of the compound. Alkoxyalkyl groups can have any suitable number of carbon atoms, such as 2 to 6 (C 2-6 alkoxyalkyl), 2 to 5 (C 2-5 Alkoxyalkyl), 2 to 4 (C 2-4 alkoxyalkyl), or 2 to 3 (C 2-3 Alkoxyalkyl). Alkoxy and alkyl are as defined above. Examples of "alkoxyalkyl" include, but are not limited to, methoxymethyl (CH3OCH2-) and methoxyethyl (CH3OCH2CH2).

[0178] "Bridged" means a ring system in which non-adjacent atoms in the ring are connected through a divalent substituent, such as an alkylene or heteroalkylene group or a single heteroatom.

[0179] "Hydroxyalkyl" refers to a hydroxyl group -OH attached to an alkyl group that is attached to the rest of the compound, such that the alkyl group is divalent. The hydroxyalkyl group can have any suitable number of carbon atoms, such as 1 to 8 (C 1-8 hydroxyalkyl), 1 to 6 (C 1-6 hydroxyalkyl), 2 to 6 (C 2-6 hydroxyalkyl), 2 to 4 (C 2-4 hydroxyalkyl), or 2 to 3 (C 2-3 Alkyl is as defined above, wherein the alkyl group is divalent.

[0180] As used herein, "halo" or "halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (-I).

[0181] "Haloalkyl" is an alkyl group as defined above in which one or more of the hydrogen atoms of the alkyl group is replaced by a halogen atom. The alkyl portion of the haloalkyl group may have from 1 to 20 carbon atoms (i.e., C1-C 20 haloalkyl), 1 to 12 carbon atoms (i.e., C1-C 12 The alkyl group may be substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, or more halogens. Examples of suitable haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CFH2, -CH2CF3, fluorochloromethyl, difluorochloromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0182] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced by halogen atoms. With respect to alkyl groups, a haloalkoxy group can have any suitable number of carbon atoms, such as C 1-6 Alkoxy groups can be substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9 or more halogens. When all hydrogens are replaced by halogens (e.g., fluorine), the compound is fully substituted, e.g., perfluorinated. Haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, and the like.

[0183] "Thioalkyl" refers to a thio group -SH attached to an alkyl group that is attached to the rest of the compound, such that the alkyl group is divalent. The thioalkyl group can have any suitable number of carbon atoms, such as 1 to 8 (C 1-8 Thioalkyl), 1 to 6 (C 1-6 Thioalkyl), 2 to 6 (C 2-6 thioalkyl), 2 to 4 (C 2-4 thioalkyl), or 2 to 3 (C 2-3 Alkyl is as defined above, wherein the alkyl group is divalent.

[0184] "Haloalkylthio" is an alkylthio group as defined above in which one or more hydrogen atoms of the alkyl group are replaced by a halogen atom. The alkyl portion of the haloalkylthio group may have 1 to 20 carbon atoms (i.e., C1-C 20 haloalkylthio), 1 to 12 carbon atoms (i.e., C1-C 12 The alkylthio group may be substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9 or more halogens.

[0185] "Heteroalkyl" refers to an unbranched or branched saturated hydrocarbon chain containing 1 to 4 heteroatoms.

[0186] "Cyanoalkyl" refers to a cyano group, -CN, attached to an alkyl group attached to the rest of the compound such that the alkyl group is divalent. The cyanoalkyl group can have any suitable number of carbon atoms, such as 1 to 8 (C 1-8 cyanoalkyl), 1 to 6 (C 1-6 cyanoalkyl), 2 to 6 (C 2-6 cyanoalkyl), 2 to 4 (C 2-4 cyanoalkyl), or 2 to 3 (C 2-3 Alkyl is as defined above, wherein the alkyl group is divalent.

[0187] "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings, such as 2, 3, 4 or more rings, wherein the multiple rings may be fused, bridged, spiro or any combination thereof. As used herein, a cycloalkyl group has 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl) or 3 to 6 ring carbon atoms (i.e., C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups also include partially unsaturated ring systems containing one or more double bonds, including fused ring systems having one aromatic ring and one non-aromatic ring, but not fully aromatic ring systems.

[0188] The term "fused" refers to ring systems in which two or more rings in the system share a pair of adjacent ring atoms.

[0189] "Spiro" refers to at least two rings linked together by a common atom. "Spiro" also refers to a ring substituent joined by two bonds at the same carbon atom. Examples of spiro groups include, but are not limited to, 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, where cyclopentane and piperidine are spiro substituents.

[0190] "Alkyl-cycloalkyl" refers to a group having an alkyl component and a cycloalkyl component, wherein the alkyl component is connected to the cycloalkyl component at the point of attachment. The alkyl component is as defined above, except that the alkyl component is an at least divalent alkylene group connected to the cycloalkyl component and the point of attachment. In some cases, the alkyl component may not be present. The alkyl component may include any number of carbon atoms, such as C 1-6 、C 1-2 、C 1-3 、C 1-4 、C 1-5 、C 2-3 、C 2-4 、C 2-5 、C 2-6 、C 3-4 、C 3-5 、C 3-6 、C 4-5 、C 4-6 and C 5-6 The cycloalkyl component is as defined herein. Exemplary alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, and methyl-cyclohexyl.

[0191] "Heterocycle" or "heterocyclyl" or "heterocycloalkyl" refers to a saturated or unsaturated cyclic alkyl group in which one or more ring heteroatoms are independently selected from nitrogen, oxygen, sulfur and silicon. A heterocyclyl group can be a single ring or multiple rings, such as 2, 3, 4 or more rings, wherein the multiple rings can be fused, bridged, spiro or any combination thereof. As used herein, a heterocyclyl group has 3 to 20 ring atoms (i.e., 3 to 20 membered heterocyclyls), 3 to 12 ring atoms (i.e., 3 to 12 membered heterocyclyls), 3 to 10 ring atoms (i.e., 3 to 10 membered heterocyclyls), 3 to 8 ring atoms (i.e., 3 to 8 membered heterocyclyls), 4 to 12 ring carbon atoms (i.e., 4 to 12 membered heterocyclyls), 4 to 8 ring atoms (i.e., 4 to 8 membered heterocyclyls) or 4 to 6 ring atoms (i.e., 4 to 6 membered heterocyclyls). Examples of heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl.

[0192] "Alkyl-heterocycloalkyl" refers to a group having an alkyl component and a heterocycloalkyl component, wherein the alkyl component is connected to the heterocycloalkyl component at a point of attachment. The alkyl component is as defined above, except that the alkyl component is an at least divalent alkylene group connected to the heterocycloalkyl component and the point of attachment. The alkyl component may include any number of carbon atoms, such as C 0-6 、C 1-2 、C 1-3 、C 1-4 、C 1-5 、C 1-6 、C 2-3 、C 2-4 、C 2-5 、C 2-6 、C 3-4 、C 3-5 、C 3-6 、C 4-5 、C 4-6 and C 5-6 In some cases, the alkyl component may not be present. The heterocycloalkyl component is as defined above.

[0193] "Aryl" means an aromatic hydrocarbon radical derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Exemplary aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), naphthalene, anthracene, biphenyl, and the like.

[0194] "Alkyl-aryl" refers to a group having an alkyl component and an aryl component, wherein the alkyl component is connected to the aryl component at the point of attachment. The alkyl component is as defined above, except that the alkyl component is an at least divalent alkylene group connected to the aryl component and the point of attachment. The alkyl component may include any number of carbon atoms, such as C 0-6 、C1-2 、C 1-3 、C 1-4 、C 1-5 、C 1-6 、C 2-3 、C 2-4 、C 2-5 、C 2-6 、C 3-4 、C 3-5 、C 3-6 、C 4-5 、C 4-6 and C 5-6 In some cases, the alkyl component may not be present. The aryl component is as defined above. Examples of alkyl-aryl groups include, but are not limited to, benzyl and ethyl-benzene.

[0195] "Heteroaryl" refers to an aromatic group, including groups having aromatic tautomers or resonance structures, monocyclic, polycyclic or polycondensed rings, having at least one heteroatom in the ring, i.e., one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the nitrogen or sulfur may be oxidized. Thus, the term includes rings having one or more cyclic O, N, S, S(O), S(O)2 and N-oxide groups. The term includes rings having one or more cyclic C(O) groups. As used herein, heteroaryl includes 5 to 20 ring atoms (i.e., 5 to 20 membered heteroaryl), 5 to 12 ring atoms (i.e., 5 to 12 membered heteroaryl) or 5 to 10 ring atoms (i.e., 5 to 10 membered heteroaryl) and 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur, as well as oxidized forms of heteroatoms. Examples of heteroaryl groups include, but are not limited to, pyridin-2(1H)-one, pyridazin-3(2H)-one, pyrimidin-4(3H)-one, quinolin-2(1H)-one, pyrimidinyl, purinyl, pyridinyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with aryl as defined above.

[0196] "Alkyl-heteroaryl" refers to a group having an alkyl component and a heteroaryl component, wherein the alkyl component is connected to the heteroaryl component at a point of attachment. The alkyl component is as defined above, except that the alkyl component is an at least divalent alkylene group connected to the heteroaryl component and the point of attachment. The alkyl component may include any number of carbon atoms, such as C 0-6 、C 1-2 、C 1-3 、C 1-4 、C 1-5 、C 1-6 、C 2-3 、C 2-4 、C 2-5 、C 2-6 、C 3-4 、C 3-5 、C 3-6 、C4-5 、C 4-6 and C 5-6 In some cases, the alkyl component may be absent. The heteroaryl component is as defined herein.

[0197] "KRAS G12D" refers to the G12D mutation of the KRAS protein, in which an aspartic acid is substituted for a glycine at amino acid position 12.

[0198] "KRASG12D inhibitors" refers to compounds of the present disclosure, including compounds of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), and (IIb-2). These compounds modulate or inhibit some or all of the activity of KRASG12D.

[0199] A "KRAS G12D-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRAS G12D mutation. Representative diseases or disorders include, but are not limited to, KRAS G12D-associated cancers.

[0200] "Oxo" refers to the group (=O) or (O).

[0201] Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, formulations, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0202] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts, or as free bases where appropriate. Pharmaceutically acceptable salts are non-toxic salts of the free base form of the compound that have the desired pharmacological activity of the free base. These salts can be derived from inorganic acids, organic acids, or bases. For example, compounds containing basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyrates, succinates, octanedioates ... Pharmaceutically acceptable salts include benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in "Remington: The Science and Practice of Pharmacy," 21st edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0203] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include those derived from suitable bases such as alkali metals (eg, sodium, potassium), alkaline earth metals (eg, magnesium), ammonium, and NX4. + (wherein X is C1-C4 alkyl). Also included are base addition salts such as sodium or potassium salts.

[0204] Also provided are compounds as described herein or pharmaceutically acceptable salts, isomers or mixtures thereof, wherein 1 to n hydrogen atoms attached to a carbon atom may be substituted with a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds can increase resistance to metabolism and are therefore useful for increasing the half-life of a compound as described herein or a pharmaceutically acceptable salt, isomer or mixture thereof when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., Vol. 5, No. 12, pp. 524-527, 1984. Such compounds are synthesized by methods well known in the art, for example, by employing starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0205] Examples of isotopes that may be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. Use of positron-emitting isotopes such as 11 C. 18 F. 15 O and 13 Substitution of N can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), and (IIb-2) can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the Examples listed below, using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.

[0206] The compounds of the embodiments disclosed herein or their pharmaceutically acceptable salts may include one or more asymmetric centers and therefore may produce enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- or as (D)- or (L)- for amino acids based on absolute stereochemistry. The disclosure is intended to include all such possible isomers and their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or using, for example, chiral high pressure liquid chromatography (HPLC) to resolve racemates (or racemates of salts or derivatives). When the compounds described herein contain olefinic double bonds or other geometric asymmetric centers, and unless otherwise indicated, it is intended that the compounds include E and Z geometric isomers. Likewise, it is also intended to include all tautomeric forms. Where a compound is represented in its chiral form, it is understood that the embodiment encompasses, but is not limited to, the specific diastereoisomer or enantiomerically enriched form. Where chirality is not specified but present, it is understood that the embodiment relates to the specific diastereoisomer or enantiomerically enriched form; or a racemic or non-racemic mixture of such a compound. As used herein, a "non-racemic mixture" is a mixture of stereoisomers that is not in a 1:1 ratio.

[0207] "Racemate" refers to a mixture of enantiomers. The mixture may contain equal or unequal amounts of each enantiomer.

[0208] One or more "stereoisomers" refer to compounds with different chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. If a compound has one or more asymmetric centers or a double bond with asymmetrical substitution, the compound can exist in stereoisomeric forms and can therefore be prepared as a single stereoisomer or as a mixture. Unless otherwise indicated, this specification is intended to include single stereoisomers and mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry, 4th edition, J. March, John Wiley and Sons, New York, 1992).

[0209] "Subject" or "patient" refers to a human or a vertebrate, including dogs, cats, marmosets, marmosets, horses, cows, pigs, sheep, goats, elephants, giraffes, chickens, lions, monkeys, owls, rats, squirrels, lorises, and mice. "Packed pets" refers to a group of vertebrates that can fit into a pocket, for example, hamsters, chinchillas, ferrets, rats, guinea pigs, gerbils, rabbits, and sugar gliders.

[0210] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Dashes at the beginning or end of a chemical group are for convenience; a chemical group can be depicted without one or more dashes without losing its ordinary meaning. A wavy line drawn through the line in the structure indicates the point of attachment of the group. A dotted line represents an optional bond. Unless chemically or structurally required, the order in which the chemical groups are written or the points at which they are attached to the rest of the molecule do not indicate or imply directionality. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-", and the two can be attached in either direction. Similarly, an "arylalkyl" group can be attached to the rest of the molecule, for example, at the aryl or alkyl portion of the group. Prefixes such as "C u-v " or (C u -C v ) means that the group that follows has u to v carbon atoms. For example, "C 1-6 "C1-C6 alkyl" and "C1-C6 alkyl" both mean an alkyl group having 1 to 6 carbon atoms.

[0211] Unless otherwise specified, a carbon atom of a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2) has a valence of four. If, in some chemical structure representations, a carbon atom is not attached to a sufficient number of variables to produce a valence of four, the remaining carbon substituents required to provide the four valences are assumed to be hydrogen.

[0212] "Treatment" is a method for obtaining a beneficial or desired result, including a clinical result. A beneficial or desired clinical result may include one or more of the following: (a) inhibiting the disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the extent of the disease or condition); (b) slowing or preventing the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis of the disease or condition); and / or (c) alleviating the disease, i.e., causing regression of clinical symptoms (e.g., improving the disease state, providing partial or total remission of the disease or condition, enhancing the effect of another drug, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival).

[0213] As used herein, the term "therapeutically effective amount" is the amount of a compound disclosed herein present in a formulation described herein that is required to provide the desired level of drug in the secretions and tissues of the airways and lungs, or alternatively, when such a formulation is administered by a selected route of administration, to produce the desired physiological response or desired biological effect in the bloodstream of the subject to be treated. The exact amount will depend on many factors, such as the specific compound disclosed herein, the specific activity of the formulation, the delivery device employed, the physical properties of the formulation and its intended use, as well as considerations of the subject such as the severity of the disease, the subject's cooperation, etc., and the exact amount can be readily determined by one skilled in the art based on the information provided herein. The term "therapeutically effective amount" or "effective amount" also refers to an amount that eliminates or reduces the viral load and / or viral reservoir of a subject.

[0214] "Administering" refers to oral administration, administration as a suppository, topical contact, parenteral administration, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration or implantation of a slow-release device (e.g., a mini-osmotic pump) to a subject. Administration can be carried out according to a schedule specifying the frequency of administration, the dosage administered, and other factors.

[0215] As used herein, "co-administration" refers to administering a unit dose of a compound disclosed herein before or after administering a unit dose of one or more additional therapeutic agents, for example, administering a compound disclosed herein within seconds, minutes, or hours of administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by administration of a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the present disclosure within seconds or minutes. In some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by administration of a unit dose of one or more additional therapeutic agents a few hours (e.g., 1 hour to 12 hours) later. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the present disclosure a few hours (e.g., 1 hour to 12 hours) later. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to administering a compound disclosed herein and one or more additional therapeutic agents simultaneously or sequentially, such that a therapeutically effective amount of each agent is present in the patient's body.

[0216] "Subject" refers to an animal, such as a mammal, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some embodiments, the subject is a human.

[0217] "Disease" or "disorder" refers to the state of being or health of a patient or subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein. The disease can be an autoimmune disease, inflammatory disease, cancer, infectious disease (e.g., viral infection), metabolic disease, developmental disease, cardiovascular disease, liver disease, intestinal disease, endocrine disease, neurological disease, or other disease. In some embodiments, the disease is cancer (e.g., lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer (e.g., Merkel cell carcinoma), testicular cancer, leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma).

[0218] "Cancer" refers to all types of cancers, tumors or malignancies found in mammals, including leukemias, lymphomas, melanomas, neuroendocrine tumors, carcinomas and sarcomas. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions or methods provided herein include lymphomas, sarcomas, bladder cancer, bone cancer, brain cancer, cervical cancer, colon cancer, esophageal cancer, gastric cancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia, prostate cancer, breast cancer (e.g., triple negative, ER positive, ER negative, chemotherapy resistance, Herceptin resistance, HER2 positive, doxorubicin resistance, tamoxifen resistance, ductal carcinoma, lobular carcinoma, primary, metastatic), ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung cancer, adenocarcinoma, large cell lung cancer, small cell lung cancer, carcinoid, sarcoma), glioblastoma multiforme, glioma, melanoma, prostate cancer, castration-resistant prostate cancer. cancer), breast cancer, triple-negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., of the head, neck, or esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma.

[0219] Additional examples include thyroid cancer, cancer of the endocrine system, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, esophageal cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterine cancer or medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiform myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, essential macroglobulinemia, primary brain tumor, cancer , malignant pancreatic insulinoma, malignant carcinoid tumor, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic tumor, medullary thyroid cancer, medullary thyroid cancer, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget's disease of the breast, phyllodes tumor, lobular carcinoma, ductal carcinoma, pancreatic stellate cell carcinoma, hepatic stellate cell carcinoma, or prostate cancer.

[0220] "Leukemia" broadly refers to progressive malignant diseases of the blood-forming organs and is generally characterized by the distorted proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemias are generally classified clinically based on: (1) the duration and characteristics of the disease - acute or chronic; (2) the type of cells affected - myeloid (myeloid), lymphoid (lymphocytic), or monocytic; and (3) the presence or absence of an increase in the number of abnormal cells in the blood - leukemic or non-leukemic (meta-leukemic). Exemplary leukemias that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukocytic leukemia, basophylic leukemia, stem cell leukemia, bovine leukemia, chronic myeloid leukemia, leukemia cutis, stem cell leukemia, eosinophilic leukemia, Gross's leukemia, hairy cell leukemia, hemoblastic leukemia, leukemia), hematoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia leukemia), stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia.

[0221] "Sarcoma" generally refers to a tumor composed of material such as embryonic connective tissue and is generally composed of closely packed cells embedded in a fibril or uniform material. Sarcomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar sarcoma of soft tissue, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriosarcoma, embryonal sarcoma, Wilms tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma of the cutaneous tissue, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemic sarcoma, malignant mesenchymal sarcoma, periosseous sarcoma, reticulum cell sarcoma, Rous sarcoma, serosal cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0222] "Melanoma" refers to a tumor arising from the melanocyte system of the skin and other organs. Melanomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.

[0223] "Carcinoma" refers to a malignant new growth composed of epithelial cells that tends to infiltrate surrounding tissues and produce metastases. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, cystic adenoid carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, gyriform carcinoma, cholangiocellular carcinoma, choriocarcinoma, colloid carcinoma, comedocarcinoma, uterine corpus carcinoma, cribriform carcinoma, thoracic carcinoma, skin carcinoma, cylindrical cell carcinoma, duct carcinoma, ductal carcinoma, dural carcinoma, embryonal carcinoma, encephaloid carcinoma, epidermoid carcinoma, carcinoma epithelial adenoides), explanted carcinoma, ulcerative carcinoma, fibrous carcinoma (carcinoma fibrosum), gelatinous carcinoma, colloid carcinoma, giant cell carcinoma (carcinoma gigantocellulare), adenocarcinoma, granular cell carcinoma, pilomatricoma, hematogenous carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, clear carcinoma, adrenal carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma (carcinoma lenticulare), lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, medullary carcinoma (carcinoma medullare), melanotic carcinoma, soft carcinoma, mucinous carcinoma (carcinoma muciparum), mucous cell carcinoma, mucoepidermoid carcinoma, colloid carcinoma, mucous carcinomacarcinoma), myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteocarcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, acanthotic cell carcinoma, comedo carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato-shaped carcinoma, spheroid cell carcinoma, spindle cell carcinoma, spongiosum carcinoma, squamous cell carcinoma, squamous cell carcinoma, cord-like carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tubular carcinoma, tuberous carcinoma, verrucous carcinoma, or villous carcinoma.

[0224] "Metastasis", "metastatic" and "metastatic cancer" are used interchangeably and refer to the spread of a proliferative disease or disorder (e.g., cancer) from one organ or another non-adjacent organ or body part. Cancer occurs at the starting site, such as the breast, which is referred to as a primary tumor, such as primary breast cancer. Some cancer cells in the primary tumor or starting site acquire the ability to penetrate and infiltrate surrounding normal tissues in a local area and / or the ability to penetrate the walls of the lymphatic system or vascular system, thereby circulating to other parts of the body and tissues through this system. The second clinically detectable tumor formed by the cancer cells of the primary tumor is referred to as a metastatic or secondary tumor. When cancer cells metastasize, it is speculated that the metastatic tumor and its cells are similar to those of the original tumor and its cells. Therefore, if lung cancer metastasizes to the breast, the secondary tumor at the breast site is composed of abnormal lung cells rather than abnormal breast cells. Secondary tumors in the breast are referred to as metastatic lung cancer. Therefore, the phrase metastatic cancer refers to a disease in which a subject suffers from or has a primary tumor and has one or more secondary tumors. The phrases non-metastatic cancer or a subject with a cancer that is not metastatic refers to a disease in which a subject has a primary tumor but does not have one or more secondary tumors. For example, metastatic lung cancer refers to a disease in which a subject has a primary lung tumor or a history of a primary lung tumor and has one or more secondary tumors at a secondary location or locations (e.g., in the breast).

[0225] By "associated with" or "associated with" in the context of a substance or substance activity or function associated with a disease (e.g., diabetes, cancer (e.g., prostate cancer, kidney cancer, metastatic cancer, melanoma, castration-resistant prostate cancer, breast cancer, triple-negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., of the head, neck, or esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma)) is meant that the disease (e.g., lung cancer, ovarian cancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer, kidney cancer, skin cancer (e.g., Merkel cell carcinoma)), testicular cancer, leukemia, lymphoma, head and neck cancer, colorectal cancer, prostate cancer, pancreatic cancer, melanoma, breast cancer, neuroblastoma) is caused (in whole or in part) by the substance or substance activity or function, or that the symptoms of the disease are caused (in whole or in part) by the substance or substance activity or function.

[0226] As used herein, the term "adjacent carbons" refers to consecutive carbon atoms that are directly connected to each other. For example, in In , C1 and C2 are adjacent carbons, C2 and C3 are adjacent carbons, C3 and C4 are adjacent carbons, and C4 and C5 are adjacent carbons. Similarly, in , C1 and C2 are adjacent carbons, C2 and C3 are adjacent carbons, C3 and C4 are adjacent carbons, and C4 and C5 are adjacent carbons, C5 and C6 are adjacent carbons, and C6 and C1 are adjacent carbons.

[0227] As used herein, "solvate" refers to the result of the interaction of a solvent and a compound. Also provided are solvates of the salts of the compounds described herein. Also provided are hydrates of the compounds described herein.

[0228] As used herein, a "prodrug" is a derivative of a drug that is converted to the parent drug according to some chemical or enzymatic pathway when administered to the human body.

[0229] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes, but is not limited to, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and combinations thereof. The use of pharmaceutically acceptable carriers and pharmaceutically acceptable excipients for pharmaceutically active substances is well known in the art. Unless any conventional media or agents are incompatible with the active ingredient, their use in therapeutic formulations is contemplated. Supplementary active ingredients may also be incorporated into the formulation. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not physiologically deleterious to the recipient thereof.

[0230] III. Compounds

[0231] Disclosed herein are compounds of Formula I, IA, II, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (II-1), (IIa), (IIa-1), (IIb), (IIb-1), and (IIb-2), as well as other compounds. In some embodiments, the present disclosure provides a compound of Formula I:

[0232]

[0233] or a pharmaceutically acceptable salt thereof,

[0234] in

[0235] X is N, CH or CR x ;

[0236] R x (CH2) m CN or halide;

[0237] m is 0, 1, 2, or 3;

[0238] R 1 、R 2 、R 3 and R 4 Each independently is H or C1-C3 alkyl;

[0239] L 1 O, S or CR 1a R 1b ;

[0240] R 1a and R 1b Each is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, C1-C3 cyanoalkyl or C3-C6 cycloalkyl;

[0241] Alternatively, R 1a and R 1b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0242] L 2 CR 2a R 2b ;

[0243] Alternatively, L 2 is O or S, and L 1 CR 1a R 1b ;

[0244] R 2a and R 2b Each is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, C1-C3 cyanoalkyl or C3-C6 cycloalkyl;

[0245] Alternatively, R 2a and R 2b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0246] Alternatively, R 1b and R 2b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0247] L 3 key or CR 3a R 3b ;

[0248] R 3a and R 3b Each is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, C1-C3 cyanoalkyl or C3-C6 cycloalkyl;

[0249] Alternatively, R 3a and R 3b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0250] Alternatively, R 2b and R 3b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0251] R A is phenyl or naphthyl, wherein R A 0, 1, 2, 3, 4 or 5 R A2 replace;

[0252] Each R A2 are independently -OH, C1-C 10 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C 10 Alkoxy, C1-C 10 Hydroxyalkyl, C2-C 10 Alkoxyalkyl, C1-C6 alkyl-N(R A2a )(R A2b ), C1-C 10 Thioalkyl, halogen, C1-C6 haloalkyl, -CN, -C(O)R A2a、-C(O)OR A2a 、-OC(O)R A2a 、-OC(O)OR A2a 、-C(O)N(R A2a )(R A2b )、-N(R A2a )C(O)(R A2b )、-OC(O)N(R A2a )(R A2b )、-N(R A2a )C(O)(OR A2b ), oxo, -OR A2a 、-SR A2a 、-S(O)2R A2a 、-S(O)2OR A2a 、-N(R A2a )(R A2b )、-(C0-C3 alkyl)-SF5、-OP(O)(OR A2a )(OR A2b ), C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C3-C8 cycloalkyl), 3- to 14-membered heterocyclic group, -(C1-C6 alkyl)-(3- to 14-membered heterocyclic group), C6-C 14 Aryl, -(C1-C6 alkyl)-(C6-C 14 aryl), 5- to 14-membered heteroaryl, or -(C1-C6 alkyl)-(5- to 14-membered heteroaryl), wherein each alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, and haloalkyl group is replaced by 0, 1, 2, or 3 R A3 substituted, and wherein each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl and alkyl-heteroaryl is replaced by 0, 1, 2 or 3 R A4 replace;

[0253] Each R A2a and R A2b are independently H, C1-C 10 Alkyl, C1-C6 haloalkyl or C3-C8 cycloalkyl;

[0254] Each R A3 are independently halogen, -CN, -OR A3a 、-SR A3a 、-N(R A3a )(R A3b ), C3-C8 cycloalkyl or 5- to 14-membered heteroaryl;

[0255] Each R A3a and R A3b are independently H, C1-C 10Alkyl, C1-C6 haloalkyl or C3-C8 cycloalkyl;

[0256] Each R A4 C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkylthio, C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C6-C 10 aryl), halogen, -CN, -OH or -N(R A4a )(R A4b );

[0257] Each R A4a and R A4b are independently H or C1-C6 alkyl;

[0258] Alternatively, in R A On two adjacent atoms, two R A2 Can combine to form C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocyclyl, or 5- to 14-membered heteroaryl;

[0259] R B H, -C(O)R B1 or-C(O)OR B2 ;

[0260] R B1 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl, wherein C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl is substituted with 0, 1, 2 or 3 R B1a replace;

[0261] R B2 C1-C6 alkyl, C1-C6 haloalkyl, (C1-C6 alkyl)-OC(O)R B3 , C3-C8 cycloalkyl, C6-C 14 aryl, 5- to 14-membered heteroaryl, or

[0262]

[0263] wherein the C3-C8 cycloalkyl, the C6-C 14 The aryl group or the 5- to 14-membered heteroaryl group is replaced by 0, 1, 2 or 3 R B2a replace;

[0264] R B3C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl, wherein C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl is substituted with 0, 1, 2 or 3 R B3a replace;

[0265] Each R B1a 、R B2a and R B3a C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkoxyalkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, oxo, -OH, -CN or C3-C 10 Cycloalkyl;

[0266] L C For key or

[0267]

[0268] Y is C or Si;

[0269] n is 0, 1, 2, or 3;

[0270] q is 0, 1, 2, or 3;

[0271] R Y1 is H or C1-C3 alkyl;

[0272] R Y2 is H or C1-C3 alkyl;

[0273] Alternatively, R Y1 and R Y2 Combined to form C3-C 10 a cycloalkyl group or a 3- to 10-membered heterocyclic group;

[0274] R C H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, -NH2, -NHR C1 、-N(R C1 )2, C3-C8 cycloalkyl, 3- to 14-membered heterocyclic group, C6-C 14 aryl or 5- to 14-membered heteroaryl, wherein each C3-C8 cycloalkyl, 3- to 14-membered heterocyclyl, C6-C 14 Aryl and 3- to 14-membered heteroaryl groups are substituted with 0, 1, 2, 3, or 4 R C3 replace;

[0275] Each R C1 Independently selected from C1-C6 alkyl;

[0276] Each R C3 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C8 alkynyl, C1-C6 alkoxyalkyl, C1-C6 hydroxyalkyl, halo, C1-C6 haloalkyl, C1-C6 heteroalkyl, -(C1-C6 alkyl)-N(R C3a )(R C3b )、-CN、-C(O)R C3a 、-C(O)OR C3a 、-C(O)N(R C3a )(R C3b )、-N(R C3a )C(O)(R C3b )、-OC(O)N(R C3a )(R C3b )、-N(R C3a )C(O)(OR C3b ), =CH2, =CF2, oxo, -OR C3a 、-SR C3a 、-N(R C3a )(R C3b ), -N3, SF5, C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C3-C8 cycloalkyl), 3- to 10-membered heterocyclic group, -(C1-C6 alkyl)-(3- to 10-membered heterocyclic group), C6-C 10 Aryl, -(C1-C6 alkyl)-(C6-C 10 aryl), 5- to 10-membered heteroaryl, or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), wherein each alkyl is replaced by 0, 1, 2, or 3 -CN, -C(O)OR C3a1 、-C(O)N(R C3a1 )(R C3a2 )、-N(R C3a1 )C(O)(R C3a2 )、-OC(O)N(R C3a1 )(R C3a2 ),-OR C3a1 、-SR C3a1 , N3, SF5 or 0, 1, 2 or 3 3R C3a2 substituted 3- to 10-membered heterocyclyl, each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl and alkyl-heteroaryl being replaced by 0, 1, 2 or 3 halo, -CN or R C3a2 substituted, each alkenyl group is substituted by 0, 1, 2 or 3 halo groups, and each alkoxyalkyl and alkynyl group is substituted by 0, 1, 2 or 3 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl substituted by 0 or 1 C1-C6 haloalkyl, C6-C10 substituted with aryl or 5- to 10-membered heteroaryl;

[0277] Each R C3a and R C3b are independently H, C1-C 10 Alkyl, C1-C6 haloalkyl, C6-C 10 Aryl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein each aryl and heteroaryl is substituted by 0, 1, 2 or 3 halogen, -CN or R C3a2 replace;

[0278] Alternatively, R C3a and R C3b Together with the nitrogen to which they are attached, they form a 3- to 8-membered heterocyclic ring;

[0279] Each R C3a1 and R C3a2 C1-C3 alkyl, halo, C1-C6 haloalkyl, C3-C8 cycloalkyl, -(C1-C3 alkyl)-(C3-C8 cycloalkyl), 3- to 10-membered heterocyclyl, -(C1-C3 alkyl)-(3- to 10-membered heterocyclyl), C6-C 10 Aryl, -(C1-C3 alkyl)-(C6-C 10 Aryl), -(C2-C4 alkynyl)-(C6-C 10 aryl), 5- to 10-membered heteroaryl, -(C1-C3 alkyl)-(5- to 10-membered heteroaryl), or SF5, wherein each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, alkynyl-aryl, heteroaryl and alkyl-heteroaryl is substituted with 0, 1, 2 or 3 halo, C1-C3 haloalkyl, C1-C3 haloalkoxy or SF5;

[0280] Alternatively, R C3a1 and R C3a2 Together with the nitrogen to which they are attached, they form a 3- to 8-membered heterocyclic ring;

[0281] R D is a halogen group;

[0282] Each heterocyclyl group has 1, 2, 3 or 4 heteroatoms selected from N, O, S and Si; and

[0283] Each heteroaryl group has 1, 2, 3 or 4 heteroatoms selected from N, O and S.

[0284] In some embodiments, the present disclosure provides compounds of Formula I, wherein R 1 、R 2 、R 3 and R 4Each is independently H or methyl. In some embodiments, the present disclosure provides a compound of Formula I, wherein R 1 、R 2 、R 3 and R 4 In some embodiments, the present disclosure provides compounds of Formula I, wherein R 1 and R 2 In some embodiments, the present disclosure provides compounds of Formula I, wherein R 1 、R 2 、R 3 and R 4 Each is H.

[0285] In some embodiments, the present disclosure provides a compound of Formula IA:

[0286]

[0287] or a pharmaceutically acceptable salt thereof, wherein

[0288] X is N, CH or CR x ;

[0289] R x (CH2) m CN or halide;

[0290] m is 0, 1, 2, or 3;

[0291] L 1 O, S or CR 1a R 1b ;

[0292] R 1a and R 1b Each is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, C1-C3 cyanoalkyl or C3-C6 cycloalkyl;

[0293] Alternatively, R 1a and R 1b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0294] L 2 CR 2a R 2b ;

[0295] Alternatively, L 2 is O or S, and L 1 CR 1a R 1b ;

[0296] R 2a and R 2b Each is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, C1-C3 cyanoalkyl or C3-C6 cycloalkyl;

[0297] Alternatively, R 2a and R 2b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0298] Alternatively, R 1b and R 2b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0299] L 3 key or CR 3a R 3b ;

[0300] R 3a and R 3b Each is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, C1-C3 cyanoalkyl or C3-C6 cycloalkyl;

[0301] Alternatively, R 3a and R 3b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0302] Alternatively, R 2b and R 3b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0303] R A is phenyl or naphthyl, wherein R A 0, 1, 2, 3, 4 or 5 R A2 replace;

[0304] Each R A2 are independently -OH, C1-C 10 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C 10 Alkoxy, C1-C 10 Hydroxyalkyl, C2-C 10 Alkoxyalkyl, C1-C6 alkyl-N(R A2a )(R A2b ), C1-C 10 Thioalkyl, halogen, C1-C6 haloalkyl, -CN, -C(O)R A2a 、-C(O)ORA2a 、-OC(O)R A2a 、-OC(O)OR A2a 、-C(O)N(R A2a )(R A2b )、-N(R A2a )C(O)(R A2b )、-OC(O)N(R A2a )(R A2b )、-N(R A2a )C(O)(OR A2b ), oxo, -OR A2a 、-SR A2a 、-S(O)2R A2a 、-S(O)2OR A2a 、-N(R A2a )(R A2b )、-(C0-C3 alkyl)-SF5、-OP(O)(OR A2a )(OR A2b ), C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C3-C8 cycloalkyl), 3- to 14-membered heterocyclic group, -(C1-C6 alkyl)-(3- to 14-membered heterocyclic group), C6-C 14 Aryl, -(C1-C6 alkyl)-(C6-C 14 aryl), 5- to 14-membered heteroaryl, or -(C1-C6 alkyl)-(5- to 14-membered heteroaryl), wherein each alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, and haloalkyl group is replaced by 0, 1, 2, or 3 R A3 substituted, and wherein each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl and alkyl-heteroaryl is replaced by 0, 1, 2 or 3 R A4 replace;

[0305] Each R A2a and R A2b are independently H, C1-C 10 Alkyl, C1-C6 haloalkyl or C3-C8 cycloalkyl;

[0306] Each R A3 are independently halogen, -CN, -OR A3a 、-SR A3a 、-N(R A3a )(R A3b ), C3-C8 cycloalkyl or 5- to 14-membered heteroaryl;

[0307] Each R A3a and R A3b are independently H, C1-C 10Alkyl, C1-C6 haloalkyl or C3-C8 cycloalkyl;

[0308] Each R A4 C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkylthio, C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C6-C 10 aryl), halogen, -CN, -OH or -N(R A4a )(R A4b );

[0309] Each R A4a and R A4b are independently H or C1-C6 alkyl;

[0310] Alternatively, in R A On two adjacent atoms, two R A2 Can combine to form C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocyclyl, or 5- to 14-membered heteroaryl;

[0311] R B H, -C(O)R B1 or-C(O)OR B2 ;

[0312] R B1 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl, wherein C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl is substituted with 0, 1, 2 or 3 R B1a replace;

[0313] R B2 C1-C6 alkyl, C1-C6 haloalkyl, (C1-C6 alkyl)-OC(O)R B3 , C3-C8 cycloalkyl, C6-C 14 aryl, 5- to 14-membered heteroaryl, or

[0314]

[0315] wherein the C3-C8 cycloalkyl, the C6-C 14 The aryl group or the 5- to 14-membered heteroaryl group is replaced by 0, 1, 2 or 3 R B2a replace;

[0316] R B3C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl, wherein C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl is substituted with 0, 1, 2 or 3 R B3a replace;

[0317] Each R B1a 、R B2a and R B3a C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkoxyalkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, oxo, -OH, -CN or C3-C 10 Cycloalkyl;

[0318] L C For key or

[0319]

[0320] Y is C or Si;

[0321] n is 0, 1, 2, or 3;

[0322] q is 0, 1, 2, or 3;

[0323] R Y1 is H or C1-C3 alkyl;

[0324] R Y2 is H or C1-C3 alkyl;

[0325] Alternatively, R Y1 and R Y2 Combined to form C3-C 10 a cycloalkyl group or a 3- to 10-membered heterocyclic group;

[0326] R C H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, -NH2, -NHR C1 、-N(R C1 )2, C3-C8 cycloalkyl, 3- to 14-membered heterocyclic group, C6-C 14 aryl or 5- to 14-membered heteroaryl, wherein each C3-C8 cycloalkyl, 3- to 14-membered heterocyclyl, C6-C 14 Aryl and 3- to 14-membered heteroaryl groups are substituted with 0, 1, 2, or 3 R C3 replace;

[0327] Each R C1 Independently selected from C1-C6 alkyl;

[0328] Each R C3 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C8 alkynyl, C1-C6 alkoxyalkyl, C1-C6 hydroxyalkyl, halo, C1-C6 haloalkyl, C1-C6 heteroalkyl, -(C1-C6 alkyl)-N(R C3a )(R C3b )、-CN、-C(O)R C3a 、-C(O)OR C3a 、-C(O)N(R C3a )(R C3b )、-N(R C3a )C(O)(R C3b )、-OC(O)N(R C3a )(R C3b )、-N(R C3a )C(O)(OR C3b ), =CH2, =CF2, oxo, -OR C3a 、-SR C3a 、-N(R C3a )(R C3b ), -N3, SF5, C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C3-C8 cycloalkyl), 3- to 10-membered heterocyclic group, -(C1-C6 alkyl)-(3- to 10-membered heterocyclic group), C6-C 10 Aryl, -(C1-C6 alkyl)-(C6-C 10 aryl), 5- to 10-membered heteroaryl, or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), wherein each alkyl is replaced by 0, 1, 2, or 3 -CN, -C(O)OR C3a1 、-C(O)N(R C3a1 )(R C3a2 )、-N(R C3a1 )C(O)(R C3a2 )、-OC(O)N(R C3a1 )(R C3a2 ),-OR C3a1 、-SR C3a1 , N3, SF5 or 0, 1, 2 or 3 3R C3a2 substituted 3- to 10-membered heterocyclyl, each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl and alkyl-heteroaryl being replaced by 0, 1, 2 or 3 halo, -CN or R C3a2 substituted, each alkenyl group is substituted by 0, 1, 2 or 3 halo groups, and each alkoxyalkyl and alkynyl group is substituted by 0, 1, 2 or 3 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl substituted by 0 or 1 C1-C6 haloalkyl, C6-C10 substituted with aryl or 5- to 10-membered heteroaryl;

[0329] Each R C3a and R C3b are independently H, C1-C 10 Alkyl, C1-C6 haloalkyl, C6-C 10 Aryl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein each aryl and heteroaryl is substituted by 0, 1, 2 or 3 halogen, -CN or R C3a2 replace;

[0330] Alternatively, R C3a and R C3b Together with the nitrogen to which they are attached, they form a 3- to 8-membered heterocyclic ring;

[0331] Each R C3a1 and R C3a2 C1-C3 alkyl, halo, C1-C6 haloalkyl, C3-C8 cycloalkyl, -(C1-C3 alkyl)-(C3-C8 cycloalkyl), 3- to 10-membered heterocyclyl, -(C1-C3 alkyl)-(3- to 10-membered heterocyclyl), C6-C 10 Aryl, -(C1-C3 alkyl)-(C6-C 10 Aryl), -(C2-C4 alkynyl)-(C6-C 10 aryl), 5- to 10-membered heteroaryl, -(C1-C3 alkyl)-(5- to 10-membered heteroaryl), or SF5, wherein each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, alkynyl-aryl, heteroaryl and alkyl-heteroaryl is substituted with 0, 1, 2, 3 or 4 halo, C1-C3 haloalkyl, C1-C3 haloalkoxy or SF5;

[0332] Alternatively, R C3a1 and R C3a2 Together with the nitrogen to which they are attached, they form a 3- to 8-membered heterocyclic ring;

[0333] R D is a halogen group;

[0334] Each heterocyclyl group has 1, 2, 3 or 4 heteroatoms selected from N, O, S and Si; and

[0335] Each heteroaryl group has 1, 2, 3 or 4 heteroatoms selected from N, O and S.

[0336] In some embodiments, the present disclosure provides a compound of Formula I or IA having the structure of Formula (I-1) or a pharmaceutically acceptable salt thereof:

[0337]

[0338] In some embodiments, the present disclosure provides a compound of Formula I, IA, or I-1 having the structure of Formula (I-2), or a pharmaceutically acceptable salt thereof:

[0339]

[0340] In some embodiments, the present disclosure provides a compound of Formula I, IA, or I-1 having a structure of Formula (I-3), or a pharmaceutically acceptable salt thereof:

[0341]

[0342] In some embodiments, the present disclosure provides compounds of Formula I, IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts thereof, wherein X is N. In some embodiments, the present disclosure provides compounds of Formula I, IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts thereof, wherein X is CH. In some embodiments, the present disclosure provides compounds of Formula I, IA, I-1, I-2, or I-3, or pharmaceutically acceptable salts thereof, wherein X is CR x , where R x (CH2) m CN, and m is 0, 1, 2, or 3. In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt thereof, wherein X is CR x , where R x In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt thereof, wherein X is CR x , where R x It is a halogen group.

[0343] In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt thereof, wherein L 1 Is 0. In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2 or I-3 having the structure of Formula (Ia) or a pharmaceutically acceptable salt thereof:

[0344]

[0345] In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt thereof, wherein L 1 For CHR 1bIn some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt thereof, wherein L 1 In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt thereof, wherein L 1 is CH(CH3). In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b Each is independently H, C1-C3 alkyl or halo. In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2 or I-3 or a pharmaceutically acceptable salt thereof, wherein R 1b In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2 or I-3 or a pharmaceutically acceptable salt thereof, wherein R 1b In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt thereof, wherein R 1b is H. In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt thereof, wherein R 1b It is a methyl group.

[0346] In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, or I-3 having the structure of Formula (Ib), or a pharmaceutically acceptable salt thereof:

[0347]

[0348] In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, I-3, (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b Each is independently H, C1-C3 alkyl, halo or C1-C6 haloalkyl. In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, I-3, (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, wherein L 2 For CHR 2b In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, I-3, (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, wherein R 2bis H or C1-C3 alkyl. In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, I-3, (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, wherein R 2b is H. In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, I-3, (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, wherein R 2b In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, I-3, (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, wherein R 2b It is a methyl group.

[0349] In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, I-3, (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, wherein L 3 CR 3a R 3b In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, I-3, (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, wherein R 3a and R 3b For H.

[0350] In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, I-3, or (Ia), or a pharmaceutically acceptable salt thereof, having the structure of Formula (Ia-1):

[0351]

[0352] In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, I-3, or (Ib) having the structure of Formula (Ib-1), or a pharmaceutically acceptable salt thereof:

[0353]

[0354] In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, I-3, Ib, or Ib-1 having the structure of Formula (Ib-2), or a pharmaceutically acceptable salt thereof:

[0355]

[0356] In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, I-3, Ib, or Ib-1 having the structure of Formula (Ib-3), or a pharmaceutically acceptable salt thereof:

[0357]

[0358] In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, I-3, Ib, or Ib-1 having the structure of Formula (Ib-4), or a pharmaceutically acceptable salt thereof:

[0359]

[0360] Disclosed herein are compounds of Formula II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), and (IIb-2), as well as other compounds. In some embodiments, the present disclosure provides a compound of Formula II:

[0361]

[0362] or a pharmaceutically acceptable salt thereof, wherein

[0363] X is N, CH or CR x ;

[0364] R x (CH2) m CN or halide;

[0365] m is 0, 1, 2, or 3;

[0366] L 1 O or CR 1a R 1b ;

[0367] R 1a and R 1b Each is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, C1-C3 cyanoalkyl or C3-C6 cycloalkyl;

[0368] Alternatively, R 1a and R 1b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0369] L 2 CR 2a R 2b ;

[0370] R 2a and R 2b Each is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, C1-C3 cyanoalkyl or C3-C6 cycloalkyl;

[0371] Alternatively, R 2a and R2b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0372] Alternatively, R 1b and R 2b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups;

[0373] R A is phenyl or naphthyl, wherein R A 0, 1, 2, 3, 4 or 5 R A2 replace;

[0374] Each R A2 are independently -OH, C1-C 10 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C 10 Alkoxy, C1-C 10 Hydroxyalkyl, C2-C 10 Alkoxyalkyl, C1-C6 alkyl-N(R A2a )(R A2b ), C1-C 10 Thioalkyl, halogen, C1-C6 haloalkyl, -CN, -C(O)R A2a 、-C(O)OR A2a 、-OC(O)R A2a 、-OC(O)OR A2a 、-C(O)N(R A2a )(R A2b )、-N(R A2a )C(O)(R A2b )、-OC(O)N(R A2a )(R A2b )、-N(R A2a )C(O)(OR A2b ), oxo, -OR A2a 、-SR A2a 、-S(O)2R A2a 、-S(O)2OR A2a 、-N(R A2a )(R A2b )、-(C0-C3 alkyl)-SF5、-OP(O)(OR A2a )(OR A2b ), C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C3-C8 cycloalkyl), 3- to 14-membered heterocyclic group, -(C1-C6 alkyl)-(3- to 14-membered heterocyclic group), C6-C 14 Aryl, -(C1-C6 alkyl)-(C6-C 14aryl), 5- to 14-membered heteroaryl, or -(C1-C6 alkyl)-(5- to 14-membered heteroaryl), wherein each alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, and haloalkyl group is replaced by 0, 1, 2, or 3 R A3 substituted, and wherein each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl and alkyl-heteroaryl is replaced by 0, 1, 2 or 3 R A4 replace;

[0375] Each R A2a and R A2b are independently H, C1-C 10 Alkyl, C1-C6 haloalkyl or C3-C8 cycloalkyl;

[0376] Each R A3 are independently halogen, -CN, -OR A3a 、-SR A3a 、-N(R A3a )(R A3b ), C3-C8 cycloalkyl or 5- to 14-membered heteroaryl;

[0377] Each R A3a and R A3b are independently H, C1-C 10 Alkyl, C1-C6 haloalkyl or C3-C8 cycloalkyl;

[0378] Each R A4 C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkylthio, C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C6-C 10 aryl), halogen, -CN, -OH or -N(R A4a )(R A4b );

[0379] Each R A4a and R A4b are independently H or C1-C6 alkyl;

[0380] Alternatively, in R A On two adjacent atoms, two R A2 Can combine to form C3-C 10 Cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocyclyl, or 5- to 14-membered heteroaryl;

[0381] R B H, -C(O)R B1 or-C(O)OR B2 ;

[0382] R B1 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl, wherein C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl is substituted with 0, 1, 2 or 3 R B1a replace;

[0383] R B2 C1-C6 alkyl, C1-C6 haloalkyl, (C1-C6 alkyl)-OC(O)R B3 , C3-C8 cycloalkyl, C6-C 14 aryl, 5- to 14-membered heteroaryl, or

[0384]

[0385] wherein the C3-C8 cycloalkyl, the C6-C 14 The aryl group or the 5- to 14-membered heteroaryl group is replaced by 0, 1, 2 or 3 R B2a replace;

[0386] R B3 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl, wherein C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl is substituted with 0, 1, 2 or 3 R B3a replace;

[0387] Each R B1a 、R B2a and R B3a C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkoxyalkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, oxo, -OH, -CN or C3-C 10 Cycloalkyl;

[0388] L C For key or

[0389]

[0390] Y is C or Si;

[0391] n is 0, 1, 2, or 3;

[0392] q is 0, 1, 2, or 3;

[0393] R Y1 is H or C1-C3 alkyl;

[0394] R Y2 is H or C1-C3 alkyl;

[0395] Alternatively, R Y1 and R Y2 Combined to form C3-C 10 a cycloalkyl group or a 3- to 10-membered heterocyclic group;

[0396] R C H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, -NH2, -NHR C1 、-N(R C1 )2, C3-C8 cycloalkyl, 3- to 14-membered heterocyclic group, C6-C 14 aryl or 5- to 14-membered heteroaryl, wherein each C3-C8 cycloalkyl, 3- to 14-membered heterocyclyl, C6-C 14 Aryl and 3- to 14-membered heteroaryl groups are substituted with 0, 1, 2, or 3 R C3 replace;

[0397] Each R C1 Independently selected from C1-C6 alkyl;

[0398] Each R C3 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C8 alkynyl, C1-C6 alkoxyalkyl, C1-C6 hydroxyalkyl, halo, C1-C6 haloalkyl, C1-C6 heteroalkyl, -(C1-C6 alkyl)-N(R C3a )(R C3b )、-CN、-C(O)R C3a 、-C(O)OR C3a 、-C(O)N(R C3a )(R C3b )、-N(R C3a )C(O)(R C3b )、-OC(O)N(R C3a )(R C3b )、-N(R C3a )C(O)(OR C3b ), =CH2, =CF2, oxo, -OR C3a 、-SR C3a 、-N(R C3a )(R C3b ), -N3, SF5, C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C3-C8 cycloalkyl), 3- to 10-membered heterocyclic group, -(C1-C6 alkyl)-(3- to 10-membered heterocyclic group), C6-C 10Aryl, -(C1-C6 alkyl)-(C6-C 10 aryl), 5- to 10-membered heteroaryl, or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), wherein each alkyl is replaced by 0, 1, 2, or 3 -CN, -C(O)OR C3a1 、-C(O)N(R C3a1 )(R C3a2 )、-N(R C3a1 )C(O)(R C3a2 )、-OC(O)N(R C3a1 )(R C3a2 ),-OR C3a1 、-SR C3a1 , N3, SF5 or 0, 1, 2 or 3 3R C3a2 substituted 3- to 10-membered heterocyclyl, each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl and alkyl-heteroaryl being replaced by 0, 1, 2 or 3 halo, -CN or R C3a2 substituted, each alkenyl group is substituted by 0, 1, 2 or 3 halo groups, and each alkoxyalkyl and alkynyl group is substituted by 0, 1, 2 or 3 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl substituted by 0 or 1 C1-C6 haloalkyl, C6-C 10 substituted with aryl or 5- to 10-membered heteroaryl;

[0399] Each R C3a and R C3b are independently H, C1-C 10 Alkyl, C1-C6 haloalkyl, C6-C 10 Aryl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein each aryl and heteroaryl is substituted by 0, 1, 2 or 3 halogen, -CN or R C3a2 replace;

[0400] Alternatively, R C3a and R C3b Together with the nitrogen to which they are attached, they form a 3- to 8-membered heterocyclic ring;

[0401] Each R C3a1 and R C3a2 C1-C3 alkyl, halo, C1-C6 haloalkyl, C3-C8 cycloalkyl, -(C1-C3 alkyl)-(C3-C8 cycloalkyl), 3- to 10-membered heterocyclyl, -(C1-C3 alkyl)-(3- to 10-membered heterocyclyl), C6-C 10 Aryl, -(C1-C3 alkyl)-(C6-C 10 Aryl), -(C2-C4 alkynyl)-(C6-C 10aryl), 5- to 10-membered heteroaryl, -(C1-C3 alkyl)-(5- to 10-membered heteroaryl), or SF5, wherein each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, alkynyl-aryl, heteroaryl and alkyl-heteroaryl is substituted with 0, 1, 2, 3 or 4 halo, C1-C3 haloalkyl, C1-C3 haloalkoxy or SF5;

[0402] Alternatively, R C3a1 and R C3a2 Together with the nitrogen to which they are attached, they form a 3- to 8-membered heterocyclic ring;

[0403] R D is a halogen group;

[0404] Each heterocyclyl group has 1, 2, 3 or 4 heteroatoms selected from N, O, S and Si; and

[0405] Each heteroaryl group has 1, 2, 3 or 4 heteroatoms selected from N, O and S.

[0406] In some embodiments, the present disclosure provides a compound of Formula II having the structure of Formula (II-1) or a pharmaceutically acceptable salt thereof:

[0407]

[0408] In some embodiments, the present disclosure provides a compound of Formula II or II-1 having a structure of Formula (II-2) or a pharmaceutically acceptable salt thereof:

[0409]

[0410] In some embodiments, the present disclosure provides a compound of Formula II or II-1 having a structure of Formula (II-3) or a pharmaceutically acceptable salt thereof:

[0411]

[0412] In some embodiments, the present disclosure provides compounds of Formula II, II-1, II-2, or II-3, or pharmaceutically acceptable salts thereof, wherein X is N. In some embodiments, the present disclosure provides compounds of Formula II, II-1, II-2, or II-3, or pharmaceutically acceptable salts thereof, wherein X is CH. In some embodiments, the present disclosure provides compounds of Formula II, II-1, II-2, or II-3, or pharmaceutically acceptable salts thereof, wherein X is CR x , where R x (CH2) mCN, and m is 0, 1, 2 or 3. In some embodiments, the present disclosure provides a compound of Formula II, II-1, II-2 or II-3, or a pharmaceutically acceptable salt thereof, wherein X is CR x , where R x In some embodiments, the present disclosure provides compounds of Formula II, II-1, II-2, or II-3, or pharmaceutically acceptable salts thereof, wherein X is CR x , where R x In some embodiments, the present disclosure provides a compound of Formula II, II-1, II-2, or II-3, or a pharmaceutically acceptable salt thereof, wherein X is C-Cl.

[0413] In some embodiments, the present disclosure provides compounds of Formula II, II-1, II-2, or II-3, or pharmaceutically acceptable salts thereof, wherein L 1 Is 0. In some embodiments, the present disclosure provides a compound of Formula II, II-1, II-2 or II-3 having a structure of Formula (IIa) or a pharmaceutically acceptable salt thereof:

[0414]

[0415] In some embodiments, the present disclosure provides a compound of Formula II, II-1, II-2, or II-3, or a pharmaceutically acceptable salt thereof, wherein L 1 For CHR 1b In some embodiments, the present disclosure provides compounds of Formula II, II-1, II-2, or II-3, or pharmaceutically acceptable salts thereof, wherein L 1 In some embodiments, the present disclosure provides compounds of Formula II, II-1, II-2, or II-3, or pharmaceutically acceptable salts thereof, wherein L 1 is CH(CH3). In some embodiments, the present disclosure provides a compound of Formula II, II-1, II-2 or II-3 or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b Each is independently H, C1-C3 alkyl or halo. In some embodiments, the present disclosure provides a compound of Formula II, II-1, II-2 or II-3 or a pharmaceutically acceptable salt thereof, wherein R 1b is a C1-C3 alkyl or halo. In some embodiments, the present disclosure provides a compound of Formula II, II-1, II-2 or II-3 or a pharmaceutically acceptable salt thereof, wherein R 1b It is a methyl group.

[0416] In some embodiments, the present disclosure provides a compound of Formula II, II-1, II-2, or II-3 having the structure of Formula (IIb), or a pharmaceutically acceptable salt thereof:

[0417]

[0418] In some embodiments, the present disclosure provides a compound of Formula II, II-1, II-2, II-3, (IIa) or (IIb), or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b Each is independently H, C1-C3 alkyl, halo or C1-C6 haloalkyl. In some embodiments, the present disclosure provides a compound of Formula II, II-1, II-2, II-3, (IIa) or (IIb) or a pharmaceutically acceptable salt thereof, wherein L 2 For CHR 2b In some embodiments, the present disclosure provides a compound of Formula II, II-1, II-2, II-3, (IIa) or (IIb), or a pharmaceutically acceptable salt thereof, wherein R 2b is H or C1-C3 alkyl. In some embodiments, the present disclosure provides a compound of Formula II, II-1, II-2, II-3, (IIa) or (IIb) or a pharmaceutically acceptable salt thereof, wherein R 2b is H. In some embodiments, the present disclosure provides a compound of Formula II, II-1, II-2, II-3, (IIa) or (IIb), or a pharmaceutically acceptable salt thereof, wherein R 2b In some embodiments, the present disclosure provides a compound of Formula II, II-1, II-2, II-3, (IIa) or (IIb), or a pharmaceutically acceptable salt thereof, wherein R 2b It is a methyl group.

[0419] In some embodiments, the present disclosure provides a compound of Formula II, II-1, II-2, II-3, or (IIa) having a structure of Formula (IIa-1), or a pharmaceutically acceptable salt thereof:

[0420]

[0421] In some embodiments, the present disclosure provides a compound of Formula II, II-1, II-2, II-3, or (IIb) having a structure of Formula (IIb-1), or a pharmaceutically acceptable salt thereof:

[0422]

[0423] In some embodiments, the present disclosure provides a compound of Formula II, II-1, II-2, II-3, (IIa), (IIb), or (IIb-1) having the structure of Formula (IIb-2), or a pharmaceutically acceptable salt thereof:

[0424]

[0425] In some embodiments, the present disclosure provides compounds of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), and (IIb-2), or pharmaceutically acceptable salts thereof, wherein R A 0, 1, 2, 3, 4 or 5 R A2 In some embodiments, the present disclosure provides compounds of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), and (IIb-2), or pharmaceutically acceptable salts thereof, wherein R A 0, 1, 2, 3, 4 or 5 R A2 Substituted naphthyl.

[0426] In some embodiments, the present disclosure provides compounds of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), and (IIb-2), or pharmaceutically acceptable salts thereof, wherein each R A2 are independently C1-C6 alkyl, -OH, C2-C6 alkenyl, C2-C6 alkynyl, halo, C1-C6 haloalkyl, -OR A2a 、-SR A2a or -(C1-C6 alkyl)-(C3-C8 cycloalkyl), wherein each alkenyl group is replaced by 0, 1, 2 or 3 R A3 Replace; each R A2a are independently C1-C6 haloalkyl or C3-C8 cycloalkyl; and each R A3In some embodiments, the present disclosure provides compounds of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), and (IIb-2), or pharmaceutically acceptable salts thereof, wherein each R A2 are independently Me, -OH, -C(Cl)=CH2, -CH=CHF2, -C≡CH, F, Cl, -CH2CF3, -OCF3, -O-cyclopropyl, -SCF3 or -CH2-cyclopropyl.

[0427] In some embodiments, the present disclosure provides compounds of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), and (IIb-2), or pharmaceutically acceptable salts thereof, wherein R A for

[0428]

[0429]

[0430] In some embodiments, the present disclosure provides compounds of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), and (IIb-2), or pharmaceutically acceptable salts thereof, wherein R A for

[0431]

[0432] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein R A for

[0433]

[0434] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein R A for

[0435]

[0436] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein R B For H.

[0437] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein

[0438] R B -C(O)R B1 or-C(O)OR B2 ;

[0439] R B1 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl, wherein C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl is substituted with 0, 1, 2 or 3 R B1a replace;

[0440] R B2 C1-C6 alkyl, C1-C6 haloalkyl, (C1-C6 alkyl)-OC(O)R B3 , C3-C8 cycloalkyl, C6-C 14 aryl, 5- to 14-membered heteroaryl, or

[0441]

[0442] wherein the C3-C8 cycloalkyl, the C6-C 14 The aryl group or the 5- to 14-membered heteroaryl group is replaced by 0, 1, 2 or 3 R B2a replace;

[0443] R B3 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl, wherein C3-C8 cycloalkyl, C6-C 14 Aryl or 5- to 14-membered heteroaryl is substituted with 0, 1, 2 or 3 R B3a replace; and

[0444] Each R B1a 、R B2a and R B3a C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkoxyalkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, oxo, -OH, -CN or C3-C 10 Cycloalkyl.

[0445] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein L C is the key.

[0446] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein L C for

[0447]

[0448] Y is C or Si; n is 0 or 1; q is 0 or 1; R Y1 is H or C1-C3 alkyl; and R Y2 is H or C1-C3 alkyl; alternatively, R Y1 and R Y2 Combined to form a C3-C6 cycloalkyl group.

[0449] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein L C for

[0450]

[0451] Y is C or Si; n is 0 or 1; q is 0 or 1; R Y1 is H or Me; and R Y2 is H or Me; alternatively, R Y1 and R Y2 Combined to form a cyclopropyl group.

[0452] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein

[0453] R C 0, 1, 2 or 3 R C3 substituted 3- to 14-membered heterocyclic group;

[0454] Each R C3 are independently C1-C6 alkyl, halo, C1-C6 haloalkyl, =CH2, -OR C3a or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), wherein each alkyl group is replaced by one -OC(O)N(R C3a1 )(R C3a2 ),-OR C3a1 or N3 substitution;

[0455] Each R C3a are independently C1-C6 haloalkyl; and

[0456] Each R C3a1 and R C3a2 are independently C1-C3 alkyl, C1-C6 haloalkyl, C6-C 10 Aryl or 5- to 10-membered heteroaryl, wherein each aryl or heteroaryl group is substituted with 0, 1, 2, 3, or 4 halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, or SF5;

[0457] Alternatively, R C3a1 and R C3a2 Together with the nitrogen to which they are attached, they form a 3- to 8-membered heterocyclic ring.

[0458] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein

[0459] R C 0, 1, 2 or 3 R C3 substituted 3- to 14-membered heterocyclic group;

[0460] Each R C3 are independently C1-C6 alkyl, halo, C1-C6 haloalkyl, =CH2, -OR C3a or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), wherein each alkyl group is replaced by one -OC(O)N(R C3a1 )(R C3a2 ),-OR C3a1 or N3 substitution;

[0461] Each R C3a are independently C1-C6 haloalkyl; and

[0462] Each R C3a1 and R C3a2 are independently C1-C3 alkyl, C1-C6 haloalkyl or C6-C 10 Aryl, wherein each aryl group is substituted with 1 SF5;

[0463] Alternatively, R C3a1 and R C3a2 Together with the nitrogen to which they are attached, they form a 3- to 8-membered heterocyclic ring.

[0464] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein L C for

[0465]

[0466] Y is C; n is 0; q is 0; R Y1 is H; and R Y2 is H. In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein L C It is -CH2-.

[0467] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein

[0468] R C is an 8- to 14-membered heterocyclic group, surrounded by 0, 1, 2 or 3 R C3 replace;

[0469] Each R C3 are independently C1-C6 alkyl, halo, =CH2, -OR C3a or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl),

[0470] Each alkyl group is replaced by a -OC(O)N(R C3a1 )(R C3a2 ),-OR C3a1 or N3 substitution;

[0471] Each R C3a are independently C1-C6 haloalkyl; and

[0472] Each R C3a1 and R C3a2 are independently C1-C3 alkyl, C1-C6 haloalkyl or C6-C 10 Aryl, wherein each aryl group is substituted by 1 SF5;

[0473] Alternatively, R C3a1 and R C3a2 Together with the nitrogen to which they are attached, they form a 3- to 8-membered heterocyclic ring.

[0474] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein L C for

[0475]

[0476] Y is C or Si; n is 1; q is 1; R Y1 for Me; and R Y2 for Me; alternatively, R Y1 and R Y2 In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein R C is 0, 1 or 2 R C3 substituted 3- to 7-membered heterocyclic group; and each R C3 are independently halo or C1-C6 haloalkyl.

[0477] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein R 1b is H or methyl; R C3 -CH2OR C3a1 or F; and R C3a1is a 5- to 6-membered heteroaryl substituted with one halo or C1-C2 haloalkyl. In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein R 1b is H or methyl; and R C3 is F. In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein R 1b is H or methyl; R C3 -CH2OR C3a1 ; and R C3a1 is a 6-membered heteroaryl substituted with one C1 haloalkyl. In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein R 1b is H or methyl; R C3 -CH2OR C3a1 ; and R C3a1 is pyridazine, pyrimidine or pyrazine, wherein the pyridazine, pyrimidine or pyrazine is substituted by one CF3.

[0478] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein L C -CH2-; R C For 1 RC3 substituted 3- to 14-membered heterocyclic group; R C3 To be a -OR C3a1 or -SR C3a1 Substituted C1-C6 alkyl; and R C3a1 is a 5- to 10-membered heteroaryl group substituted with 0, 1, or 2 C1-C3 haloalkyl or C1-C3 haloalkoxy groups. In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein L C -CH2-; R C For 1 R C3 substituted 4- to 8-membered heterocyclic group; R C3 -CH2OR C3a1 ; and R C3a1 is pyrimidine, wherein pyrimidine is substituted by 1 trifluoromethyl group.

[0479] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein -OL C -R C Part of

[0480]

[0481]

[0482]

[0483] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein -OL C -R C Part of

[0484]

[0485]

[0486] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein -OL C -R C Part of

[0487]

[0488] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein -OL C -R C Part of

[0489]

[0490]

[0491]

[0492] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein -OL C -R C Part of

[0493]

[0494] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein R D is F or Cl. In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein R D For F.

[0495] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), or (I-3), or a pharmaceutically acceptable salt thereof, wherein

[0496] X is N, CH or CR x ;

[0497] R x is a halogen group;

[0498] L 1 O or CR 1a R 1b ;

[0499] R 1a and R 1b Each is independently H, C1-C3 alkyl or halo;

[0500] L 2 CR 2a R 2b ;

[0501] R 2a and R 2b Each is independently H, C1-C3 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl;

[0502] L 3 key or CR 3a R 3b ;

[0503] R 3a and R 3b Each independently is H or C1-C3 alkyl;

[0504] R 1 、R2 、R 3 and R 4 Each is H;

[0505] R A is naphthyl, wherein R A 0, 1, 2, 3, 4 or 5 R A2 replace;

[0506] Each R A2 are independently -OH, C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 sulfanyl, halo, C1-C6 haloalkyl, -OR A2a 、-SR A2a 、-N(R A2a )(R A2b ) or -(C1-C6 alkyl)-(C3-C8 cycloalkyl), wherein each alkyl, alkenyl, alkynyl, alkoxy and haloalkyl group is replaced by 0, 1, 2 or 3 R A3 replace;

[0507] Each R A2a and R A2b are independently H, C1-C6 haloalkyl or C3-C8 cycloalkyl;

[0508] Each R A3 are independently halo;

[0509] R B is H;

[0510] L C For key or

[0511]

[0512] Y is C or Si;

[0513] n is 0 or 1;

[0514] q is 0 or 1;

[0515] R Y1 is H or C1-C3 alkyl;

[0516] R Y2 is H or C1-C3 alkyl;

[0517] Alternatively, R Y1 and R Y2 Combine to form a C3-C8 cycloalkyl group;

[0518] R C is a 3- to 14-membered heterocyclic group, wherein each 3- to 14-membered heterocyclic group is substituted by 0, 1, 2, 3 or 4 R C3 replace;

[0519] Each R C3 are independently C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxyalkyl, halo, C1-C6 haloalkyl, =CH2, -OR C3a , wherein each alkyl group is replaced by 0, 1, 2 or 3 -OC(O)N(R C3a1 )(R C3a2 ),-OR C3a1 、-SR C3a1 or N3 substitution;

[0520] R C3a is C1-C6 alkyl, C1-C6 haloalkyl or 5- to 10-membered heteroaryl, wherein the heteroaryl is replaced by one R C3a2 replace;

[0521] Each R C3a1 and R C3a2 are independently C1-C3 alkyl, C1-C6 haloalkyl, C6-C 10 Aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is substituted with 1 or 2 halo groups, C1-C3 haloalkyl groups, C1-C3 haloalkoxy groups, or SF5 groups;

[0522] Alternatively, R C3a1 and R C3a2 Together with the nitrogen to which they are attached, they form a 3- to 8-membered heterocyclic ring; and

[0523] R D For F.

[0524] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), or (I-3), or a pharmaceutically acceptable salt thereof, wherein

[0525] X is N, CH or C-Cl;

[0526] L 1 is O, CH2, CHCH3, CHCH2CH3, CHF or CF2;

[0527] L 2 is CH2, CHCH3, CHCH2CH3, CHCHF2 or

[0528]

[0529] L 3 is a bond, CH2 or CHCH3;

[0530] R 1 、R 2 、R 3 and R4 Each is H;

[0531] R A for

[0532]

[0533]

[0534] R B is H;

[0535] The-ol C -R C Part of

[0536]

[0537]

[0538] and

[0539] R D For F.

[0540] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein L 1 It is CH2, CHCH3, CHCH2CH3, CHF or CF2.

[0541] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein L 3 It is CH2 or CHCH3.

[0542] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein R A for

[0543]

[0544] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), or (I-3), or a pharmaceutically acceptable salt thereof, wherein

[0545] X is N;

[0546] R 1 、R 2 、R 3 and R 4 Each is H;

[0547] L 1 CR 1a R 1b ;

[0548] R 1a and R 1b Each independently is H or C1-C3 alkyl;

[0549] L 2 CR 2a R 2b ;

[0550] R 2a and R 2b Each is H;

[0551] L 3 CR 3a R 3b ;

[0552] R 3a and R 3b Each is H;

[0553] R A is naphthyl, wherein R A By 2 R A2 replace;

[0554] Each R A2 are independently C2-C6 alkynyl or halo;

[0555] R B is H;

[0556] L C for

[0557]

[0558] Y is C;

[0559] n is 0;

[0560] q is 0;

[0561] R Y1 is H;

[0562] R Y2 is H;

[0563] R C is a 3-membered to 14-membered heterocyclic group, wherein the 3-membered to 14-membered heterocyclic group is replaced by one R C3 replace;

[0564] R C3 is C1-C6 alkyl, halogen or C1-C6 haloalkyl, wherein the alkyl is replaced by one -OR C3a1 replace;

[0565] R C3a1 is a 5- to 10-membered heteroaryl group, wherein the heteroaryl group is substituted with one C1-C3 haloalkyl group; and

[0566] R D For F.

[0567] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), or (I-3), or a pharmaceutically acceptable salt thereof, wherein

[0568] X is N;

[0569] R 1 、R 2 、R 3 and R 4 Each is H;

[0570] L 1 is CH2 or CHCH3;

[0571] L 2 is CH2;

[0572] L 3 is CH2;

[0573] R A for

[0574]

[0575] R B is H;

[0576] The-ol C -R C Part of

[0577] and

[0578] R D For F.

[0579] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (Ib-5) or Formula (Ib-6):

[0580]

[0581] in

[0582] R 1b is H or methyl;

[0583] R C3 -CH2OR C3a1 or F; and

[0584] R C3a1 It is a 5- to 6-membered heteroaryl group substituted by one halogen group or C1-C2 haloalkyl group.

[0585] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (Ib-7) or Formula (Ib-8):

[0586]

[0587] in

[0588] R 1b is H or methyl;

[0589] R C3 -CH2OR C3a1 or F; and

[0590] RC3a1 It is a 5- to 6-membered heteroaryl group substituted by one halogen group or C1-C2 haloalkyl group.

[0591] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

[0639]

[0640] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), wherein the compound has the following structure:

[0641]

[0642] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

[0643]

[0644] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), wherein the compound has the following structure:

[0645]

[0646] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

[0647]

[0648] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), wherein the compound has the following structure:

[0649]

[0650] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

[0651]

[0652] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), wherein the compound has the following structure:

[0653]

[0654] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

[0655]

[0656] In some embodiments, the present disclosure provides a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), wherein the compound has the following structure:

[0657]

[0658] Also within the scope of this disclosure are the in vivo metabolic products of the compounds described herein. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, primarily due to enzymatic processes. Thus, novel and non-obvious compounds are produced by methods comprising contacting the compound with a mammal for a period of time sufficient to produce its metabolic products. Such products are typically identified by preparing a radiolabel (e.g., 14 C or 3H) compound, a detectable dose (e.g., greater than about 0.5 mg / kg) of the radiolabeled compound is administered parenterally to an animal (such as a rat, mouse, guinea pig, monkey, or human), sufficient time is allowed for metabolism (usually about 30 seconds to 30 hours), and its conversion products are isolated from urine, blood, or other biological samples. These products are easily isolated because they are labeled (other products are isolated by using antibodies that can bind to epitopes that survive in the metabolites). The metabolite structure is determined in a conventional manner, for example, by MS or NMR analysis. Generally, the analysis of metabolites is performed in the same manner as conventional drug metabolism studies. The conversion products can be used for diagnostic determination of therapeutic doses of the compound, as long as they are not otherwise found in vivo, even if they do not have HSV antiviral activity themselves.

[0659] Formulas and methods for determining the stability of compounds in alternative gastrointestinal secretions are known. Compounds are defined herein as being stable in the gastrointestinal tract, wherein less than about 50 mol % of the protecting groups are deprotected in alternative intestinal or gastric fluids after incubation at 37°C for 1 hour. Just because a compound is stable to the gastrointestinal tract does not mean that they cannot be hydrolyzed in vivo. Prodrugs are generally stable in the digestive system, but can be substantially hydrolyzed to the parent drug in the digestive cavity, liver, lungs or other metabolic organs or generally speaking in cells. As used herein, prodrugs are understood to be compounds that are chemically designed to effectively release the parent drug after overcoming the oral delivery biological barrier.

[0660] IV. Pharmaceutical Compositions

[0661] Also disclosed herein are pharmaceutical compositions comprising a pharmaceutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (II-1), (IIa), (IIb), (IIb-1), or (IIb-2)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. Also provided herein are pharmaceutical compositions comprising a pharmaceutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0662] The compounds disclosed herein can be formulated with conventional carriers and excipients. Tablets may contain, for example, excipients, glidants, fillers, binders, or combinations thereof. Aqueous formulations are prepared in a sterile form and, when intended for delivery by non-oral administration, will generally be isotonic. Exemplary excipients include, but are not limited to, "H ANDBOOK OF P HARMACEUTICALE XCIPIENTS " (1986). Excipients may include, for example, ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, and combinations thereof. In some embodiments, the formulation is alkaline. In some embodiments, the formulation is acidic. In some embodiments, the formulation has a neutral pH. In some embodiments, the pH of the formulation is 2 to 11 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 2-3, 2 7, 7-9, 7-10, 7-11, 8-9, 8-10, 8-11, 9-10 or 9-11).

[0663] In some embodiments, the compounds disclosed herein have pharmacokinetic properties (e.g., oral bioavailability) suitable for oral administration of the compound. Formulations suitable for oral administration can, for example, be provided in discrete units such as capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient can also be administered, for example, as a pill, elixir, or paste.

[0664] Tablet can be prepared by optionally compressing or molding with at least auxiliary components.Compressed tablets can be prepared by compressing the active ingredient of free-flowing form (such as, for example, powdered or granular) in a suitable machine, optionally mixed with binding agent, lubricant, inert diluent, preservative, surfactant, dispersant or its combination.Moulded tablets can be prepared by molding the mixture of the powdered active ingredient moistened with an inert liquid diluent in a suitable machine.Tablet can be optionally coated or scored, and optionally formulated to provide active ingredient therefrom slowly or controlled release.

[0665] For infections of the eye or other external tissues (e.g., mouth and skin), the formulations can be applied as topical ointments or creams containing the active ingredient in amounts of, for example, 0.075% w / w to 20% w / w (including active ingredients in a range between 0.1% and 20% in increments of 0.1% w / w, such as 0.6% w / w, 0.7% w / w, etc.), 0.2% w / w to 15% w / w, or 0.5% w / w to 10% w / w. When formulated as an ointment, in some embodiments the active ingredient can be used with a paraffin base or a water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream with an oil-in-water cream base.

[0666] In some embodiments, the aqueous phase of the cream base may comprise, for example, 30% to 90% (e.g., 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%) w / w of a polyol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures thereof. In some embodiments, the cream base may comprise, for example, a compound that enhances the absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin penetration enhancers include, but are not limited to, dimethyl sulfoxide and related analogs. In some embodiments, the cream or emulsion does not include water.

[0667] The oil phase of the emulsion can be composed of known ingredients in a known manner. In some embodiments, the phase comprises only an emulsifier (otherwise referred to as an emulsifier). In some embodiments, the phase comprises a mixture of at least one emulsifier and a fat, an oil, or a combination thereof. In some embodiments, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. The emulsifier, with or without a stabilizer, can together constitute a so-called emulsifying wax, and the wax, together with the oil and fat, constitutes a so-called emulsifying ointment base, which can form the oily dispersed phase of the cream formulation.

[0668] Emulsifiers and emulsion stabilizers suitable for the formulation may include but are not limited to 60. 80. 80, cetearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate and combinations thereof.

[0669] The appropriate oil or fat may be selected for the formulation based on achieving the desired cosmetic properties. In some embodiments, the cream may be a non-greasy, non-staining, and washable product with a suitable consistency to avoid leakage from tubes or other containers. In some embodiments, an ester may be included, for example, a linear or branched mono- or di-alkyl ester such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, known as A mixture or combination of branched chain esters of CAP. In some embodiments, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be included.

[0670] In some embodiments, the compounds disclosed herein are administered alone. In some embodiments, the compounds disclosed herein are administered as pharmaceutical compositions. In some embodiments, the pharmaceutical compositions are for veterinary use. In some embodiments, the pharmaceutical compositions are for human use. In some embodiments, the pharmaceutical compositions disclosed herein include at least one additional therapeutic agent. In some embodiments, the pharmaceutical compositions disclosed herein include one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are independently chemotherapeutic agents, immunotherapeutic agents, hormonal agents, antihormonal agents, targeted therapeutic agents, or anti-angiogenic agents.

[0671] The pharmaceutical compositions disclosed herein can be in any form suitable for the intended method of administration. The pharmaceutical compositions disclosed herein can be in unit dosage form and can be prepared by any of the methods well known in the pharmaceutical field. Exemplary techniques and formulations can be found in, for example, "Remington's Pharmaceutical Sciences" (Mack Publishing Co., Easton, PA). Such methods may include the step of associating the compounds disclosed herein with a carrier constituting at least an auxiliary component. Generally speaking, the formulation can be prepared by uniformly and closely associating the active ingredient with a liquid carrier or a finely dispersed solid carrier or both, and then, if necessary, shaping the product.

[0672] For example, when used for oral administration, tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups, or elixirs can be prepared. Formulations intended for oral use can be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such formulations may contain at least pharmaceutical agents, including sweeteners, flavorings, colorants, and preservatives, in order to provide a palatable formulation. Tablets containing the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0673] Formulations for oral use may also be provided as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0674] Aqueous suspensions can contain active substances mixed with excipients suitable for making aqueous suspensions. Such excipients can include, for example, suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth gum and gum arabic; and dispersants or wetting agents, such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (e.g., heptadecanol), condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions can also contain, for example, one or more preservatives, such as ethyl parahydroxybenzoate or n-propyl parahydroxybenzoate, one or more coloring agents, one or more flavoring agents, one or more sweeteners (e.g., sucrose or saccharin) or combinations thereof. Other non-limiting examples of suspending agents include cyclodextrins. In some embodiments, the suspending agent is sulfobutyl ether β-cyclodextrin (SEB-β-CD), e.g.

[0675] Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil, or a combination thereof), a mineral oil (such as liquid paraffin), or a combination thereof. Oral suspensions may contain, for example, thickeners such as beeswax, hard paraffin, cetyl alcohol, or a combination thereof. In some embodiments, sweeteners (such as those described above) and / or flavorings are added to provide a palatable oral formulation. In some embodiments, the formulations disclosed herein are preserved by adding an antioxidant such as ascorbic acid.

[0676] Dispersible powders and granules suitable for preparing an aqueous suspension by adding water can provide the active ingredient in admixture with a dispersant or wetting agent, a suspending agent, a preservative, and combinations thereof. Suitable dispersants or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, such as sweeteners, flavorings, and coloring agents, may also be present.

[0677] Pharmaceutical compositions can also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil (such as olive oil or peanut oil), a mineral oil (such as liquid paraffin), or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as gum arabic and gum tragacanth; naturally occurring phospholipids such as soy lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions can also contain sweeteners and flavorings. Syrups and elixirs can be formulated with sweeteners such as, for example, glycerol, sorbitol, or sucrose. Such preparations can also contain, for example, a demulcent, a preservative, a flavoring, a coloring agent, or a combination thereof.

[0678] The pharmaceutical composition may be in the form of a sterile injectable or intravenous preparation, such as a sterile injectable aqueous or oily suspension. The suspension may be prepared according to known techniques using the suitable dispersants or wetting agents and suspending agents mentioned above. The sterile injectable or intravenous preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (such as a solution in 1,3-butanediol), or may be prepared as a lyophilized powder. Acceptable solvents and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may be used as solvents or suspending media. For this purpose, any mild fixed oil may be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid may also be used to prepare injections. Acceptable solvents and solvents that may be used include, but are not limited to, water, Ringer's solution, isotonic sodium chloride solution, and hypertonic sodium chloride solution.

[0679] The amount of active ingredient that can be combined with carrier material to produce single dosage form will vary according to the host being treated and specific mode of administration. For example, it is intended that the sustained-release formulation for oral administration to people can contain about 1mg to 2000mg of active material, and this active material is compounded with the carrier material of suitable and convenient amount, and this carrier material can change between 5% to 95% (weight: weight) of total preparation. For example, it is intended that the sustained-release formulation for oral administration to people can contain about 1mg to 1000mg of active material, and this active material is compounded with the carrier material of suitable and convenient amount, and this carrier material can change between 5% to 95% (weight: weight) of total preparation. Pharmaceutical composition can be prepared to provide the dosage that is easy to measure. For example, it is intended that every milliliter of solution of aqueous solution for intravenous infusion can contain 3 μ g to 500 μ g of active ingredient, so that suitable volume is infused at a rate of 30mL / hr.

[0680] Formulations suitable for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent for the active ingredient. In some embodiments, the compounds disclosed herein are included in the pharmaceutical compositions disclosed herein at a concentration of 0.5% to 20% (e.g., 0.5% to 10%, 1.5% w / w).

[0681] Formulations suitable for topical administration in the mouth include lozenges which may contain the active ingredient (i.e., a compound disclosed herein and / or an additional therapeutic agent) in a flavored basis, usually sucrose and acacia or tragacanth; lozenges containing an inert active ingredient such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0682] Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

[0683] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[0684] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes to render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0685] The preparation can be present in unit dose or multidose containers, such as sealed ampoules and vials, and can be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Extemporaneous injections and suspensions are prepared from sterile powders, granules, and tablets of the aforementioned types. Preferred unit dose formulations are preparations containing a daily dose or unit daily subdose of the active ingredient as described above, or an appropriate portion thereof.

[0686] It should be understood that in addition to the ingredients particularly mentioned above the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0687] Also provided are veterinary formulations comprising a compound disclosed herein and a veterinary carrier therefor.

[0688] Veterinary carriers are materials useful for administering the formulation and can be solid, liquid, or gaseous materials that are otherwise inert or acceptable in the veterinary art and compatible with the active ingredient. These veterinary formulations can be administered orally, parenterally, or by any other desired route.

[0689] The compounds herein are useful in providing controlled-release pharmaceutical compositions ("controlled-release formulations") comprising one or more of these compounds as active ingredients, wherein the release of the active ingredient can be controlled and regulated to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0690] The effective dose of the active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is used prophylactically (lower dose) or for use against active viral infection, the method of delivery, and the pharmaceutical composition, and will be determined by the clinician using conventional dose escalation studies. In some embodiments, the effective dose is from about 0.0001 mg / kg body weight to about 100 mg / kg body weight per day; for example, from 10 mg / kg body weight to 30 mg / kg body weight per day; from 15 mg / kg body weight to 25 mg / kg body weight per day; from 10 mg / kg body weight to 15 mg / kg body weight per day; or from 20 mg / kg body weight to 30 mg / kg body weight per day. For example, a candidate daily dose range for an adult weighing approximately 70 kg may be from 1 mg to 2000 mg (e.g., 5 mg to 500 mg, 500 mg to 1000 mg, 1000 mg to 1500 mg, 1500 mg to 2000 mg), and may be in the form of a single dose or multiple doses. For example, a candidate daily dosage for an adult human weighing approximately 70 kg may range from 1 mg to 1000 mg (eg, 5 mg to 500 mg), and may be in the form of a single dose or multiple doses.

[0691] V. Kit

[0692] Also provided herein are kits comprising the compounds disclosed herein or pharmaceutically acceptable salts thereof. In some embodiments, the kits described herein may include labels and / or instructions for using the compounds to treat a disease or condition in a subject (e.g., a human) in need thereof. In some embodiments, the disease or condition is a viral infection.

[0693] In some embodiments, the kit may further comprise one or more additional therapeutic agents and / or instructions for using the additional therapeutic agents in combination with the compounds disclosed herein to treat a disease or condition in a subject (e.g., a human) in need thereof.

[0694] In some embodiments, the kits provided herein contain individual dosage units of a compound as described herein, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate thereof. Examples of individual dosage units may include pills, tablets, capsules, prefilled syringes or syringes, IV bags, inhalers, nebulizers, and the like, each of which includes a therapeutically effective amount of the compound in question, or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph, amorphous form, hydrate, or solvate thereof. In some embodiments, the kit may contain a single dosage unit, and in other embodiments, there may be multiple dosage units, such as the number of dosage units required for a given regimen or cycle.

[0695] Also provided are articles of manufacture comprising: a compound disclosed herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof; and a container. In some embodiments, the container of the article of manufacture is a vial, a jar, an ampoule, a prefilled syringe, a blister pack, a can, a tin, a bottle, a box, an intravenous bag, an inhaler, or a nebulizer.

[0696] VI. Application

[0697] One or more compounds of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2) (referred to herein as the active ingredient) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural), among others. It will be appreciated that the route may vary depending, for example, on the condition of the recipient. An advantage of the compounds herein is that they are orally bioavailable and can be administered orally.

[0698] The compounds of the present disclosure (also referred to herein as active ingredients) may be administered by any route appropriate to the condition to be treated.

[0699] Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), etc. It will be appreciated that the route may vary depending, for example, on the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0700] The compounds of the present disclosure can be administered to an individual for a desired period of time or duration according to an effective dosing regimen, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In some embodiments, the compounds are administered on a daily or intermittent schedule during the life of the individual.

[0701] The dosage or frequency of administration of the disclosed compounds may be adjusted during the course of treatment according to the judgment of the administering physician.

[0702] The compound can be administered to an individual (eg, a human) in an effective amount. In some embodiments, the compound is administered once daily.

[0703] The compound can be used by any available approach and method, such as by oral or parenteral (for example, intravenous) administration.The therapeutically effective amount of the compound can include about 0.00001mg / kg body weight / day to about 10mg / kg body weight / day, such as about 0.0001mg / kg body weight / day to about 10mg / kg body weight / day, or such as about 0.001mg / kg body weight / day to about 1mg / kg body weight / day, or such as about 0.01mg / kg body weight / day to about 1mg / kg body weight / day, or such as about 0.05mg / kg body weight / day to about 0.5mg / kg body weight / day, or such as about 0.3mg / day to about 30mg / day, or such as about 30mg / day to about 300mg / day.

[0704] The compounds of the present disclosure can be combined with one or more additional therapeutic agents in any dose of the compounds of the present disclosure (e.g., about 1 mg to about 1000 mg of compound). A therapeutically effective amount can include about 1 mg / dose to about 1000 mg / dose, such as about 50 mg / dose to about 500 mg / dose, or such as about 100 mg / dose to about 400 mg / dose, or such as about 150 mg / dose to about 350 mg / dose, or such as about 200 mg / dose to about 300 mg / dose. Other therapeutically effective amounts of the compounds of the present disclosure are about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg per dose. Other therapeutically effective amounts of the disclosed compounds are about 100 mg per dose, or about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, or about 500 mg per dose. A single dose can be administered hourly, daily, or weekly. For example, a single dose can be administered once every 1 hour, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 16 hours, or about every 24 hours. A single dose can also be administered once every 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about every 7 days. A single dose can also be administered once every 1 week, about 2 weeks, about 3 weeks, or about every 4 weeks. In some embodiments, a single dose can be administered approximately once a week. A single dose may also be administered about once a month.

[0705] Other therapeutically effective amounts of the compounds of the present disclosure are about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg per dose.

[0706] The dosage frequency of the compounds of the present disclosure can be determined by the needs of each patient and can be, for example, once a day or twice a day or more. The administration of the compound is continued as long as the treatment of the disease or condition requires. For example, the compound can be administered to a person suffering from cancer for a period of about 20 days to about 180 days, or for example, a period of about 20 days to about 90 days, or for example, a period of about 30 days to about 60 days.

[0707] Administration may be intermittent, with the patient receiving a daily dose of a compound of the present disclosure over a period of several or more days, followed by a period of several or more days where the patient does not receive a daily dose of the compound. For example, the patient may receive a dose of the compound every other day or three times a week. For example, the patient may receive a dose of the compound daily for a period of about 1 day to about 14 days, followed by a period of about 7 days to about 21 days where the patient does not receive a dose of the compound, followed by a period of daily doses of the compound again in subsequent time periods (e.g., about 1 day to about 14 days). Depending on the clinical needs of the patient being treated, alternating time periods of administration of the compound followed by no administration of the compound may be repeated.

[0708] In some embodiments, pharmaceutical compositions are provided that include a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents and a pharmaceutically acceptable excipient.

[0709] In some embodiments, kits are provided that include a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

[0710] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and / or they may be selected from different classes of therapeutic agents.

[0711] In some embodiments, when the compounds of the present disclosure are combined with one or more additional therapeutic agents as described herein, the components of the composition are administered in a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more administrations.

[0712] In some embodiments, a compound of the present disclosure is combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, eg, as a solid dosage form for oral administration.

[0713] In some embodiments, compounds of the present disclosure are co-administered with one or more additional therapeutic agents.

[0714] In order to prolong the effect of the compounds of the present invention, it is generally desirable to slow down the absorption of the compounds from subcutaneous or intramuscular injections. This can be achieved by using a liquid suspension of crystalline or amorphous materials with poor water solubility. The absorption rate of the compound depends on its dissolution rate, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of the compound form administered parenterally can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer (such as polylactide-polyglycolide). Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by embedding the compound in liposomes or microemulsions that are compatible with body tissues.

[0715] VII. Instructions for use

[0716] The present disclosure also relates to the use of the compounds disclosed herein for treating and / or preventing diseases and / or conditions by inhibiting KRAS G12D and / or G12C. In addition, the present disclosure relates to the use of the compounds in the preparation of a medicament for treating and / or preventing cancer.

[0717] Medicaments as referred to herein can be prepared by conventional methods, comprising combining a compound according to the present disclosure and a pharmaceutically acceptable carrier.

[0718] In some embodiments, provided herein are methods of inhibiting KRAS G12D protein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an agent of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2). A compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2).

[0719] In some embodiments, provided herein are methods for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (Ib-2). Ib-2) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1) or (IIb-2).

[0720] In some embodiments, provided herein are methods of treating and / or preventing cancer.

[0721] In some embodiments, provided herein are methods of treating and / or preventing KRAS G12D-associated cancers.

[0722] In some embodiments, provided herein are methods of reducing cell proliferation comprising contacting the cell with a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2).

[0723] In some embodiments, KRAS G12D related diseases or conditions include cancer. In some embodiments, the cancer is a blood cancer. In some embodiments, the cancer may be a solid tumor. In some embodiments, cancer includes a malignant tumor. In some embodiments, cancer includes metastatic cancer. In some embodiments, the cancer is resistant or refractory to one or more anti-cancer therapies. In some embodiments, greater than about 50% of cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., so-called "hot" cancer or tumor). In some embodiments, greater than about 1% and less than about 50% of cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., so-called "warm" cancer or tumor). In some embodiments, less than about 1% of cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., so-called "cold" cancer or tumor).

[0724] In some embodiments, the KRAS G12D-associated disease or disorder is a blood cancer, such as a leukemia (e.g., acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), B-cell ALL, myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), undifferentiated leukemia), a lymphoma (e.g., small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM), and / or a myeloma (e.g., multiple myeloma (MM)).

[0725] In some embodiments, the KRAS G12D-associated disease or disorder is an epithelial tumor (e.g., carcinoma, squamous cell carcinoma, basal cell carcinoma, squamous intraepithelial neoplasia), a glandular tumor (e.g., adenocarcinoma, adenoma, adenomyoma), a mesenchymal or soft tissue tumor (e.g., sarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, dermatofibrosarcoma, neurofibrosarcoma, fibrohistiocytoma, angiosarcoma, angiomyxoma, leiomyomas, enchondromas, chondrosarcomas, alveolar soft part sarcomas, epithelioid hemangioendothelioma, Spitz tumor, synovial sarcoma), or a lymphoma.

[0726] In some embodiments, the KRAS G12D-associated disease or disorder comprises a solid tumor in or arising from a tissue or organ, such as:

[0727] Skeletal (e.g., adamantoma, aneurysmal bone cyst, angiosarcoma, chondroblastoma, enchondroma, chondromyxoid fibroma, chondrosarcoma, chordoma, dedifferentiated chondrosarcoma, enchondroma, epithelioid hemangioendothelioma, fibrous dysplasia of bone, giant cell tumor of bone, hemangioma and related lesions, osteoblastoma, osteochondroma, osteosarcoma, osteoid osteoma, osteoma, periosteal chondroma, desmoid tumor, Ewing sarcoma);

[0728] Lips and oral cavity (e.g., odontogenic ameloblastoma, oral leukoplakia, oral squamous cell carcinoma, primary oral mucosal melanoma); salivary glands (e.g., pleomorphic salivary adenoma, salivary adenoid cystic carcinoma, salivary mucoepidermoid carcinoma, salivary Warthin's tumor);

[0729] esophagus (e.g., Barrett's esophagus, dysplasia, and adenocarcinoma);

[0730] Gastrointestinal tract, including stomach (e.g., gastric adenocarcinoma, primary gastric lymphoma, gastrointestinal stromal tumor (GIST), metastatic deposits, gastric cancer, gastric sarcoma, neuroendocrine carcinoma, primary squamous cell carcinoma of the stomach, gastric adenoacanthocarcinoma), intestine and smooth muscle (e.g., intravenous leiomyoma), colon (e.g., colorectal adenocarcinoma), rectum, and anus;

[0731] Pancreas (e.g., serous tumors, including microcystic or macrocystic serous cystadenomas, solid serous cystadenomas, Von Hippel-Landau (VHL)-associated serous cystic neoplasms, serous cystadenocarcinomas; mucinous cystic neoplasms (MCNs), intraductal papillary mucinous neoplasms (IPMNs), intraductal oncocytic papillary neoplasms (IOPNs), intraductal tubular neoplasms, cystic acinar tumors (including acinar cell cystadenoma and acinar cell cystadenocarcinoma), pancreatic cancer, invasive pancreatic ductal adenocarcinoma (including tubular adenocarcinoma and adenosquamous carcinoma), colloid carcinoma, medullary carcinoma, hepatoid carcinoma, signet ring cell carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, acinar cell carcinoma, neuroendocrine tumors, neuroendocrine microadenomas, neuroendocrine tumors (NETs), neuroendocrine carcinoma (NEC) (including small cell or large cell NECs), insulinomas, gastrinomas, glucagonomas, serotonin-producing NETs, ​​somatostatinomas, VIPomas, solid pseudopapillary neoplasms (SPNs), pancreatoblastomas);

[0732] Gallbladder (e.g., gallbladder cancer and extrahepatic and intrahepatic bile duct cancer);

[0733] Neuroendocrine glands (e.g., adrenal cortical carcinoma, carcinoid, pheochromocytoma, pituitary adenoma);

[0734] Thyroid (e.g., anaplastic (undifferentiated) carcinoma, medullary carcinoma, oncocytic tumor, papillary carcinoma, adenocarcinoma);

[0735] Liver (e.g., adenoma, combined hepatocellular and cholangiocarcinoma, fibrolamellar carcinoma, hepatoblastoma, hepatocellular carcinoma, mesenchymal nested stromal epithelial tumor, undifferentiated carcinoma; hepatocellular carcinoma, intrahepatic bile duct carcinoma, biliary cystadenocarcinoma, epithelioid hemangioendothelioma, angiosarcoma, embryonal sarcoma, rhabdomyosarcoma, solitary fibrous tumor, teratoma, yolk sac tumor, carcinosarcoma, rhabdoid tumor);

[0736] Kidney (e.g., ALK-rearranged renal cell carcinoma, chromophobe renal cell carcinoma, clear cell renal cell carcinoma, clear cell sarcoma, metanephric adenoma, metanephric adenofibroma, mucinous tubular and spindle cell carcinoma, nephroma, Wilms tumor, papillary adenoma, papillary renal cell carcinoma, renal oncocytoma, renal cell carcinoma, succinate dehydrogenase-deficient renal cell carcinoma, collecting duct carcinoma);

[0737] Breast (e.g., invasive ductal carcinoma, including but not limited to acinar cell carcinoma, adenoid cystic carcinoma, apocrine carcinoma, cribriform carcinoma, glycogen-rich / clear cell inflammatory carcinoma, lipid-rich carcinoma, medullary carcinoma, metaplastic carcinoma, micropapillary carcinoma, mucinous carcinoma, neuroendocrine carcinoma, oncocytic carcinoma, papillary carcinoma, sebaceous carcinoma, secretory breast carcinoma, tubular carcinoma; lobular carcinoma, including but not limited to pleomorphic carcinoma, signet ring cell carcinoma);

[0738] Peritoneum (e.g., mesothelioma; primary peritoneal carcinoma);

[0739] Tissues of the female sex organs, including ovary (e.g., choriocarcinoma, epithelial cell tumor, germ cell tumor, sex cord-stromal tumor), fallopian tube (e.g., serous adenocarcinoma, mucinous adenocarcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma, undifferentiated carcinoma, müllerian tumor, adenosarcoma, leiomyosarcoma, teratoma, germ cell tumor, choriocarcinoma, trophoblastoma), uterus (e.g., cervical cancer, endometrial polyps, endometrial hyperplasia, intraepithelial carcinoma (EIC), endometrial cancer (e.g., endometrioid carcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, squamous cell carcinoma, transitional carcinoma, small cell carcinoma, undifferentiated carcinoma, mesenchymal tumor), leiomyoma (e.g., endometrial stromal nodule, leiomyosarcoma, endometrial stromal sarcoma (ESS), mesenchymal tumor), mixed epithelial and mesenchymal tumor (e.g., adenofibroma, carcinofibroma, adenosarcoma, carcinosarcoma (malignant mixed mesodermal sarcoma - MMMT)), endometrial stromal tumor, malignant mixed Müllerian tumor of the endometrium, gestational trophoblastic tumor (partial hygroma, complete hygroma, invasive hygroma, placental site tumor)), vulva, vagina;

[0740] Male sex organ tissue, including the prostate, testicles (e.g., germ cell tumors, spermatocytic seminoma), and penis;

[0741] Bladder (e.g., squamous cell carcinoma, urothelial carcinoma, urothelial bladder carcinoma);

[0742] Brain (e.g., gliomas (e.g., astrocytomas (including non-invasive, low-grade, anaplastic), glioblastomas; oligodendrogliomas, ependymomas), meningiomas, gangliogliomas, schwannomas (neurilemmomas), craniopharyngiomas, chordomas, non-Hodgkin lymphomas (NHL), indolent non-Hodgkin lymphomas (iNHL), refractory iNHL, pituitary tumors);

[0743] Eyes (e.g., retinocytoma, retinoblastoma, ocular melanoma, choroidal melanoma, iris hamartoma);

[0744] Head and neck (e.g., nasopharyngeal carcinoma, endolymphatic sac tumor (ELST), epidermoid carcinoma, laryngeal cancer (including squamous cell carcinoma (SCC)) (e.g., glottic cancer, supraglottic cancer, subglottic cancer, transglottic cancer), carcinoma in situ, verrucous hemangioma, spindle cell and basal cell SCC, undifferentiated carcinoma, laryngeal adenocarcinoma, adenoid cystic carcinoma, neuroendocrine carcinoma, laryngeal tumor), head and neck paraganglioma (e.g., carotid body tumor, cervicotympanic tumor, vagal neuroma);

[0745] thymus (e.g., thymoma);

[0746] Heart (e.g. cardiac myxoma);

[0747] Lung (e.g., small cell carcinoma (SCLC), non-small cell lung cancer (NSCLC) (including squamous cell carcinoma (SCC)), adenocarcinoma, and large cell carcinoma), carcinoid (typical or atypical), carcinosarcoma, pulmonary blastoma, giant cell carcinoma, spindle cell carcinoma, pleuropulmonary blastoma);

[0748] Lymphoma (e.g., lymphoma, including Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), indolent non-Hodgkin lymphoma (iNHL), refractory iNHL, Epstein-Barr virus (EBV)-associated lymphoproliferative disorders, including B-cell lymphoma and T-cell lymphoma (e.g., Burkitt lymphoma; large B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, indolent B-cell lymphoma, low-grade B-cell lymphoma, fibrinogen-associated diffuse large cell lymphoma; primary effusion lymphoma; plasmablastic lymphoma; extranodal NK / T-cell lymphoma, nasal type; peripheral T-cell lymphoma, cutaneous T-cell lymphoma, angioimmunoblastic T-cell lymphoma; follicular T-cell lymphoma; systemic T-cell lymphoma), lymphangioleiomyomatosis);

[0749] Central nervous system (CNS) (e.g., gliomas, including astrocytic tumors (e.g., pilocytic astrocytoma, fluid-like astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, diffuse astrocytoma, fibrillary astrocytoma, fat cell astrocytoma, protoplasmic astrocytoma, anaplastic astrocytoma), glioblastoma (e.g., giant cell glioblastoma, gliosarcoma, glioblastoma multiforme), and gliomatosis cerebri), oligodendroglial tumors (e.g., oligodendroglioma, anaplastic oligodendroglioma), oligoastrocytic tumors (e.g., oligoastrocytoma, anaplastic oligoastrocytoma), ependymoma tumors (e.g., ependymomas, myxopapillary ependymomas, ependymomas (e.g., cellular, papillary, clear cell, elongated cell), anaplastic ependymomas), optic nerve gliomas, and non-glial tumors (e.g., choroid plexus tumors, neuronal and mixed neuronal-glial tumors, pineal region tumors, embryonal tumors, medulloblastomas, meningeal tumors, primary CNS lymphomas, germ cell tumors, pituitary adenomas, cranial and paraspinal nerve tumors, stellate region tumors); neurofibromas, meningiomas, peripheral nerve sheath tumors, peripheral neuroblastic tumors (including but not limited to neuroblastomas, ganglioneuroblastomas, ganglioneuromas), trisomy 19 ependymomas);

[0750] Neuroendocrine tissue (e.g., paraganglionic system, including adrenomedullin (pheochromocytoma) and extraadrenal paraganglia ((extraadrenal) paraganglioma);

[0751] Skin (e.g., clear cell hidradenoma, benign fibrous histiocytoma of the skin, cylindroma, hidradenoma, melanoma (including cutaneous melanoma, mucosal melanoma), pilomatricoma, Spitz tumor); and

[0752] Soft tissue (e.g., aggressive angiomyxoma, alveolar rhabdomyosarcoma, alveolar soft tissue sarcoma, angiofibroma, angiomatoid fibrous histiocytoma, synovial sarcoma, biphasic synovial sarcoma, clear cell sarcoma, dermatofibrosarcoma protuberans, desmoid fibroma, small round cell tumor, desmoplastic small round cell tumor, fibroelastoma, embryonal rhabdomyosarcoma, Ewing tumor / primitive neuroectodermal tumor (PNET), extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, paraspinal sarcoma, inflammatory Myofibroblastoma, liposarcoma, lipoma, chondroid lipoma, liposarcoma / malignant lipoma tumor, liposarcoma, myxoid liposarcoma, fibromyxoid sarcoma, lymphoangioleiomyomas, malignant myoepithelioma, malignant melanoma of the soft tissue, myoepithelial carcinoma, myoepithelioma, myxoinflammatory fibroblastic sarcoma, undifferentiated sarcoma, pericytoma, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), soft tissue leiomyosarcoma, undifferentiated sarcoma, well-differentiated liposarcoma.

[0753] In some embodiments, the KRAS G12D-associated disease or condition is a cancer selected from lung cancer, colorectal cancer, breast cancer, prostate cancer, cervical cancer, pancreatic cancer, and head and neck cancer. In some embodiments, the cancer is metastatic.

[0754] In some embodiments, the KRAS G12D-associated disease or condition is a cancer selected from non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal carcinoma (NPC), microsatellite stable colorectal cancer (mssCRC), thymoma, and gastrointestinal stromal tumor (GIST). In some embodiments, the cancer is metastatic.

[0755] In some embodiments, the KRAS G12D-associated disease or disorder is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, uterine cancer, gastric cancer, bile duct cancer, testicular cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small cell lung cancer, myelodysplastic syndrome, thyroid cancer, or colon cancer.

[0756] In some embodiments, the KRAS G12D-associated disease or disorder is pancreatic cancer, colorectal cancer, non-small cell lung cancer, endometrial cancer, uterine endometrical carcinoma, bile duct cancer, testicular germ cell cancer, cervical squamous cell carcinoma, or myelodysplastic syndrome.

[0757] In some embodiments, the cancer is myelodysplastic syndrome. In some embodiments, the cancer is high-risk myelodysplastic syndrome or low-risk myelodysplastic syndrome. In some embodiments, the cancer is high-risk myelodysplastic syndrome. In some embodiments, the cancer is high-risk myelodysplastic syndrome.

[0758] In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is non-small cell lung cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is testicular germ cell cancer. In some embodiments, the cancer is cervical squamous cell carcinoma. In some embodiments, the cancer is bile duct cancer.

[0759] The effective dosage of the active ingredient employed may vary depending on the specific compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosages can be readily determined by those skilled in the art.

[0760] When treating or preventing KRAS G12D-related diseases or conditions for which the compounds of the present invention are applicable, satisfactory results are generally obtained when the compounds of the present invention are administered at a daily dose of about 0.1 mg to about 300 mg per kilogram of animal body weight. In some embodiments, the compounds of the present invention are administered in a single daily dose or in divided doses twice to six times a day or in a sustained release form. For most large mammals, the total daily dose is about 1 mg to about 1000 mg, or about 1 mg to about 50 mg. In the case of a 70 kg adult, the total daily dose will typically be about 0.1 mg to about 200 mg. The dosage regimen can be adjusted to provide the optimal therapeutic response. In some embodiments, the total daily dose is from about 1 mg to about 900 mg, from about 1 mg to about 800 mg, from about 1 mg to about 700 mg, from about 1 mg to about 600 mg, from about 1 mg to about 400 mg, from about 1 mg to about 300 mg, from about 1 mg to about 200 mg, from about 1 mg to about 100 mg, from about 1 mg to about 50 mg, from about 1 mg to about 20 mg, or from about 1 mg to about 10 mg.

[0761] The compounds of the present application, or compositions thereof, can be administered once, twice, three times, or four times daily using any suitable mode described above. Furthermore, administration or treatment with the compounds can continue for multiple days; for example, for one treatment cycle, treatment will typically continue for at least 7, 14, or 28 days. Treatment cycles typically alternate with a rest period of about 1 to 28 days, typically about 7 or about 14 days, between cycles. In other embodiments, treatment cycles can also be continuous.

[0762] In some embodiments, the methods provided herein comprise administering to a subject an initial daily dose of about 1 mg to 800 mg of a compound described herein, and gradually increasing the dose until clinical efficacy is achieved. Increments of about 5 mg, 10 mg, 25 mg, 50 mg, or 100 mg may be used to increase the dose. The dose may be increased daily, every other day, twice a week, or once a week.

[0763] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more additional therapeutic agents or therapeutic modalities.

[0764] In some embodiments, the present disclosure provides pharmaceutical compositions or methods wherein the one or more additional therapeutic agents or additional therapeutic modalities include one, two, three, or four additional therapeutic agents and / or therapeutic modalities.

[0765] In some embodiments, the present disclosure provides pharmaceutical compositions or methods, wherein the additional therapeutic agent or therapeutic modality is selected from an immune checkpoint modulator, an antibody-drug conjugate (ADC), an anti-apoptotic agent, a targeted anti-cancer therapeutic, a chemotherapeutic agent, surgery, or radiation therapy.

[0766] In some embodiments, the present disclosure provides a pharmaceutical composition or method, wherein the immune checkpoint regulator is selected from anti-PD-(L)1 antibodies, anti-TIGIT antibodies, anti-CTLA4 antibodies, anti-CCR8 antibodies, anti-TREM1 antibodies, anti-TREM2 antibodies, CD47 inhibitors, DGKα inhibitors, HPK1 inhibitors, FLT3 agonists, adenosine receptor antagonists, CD39 inhibitors, CD73 inhibitors, IL-2 variants (IL-2v) and CAR-T cell therapy.

[0767] In some embodiments, the present disclosure provides a pharmaceutical composition or method, wherein the anti-PD-(L)1 antibody is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, rivaroxaban, or the like. retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab.

[0768] In some embodiments, the present disclosure provides a pharmaceutical composition or method, wherein the anti-TIGIT antibody is selected from tiragolumab, vibostolimab, domvanalimab, AB308, AK127, BMS-986207, and etigilimab.

[0769] In some embodiments, the present disclosure provides a pharmaceutical composition or method, wherein the anti-CTLA4 antibody is selected from ipilimumab, tremelimumab, and zalifrelimab.

[0770] In some embodiments, the present disclosure provides a pharmaceutical composition or method, wherein the CD47 inhibitor is selected from magrolimab, letaplimab, lemzoparlimab, AL-008, RRx-001, CTX-5861, FSI-189 (GS-0189), ES-004, BI-765063, ADU1805, CC-95251 and Q-1801.

[0771] In some embodiments, the present disclosure provides pharmaceutical compositions or methods, wherein the adenosine receptor antagonist is eltridinam (AB928), taminadonam, TT-10, TT-4, or M1069.

[0772] In some embodiments, the present disclosure provides pharmaceutical compositions or methods, wherein the CD39 inhibitor is TTX-030.

[0773] In some embodiments, the present disclosure provides a pharmaceutical composition or method, wherein the CD73 inhibitor is quemliclustat (AB680), uliledlimab, mupadolimab, ORIC-533, ATG-037, PT-199, AK131, NZV930, BMS-986179, or oleclumab.

[0774] In some embodiments, the present disclosure provides pharmaceutical compositions or methods, wherein IL-2v is aldesleukin (Proleukin), bemvaleukin alfa (NKTR-214), nemvaleukin alfa (ALKS-4230), THOR-202 (SAR-444245), BNT-151, ANV-419, XTX-202, RG-6279 (RO-7284755), NL-201, STK-012, SHR-1916 or GS-4528.

[0775] In some embodiments, the present disclosure provides a pharmaceutical composition or method, wherein the ADC is selected from sacituzumab govitecan, datopotamus, enfortumab vedotin, and trastuzumab deruxtecan.

[0776] In some embodiments, the present disclosure provides pharmaceutical compositions or methods, wherein the additional therapeutic agent is selected from idealisib, gosartuzumab, mololimab, GS-0189, GS-3583, sepalizumab, GS-4224, GS-9716, GS-6451, GS-1811 (JTX-1811), quetiapine (AB680), eltridinam (AB928), dunalimab, AB308, PY159, PY314, AGEN-1223, AGEN-2373, akilencil, and briginumab.

[0777] In some embodiments, the method comprises administering one or more additional therapeutic agents. The one or more additional therapeutic agents may be one or more therapeutic agents as described below. In some embodiments, the one or more additional therapeutic agents are independently a chemotherapeutic agent, an immunotherapeutic agent, a hormonal agent, an anti-hormonal agent, a targeted therapy agent, or an anti-angiogenic agent.

[0778] In some embodiments, the one or more additional therapeutic agents include a therapeutic agent used to treat high-risk myelodysplastic syndrome (HR MDS), low-risk myelodysplastic syndrome (LR MDS), colorectal cancer, non-small cell lung cancer (NSCLC), pancreatic cancer, or endometrial cancer. In some embodiments, the one or more additional therapeutic agents include a therapeutic agent used to treat high-risk myelodysplastic syndrome (HR MDS). In some embodiments, the one or more additional therapeutic agents include azacitidine. Decitabine Lenalidomide Cytarabine, idarubicin, daunorubicin, cytarabine + daunorubicin, cytarabine + idarubicin, pevonestat, venetoclax, sabatocimumab, guacitabine, reglucoseltib, ivosidenib, ensidipine, selinexor, BGB324, DSP-7888, or SNS-301.

[0779] In some embodiments, the one or more additional therapeutic agents include a therapeutic agent used to treat low-risk myelodysplastic syndrome (LR MDS). In some embodiments, the one or more additional therapeutic agents include lenalidomide, azacytidine, nivolumab, rotelocip, imelastat, LB-100, or reglucosidase.

[0780] In some embodiments, the one or more additional therapeutic agents include therapeutic agents used to treat colorectal cancer. In some embodiments, the one or more additional therapeutic agents include bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab, aflibercept, bevacizumab, Leucovorin, 5-FU, oxaliplatin (FOLFOX), pembrolizumab FOLFIRI, Regorafenib Aflibercept Cetuximab Lonsurf XELOX, FOLFOXIRI, bevacizumab + leucovorin + 5-FU + oxaliplatin (FOLFOX), bevacizumab + FOLFIRI, bevacizumab + FOLFOX, aflibercept + FOLFIRI, cetuximab + FOLFIRI, bevacizumab + XELOX, bevacizumab + FOLFOXIRI, bimetinib + encorafenib + cetuximab, trametinib + dabrafenib + panitumumab, trastuzumab + pertuzumab, nabuccal + FOLFIRI + bevacizumab, or nivolumab + ipilimumab.

[0781] In some embodiments, the one or more additional therapeutic agents include therapeutic agents used to treat non-small cell lung cancer (NSCLC). In some embodiments, the one or more additional therapeutic agents include afatinib, albumin-bound paclitaxel, alectinib, atezolizumab, bevacizumab, bevacizumab, cabozantinib, carboplatin, cisplatin, crizotinib, dabrafenib, docetaxel, erlotinib, etoposide, gemcitabine, nivolumab, paclitaxel, pembrolizumab, pemetrexed, ramucirumab, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine, vinorelbine, alectinib Dabrafenib Trametinib Osimertinib Entrectinib Crizotinib Pembrolizumab Carboplatin, pemetrexed Nab-paclitaxel Ramucirumab Docetaxel, bevacizumab Brigatinib, gemcitabine, cisplatin, afatinib Nivolumab Gefitinib Dabrafenib + trametinib, pembrolizumab + carboplatin + pemetrexed, pembrolizumab + carboplatin + nab-paclitaxel, ramucirumab + docetaxel, bevacizumab + carboplatin + pemetrexed, pembrolizumab + pemetrexed + carboplatin, cisplatin + pemetrexed, bevacizumab + carboplatin + nab-paclitaxel, cisplatin + gemcitabine, nivolumab + docetaxel, carboplatin + pemetrexed, carboplatin + nab-paclitaxel or pemetrexed + cisplatin + carboplatin, daptomycin (DS-1062), dextromethorphan (DS-1062), trastuzumab Veentumab Imfinzi, canakinumab, cemiplizumab, norgeleukin alfa, avelumab, tisleliumab, dunalimab, vembrolizumab, ospelizumab, datopotamusab drutilecan + pembrolizumab, datopotamus drutilecan + imfinzi, imfinzi + tremelimumab, pembrolizumab + lenvatinib + pemetrexed, pembrolizumab + olaparib, norgeleukin alfa (N-803) + pembrolizumab, tisleliumab + atezolizumab, vembrolizumab + pembrolizumab, or ospelizumab + tislelizumab.

[0782] In some embodiments, the one or more additional therapeutic agents include therapeutic agents used to treat pancreatic cancer. In some embodiments, the one or more additional therapeutic agents include 5-FU, leucovorin, oxaliplatin, irinotecan, gemcitabine, nab-paclitaxel, FOLFIRINOX, 5-FU + leucovorin + oxaliplatin + irinotecan, 5-FU + nanoliposomal irinotecan, leucovorin + nanoliposomal irinotecan, or gemcitabine + nab-paclitaxel.

[0783] In some embodiments, the one or more additional therapeutic agents include therapeutic agents used to treat endometrial cancer. In some embodiments, the one or more additional therapeutic agents include carboplatin, paclitaxel, cisplatin, doxorubicin, ifosfamide, progesterone, anastrozole, Letrozole Exemestane Pembrolizumab Lenvatinib or dotalimumab

[0784] In some embodiments, the one or more additional therapeutic agents are independently SNS-301, 5-FU + leucovorin + oxaliplatin + irinotecan, 5-FU + nanoliposomal irinotecan, 5-FU, afatinib, or Aflibercept Aflibercept + FOLFIRI, albumin-bound paclitaxel, alectinib Anastrozole Atezolizumab, avelumab, and azacitidine Bevacizumab Bevacizumab + carboplatin + nab-paclitaxel, bevacizumab + carboplatin + pemetrexed, bevacizumab + FOLFIRI, bevacizumab + FOLFOX, bevacizumab + FOLFOXIRI, bevacizumab + leucovorin + 5-FU + oxaliplatin (FOLFOX), bevacizumab + XELOX, bevacizumab, BGB324, bimetinib + connefenib + cetuximab, brigatinib, cabozantinib, canakinumab, capecitabine, carboplatin + nab-paclitaxel, carboplatin + pemetrexed, carboplatin, cemiplimab, cetuximab Cetuximab + FOLFIRI, cisplatin + gemcitabine, cisplatin + pemetrexed, cisplatin, crizotinib Cytarabine + daunorubicin, cytarabine + idarubicin, cytarabine, dabrafenib Dabrafenib + trametinib, daptomycin (DS-1062), daptomycin (DS-1062) + durvalumab, daptomycin (DS-1062) + pembrolizumab, daunorubicin, decitabine Docetaxel, dunalimab, and dotalimab Doxorubicin, DSP-7888, durvalumab + tremelimumab, durvalumab, ensidipine, ventuinumab Entrectinib Erlotinib, etoposide, exemestane Fluorouracil, FOLFIRI, FOLFIRINOX, FOLFOXIRI, gefitinib Gemcitabine + nab-paclitaxel, gemcitabine, sabatocin, idarubicin, ifosfamide, imelastatin, irinotecan, ivosidenib, LB-100, lenalidomide Lenalidomide, lenvatinib Letrozole Leucovorin + nanoliposomal irinotecan, leucovorin, Lonsurf Rotacept, nab-paclitaxel Nabucacin + FOLFIRI + bevacizumab, nivolumab Nivolumab + docetaxel, nivolumab + ipilimumab, norgeleukin alfa (N-803) + pembrolizumab, norgeleukin alfa, ospelizumab + tislelizumab, ospelizumab, osimertinib Oxaliplatin (FOLFOX), paclitaxel, panitumumab, pembrolizumab Pembrolizumab + carboplatin + nab-paclitaxel, pembrolizumab + carboplatin + pemetrexed, pembrolizumab + lenvatinib + pemetrexed, pembrolizumab + olaparib, pembrolizumab + pemetrexed + carboplatin, pemetrexed Pemetrexed + cisplatin + carboplatin, mololimab, progesterone, ramucirumab Ramucirumab + docetaxel, regorafenib Reglucosetib, Nordisk, sabatocinumab, selinexor, tisleliumab + atezolizumab, tisleliumab, trametinib Trametinib + dabrafenib + panitumumab, trastuzumab + pertuzumab, detrastuzumab Trastuzumab, vandetanib, vemurafenib, venetoclax, vembrolizumab plus pembrolizumab, vembrolizumab, vinblastine, vinorelbine, XELOX, or aflibercept.

[0785] In another embodiment, the present disclosure provides a method for manufacturing a medicament for treating cancer in a subject in need thereof, characterized by using a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0786] In another embodiment, the present disclosure provides a method for manufacturing a medicament for inhibiting cancer metastasis in a subject in need thereof, characterized by using a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0787] In another embodiment, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.

[0788] In another embodiment, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting cancer metastasis in a subject.

[0789] In another embodiment, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof.

[0790] In another embodiment, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in inhibiting cancer metastasis in a subject in need thereof.

[0791] In another embodiment, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0792] VIII. Combination Therapy

[0793] In some embodiments, a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2) provided herein, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more additional therapeutic agents to treat or prevent a disease or condition disclosed herein. In some embodiments, the one or more additional therapeutic agents are one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are four additional therapeutic agents.

[0794] In some embodiments, the pharmaceutical compositions provided herein comprise a compound of Formula I, IA, (I-1), (I-2), (I-3), (Ia), (Ia-1), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), II, (II-1), (IIa), (IIa), (IIb), (IIa-1), (IIb), (IIb-1), or (IIb-2) provided herein, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are four additional therapeutic agents.

[0795] In some embodiments, the additional therapeutic agent includes, for example, an inhibitory immune checkpoint blocker or inhibitor, a stimulatory immune checkpoint stimulator, agonist or activator, a chemotherapeutic agent, an anticancer agent, a radiotherapeutic agent, an antitumor agent, an antiproliferative agent, an antiangiogenic agent, an anti-inflammatory agent, an immunotherapeutic agent, a therapeutic antigen binding molecule (e.g., monospecific and multispecific antibodies or fragments thereof in any form, such as BiKE, TriKE, scFv, Fab, Fab derivatives), bispecific antibodies, non-immunoglobulin antibody mimetics (including, for example, adnectin, affibody, affilin, affimer, affitin, alphabody, anticalin, peptide aptamers, armadillo repeat protein (ARM), atrimer, avimer, designed ankyrin repeat protein fynomers, knottins, Kunitz domain peptides, single antibodies and nanoCLAMPs), antibody-drug conjugates (ADCs), antibody-peptide conjugates), oncolytic viruses, gene modifiers or gene editors, cells containing chimeric antigen receptors (CARs) (e.g., including T cell immunotherapeutics, NK cell immunotherapeutics, or macrophage immunotherapeutics), cells containing engineered T cell receptors (TCR-T), or a combination thereof.

[0796] Exemplary targets

[0797] In some embodiments, the one or more additional therapeutic agents include, for example, inhibitors, agonists, antagonists, ligands, modulators, stimulators, blockers, activators, or suppressors of a target (e.g., a polypeptide or polynucleotide), such as: 2'-5'-oligoadenylate synthetase (OAS1; NCBI Gene ID: 4938); 5'-3' exoribonuclease 1 (XRN1; NCBI Gene ID: 54464); 5'-ectonucleotidase (NT5E, CD73; NCBI Gene ID: 4907); ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1, BCR-ABL, c-ABL); BL, v-ABL; NCBI Gene ID: 25); melanoma deficiency factor 2 (AIM2; NCBI Gene ID: 9447); acetyl-CoA acyltransferase 2 (ACAA2; NCBI Gene ID: 10499); acid phosphatase 3 (ACP3; NCBI Gene ID: 55); adenosine deaminase (ADA, ADA1; NCBI Gene ID: 100); adenosine receptors (e.g., ADORA1 (A1), ADORA2A (A2a, A2AR), ADORA2B (A2b, A2BR), ADORA3 (A3); NCBI Gene IDs: 134, 135, 136, 137); AKT serine / threonine kinase AKT1, AKT, PKB; NCBI Gene ID: 207; alanyl aminopeptidase membrane (ANPEP, CD13; NCBI Gene ID: 290); ALK receptor tyrosine kinase (ALK, CD242; NCBI Gene ID: 238); alpha-fetoprotein (AFP; NCBI Gene ID: 174); copper-containing amine oxidases (e.g., AOC1 (DAO1), AOC2, AOC3 (VAP1); NCBI Gene IDs: 26, 314, 8639); androgen receptor (AR; NCBI Gene ID: 367); angiopoietins (ANGPT1, ANGPT2; NCBI Gene IDs: 284, 285); Angiotensin II receptor type 1 (AGTR1; NCBI Gene ID: 185); angiotensinogen (AGT; NCBI Gene ID: 183); apolipoprotein A1 (APOA1; NCBI Gene ID: 335); mitochondria-associated apoptosis-inducing factor 1 (AIFM1, AIF; NCBI Gene ID: 9131); arachidonic acid 5-lipoxygenase (ALOX5; NCBI Gene ID: 240); asparaginase (ASPG; NCBI Gene ID: 374569); steroidogenic homolog 1 (ASTE1; NCBI Gene ID: 28990); ATM serine / threonine kinase (ATM; NCBI Gene ID: 472);ATP-binding cassette subfamily B member 1 (ABCB1, CD243, GP170; NCBI Gene ID: 5243); ATP-dependent Clp protease (CLPP; NCBI Gene ID: 8192); ATR serine / threonine kinase (ATR; NCBI Gene ID: 545); AXL receptor tyrosine kinase (AXL; NCBI Gene ID: 558); B and T lymphocyte-associated protein (BTLA, CD272; NCBI Gene ID: 151888); baculovirus IAP repeat-containing proteins (BIRC2 (cIAP1), BIRC3 (cIAP2), XIAP (BIRC4, IAP5); and cytochrome P60 receptor kinase (CPP). P3), BIRC5 (survivin; NCBI Gene IDs: 329, 330, 331, 332); basic glycoprotein (basigin) (OK blood group) (BSG, CD147; NCBI Gene ID: 682); B cell lymphoma 2 (BCL2; NCBI Gene ID: 596); BCL2 binding component 3 (BBC3, PUMA; NCBI Gene ID: 27113); BCL2-like (e.g., BCL2L1 (Bcl-x), BCL2L2 (BIM); Bcl-x; NCBI Gene IDs: 598, 10018); β3-adrenergic receptor (ADRB3; NCBI Gene ID : 155); bone gamma-carboxyglutamate protein (BGLAP; NCBI Gene ID: 632); bone morphogenetic protein 10 ligand (BMP10; NCBI Gene ID: 27302); bradykinin receptors (e.g., BDKRB1, BDKRB2; NCBI Gene IDs: 623, 624); B-RAF (BRAF; NCBI Gene ID: 273); breakpoint cluster region (BCR; NCBI Gene ID: 613); bromodomain- and extracellular domain (BET) bromodomain-containing proteins (e.g., BRD2, BRD3, BRD4, BRDT; NCBI Gene IDs: 6046, 8019, 234 76, 676); Bruton's tyrosine kinase (BTK; NCBI Gene ID: 695); cadherins (e.g., CDH3 (p-cadherin), CDH6 (k-cadherin); NCBI Gene IDs: 1001, 1004); cancer / testis antigens (e.g., CTAG1A, CTAG1B, CTAG2; NCBI Gene IDs: 1485, 30848, 246100); cannabinoid receptors (e.g., CNR1 (CB1), CNR2 (CB2); NCBI Gene IDs: 1268, 1269); carbohydrate sulfotransferase 15 (CHST15; NCBI Gene ID: 51363);Carbonic anhydrase (e.g., CA1, CA2, CA3, CA4, CA5A, CA5B, CA6, CA7, CA8, CA9, CA10, CA11, CA12, CA13, CA14; NCBI gene IDs: 759, 760, 761, 762, 763, 765, 766, 767, 768, 770, 771, 11238, 23632, 56934, 377677); carcinoembryonic antigen-related cell adhesion molecules (e.g., CEACAM3 (CD66d), CEACAM5 (CD66e), CEACAM6 (CD66c); NCBI gene ID: 1048 , 1084, 4680); casein kinases (e.g., CSNK1A1 (CK1), CSNK2A1 (CK2); NCBI Gene IDs: 1452, 1457); caspases (e.g., CASP3, CASP7, CASP8; NCBI Gene IDs: 836, 840, 841, 864); catenin β1 (CTNNB1; NCBI Gene ID: 1499); cathepsin G (CTSG; NCBI Gene ID: 1511); Cbl proto-oncogene B (CBLB, Cbl-b; NCBI Gene ID: 868); CC motif chemokine ligand 21 (CCL21); ; NCBI Gene ID: 6366); CC motif chemokine receptor 2 (CCR2; NCBI Gene ID: 729230); CC motif chemokine receptors (e.g., CCR3 (CD193), CCR4 (CD194), CCR5 (CD195), CCR8 (CDw198); NCBI Gene IDs: 1232, 1233, 1234, 1237); CCAAT enhancer binding protein alpha (CEBPA, CEBP; NCBI Gene ID: 1050); cell adhesion molecule 1 (CADM1; NCBI Gene ID: 23705); cell division cycle 7 (CDC7; NC BI Gene ID: 8317); cell communication network factor 2 (CCN2; NCBI Gene ID: 1490); cereblon (CRBN; NCBI Gene ID: 51185); checkpoint kinases (e.g., CHEK1 (CHK1), CHEK2 (CHK2); NCBI Gene IDs: 1111, 11200); cholecystokinin B receptor (CCKBR; NCBI Gene ID: 887); chorionic somatostatin 1 (CSH1; NCBI Gene ID: 1442); claudin proteins (e.g., CLDN6, CLDN18; NCBI Gene IDs: 9074, 51208);Cluster of differentiation markers (e.g., CD1A, CD1C, CD1D, CD1E, CD2, CD3α (TRA), CDβ (TRB), CDγ (TRG), CDδ (TRD), CD4, CD8A, CD8B, CD19, CD20 (MS4A1), CD22, CD24, CD25 (IL2RA, TCGFR), CD28, CD33 (SIGLEC3), CD37, CD38, CD39 (ENTPD1), CD40 (TNFRSF5), CD44 (MIC4, PGP1), CD47 (IAP), CD48 (BLAST1), CD52, CD55 (DAF), CD58 (LFA3) ), CD74, CD79a, CD79b, CD80(B7-1), CD84, CD86(B7-2), CD96(TACTILE), CD99(MIC2), CD115(CSF1R), CD116(GMCSFR, CSF2RA), CD122(IL2RB), CD123( IL3RA), CD128(IL8R1), CD132(IL2RG), CD135(FLT3), CD137(TNFRSF9, 4-1BB), CD142(TF, TFA), CD152(CTLA4), CD160, CD182(IL8R2), CD193(CCR3), C D194(CCR4), CD195(CCR5), CD207, CD221(IGF1R), CD222(IGF2R), CD223(LAG3), CD226(DNAM1), CD244, CD247, CD248, CD276(B7-H3), CD331(FGFR1), CD332 (FGFR2), CD333 (FGFR3), CD334 (FGFR4); NCBI gene ID: 909, 911, 912, 913, 914, 919, 920, 923, 925, 926, 930, 931, 933, 940, 941, 942, 945, 951, 952, 9 53, 958, 960, 961, 962, 965, 972, 973, 974, 1043, 1232, 1233, 1234, 1237, 1436, 1438, 1493, 1604, 2152, 2260, 2261, 2263, 2322, 3480, 3482, 3559, 3560, 3561, 3563, 3577, 3579, 3604, 3902, 4267, 6955, 6957, 6964, 6965, 8832, 10666, 11126, 50489, 51744, 80381, 100133941); Clusterin (CLU; NCBI Gene ID: 1191);Coagulation factors (e.g., F7, FXA; NCBI gene IDs: 2155, 2159); type IV collagen alpha chain (e.g., COL4A1, COL4A2, COL4A3, COL4A4, COL4A5; NCBI gene IDs: 1282, 1284, 1285, 1286, 1287); collectin subfamily member 10 (COLEC10; NCBI gene ID: 10584); colony-stimulating factors (e.g., CSF1 (MCSF), CSF2 (GMCSF), CSF3 (GCSF); NCBI gene IDs: 1435, 1437, 1440); complement factors (e.g., C3, C5; NCBI gene ID: 71 8, 727); COP9 signalosome subunit 5 (COPS5; NCBI gene ID: 10987); C-type lectin domain family members (e.g., CLEC4C (CD303), CLEC9A (CD370), CLEC12A (CD371); CD371; NCBI gene IDs: 160364, 170482, 283420); CXC motif chemokine ligand 12 (CXCL12; NCBI gene ID: 6387); CXC motif chemokine receptors (CXCR1 (IL8R1, CD128), CXCR2 (IL8R2, CD182), CXCR3 (CD182, CD183, IP-10R) ), CXCR4 (CD184; NCBI gene IDs: 2833, 3577, 3579, 7852); cyclin D1 (CCND1, BCL1; NCBI gene ID: 595); cyclin-dependent kinases (e.g., CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK12; NCBI gene IDs: 983, 1017, 1018, 1019, 1020, 1021, 1022, 1024, 1025, 8558, 51755); cyclin G1 (CCNG1; NCBI gene ID: 900); cytochrome P 450 family members (e.g., CYP2D6, CYP3A4, CYP11A1, CYP11B2, CYP17A1, CYP19A1, CYP51A1; NCBI Gene IDs: 1565, 1576, 1583, 1585, 1586, 1588, 1595); cytochrome P450 oxidoreductase (POR; NCBI Gene ID: 5447); cytokine-inducible SH2-containing protein (CISH; NCBI Gene ID: 1154); cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152; NCBI Gene ID: 1493); DEAD box helicases (e.g., DDX5, DDX6, DDX58;NCBI gene IDs: 1655, 1656, 23586); Delta-like canonical Notch ligands (e.g., DLL3, DLL4; NCBI gene IDs: 10683, 54567); DiabloIAP-binding mitochondrial proteins (DIABLO, SMAC; NCBI gene ID: 56616); diacylglycerol kinases (e.g., DGKA, DGKZ; NCBI gene IDs: 1606, 8525); dickkopf WNT signaling pathway inhibitors (e.g., DKK1, DKK3; NCBI Gene IDs: 22943, 27122); dihydrofolate reductase (DHFR; NCBI Gene ID: 1719); dihydropyrimidine dehydrogenase (DPYD; NCBI Gene ID: 1806); dipeptidyl peptidase 4 (DPP4; NCBI Gene ID: 1803); discoidin domain receptor tyrosine kinases (e.g., DDR1 (CD167), DDR2; CD167; NCBI Gene IDs: 780, 4921); DNA-dependent protein kinase (PRKDC ; NCBI gene ID: 5591); DNA topoisomerases (e.g., TOP1, TOP2A, TOP2B, TOP3A, TOP3B; NCBI gene IDs: 7150, 7153, 7155, 7156, 8940); dopachrome tautomerase (DCT; NCBI gene ID: 1638); dopamine receptor D2 (DRD2; NCBI gene ID: 1318); DOT1-like histone lysine methyltransferase (DOT1L; NCBI gene ID: 84444); ectonucleotide pyrophosphatase / phosphodiesterase 3 (E333); NPP3, CD203c; NCBI Gene ID: 5169); EMAP-like 4 (EML4; NCBI Gene ID: 27436); endoglin (ENG; NCBI Gene ID: 2022); endoplasmic reticulum aminopeptidases (e.g., ERAP1, ERAP2; NCBI Gene IDs: 51752, 64167); enhancer of zeste homolog 2 polycomb repressive complex 2 subunit (EZH2; NCBI Gene ID: 2146); ephrin receptors (e.g., EPHA1, EPHA2, EPHA3, EPHA4, EPHA5 , EPHA7, EPHB4; NCBI Gene IDs: 1969, 2041, 2042, 2043, 2044, 2045, 2050); ephrins (e.g., EFNA1, EFNA4, EFNB2; NCBI Gene IDs: 1942, 1945, 1948); epidermal growth factor receptors (e.g., ERBB1 (HER1, EGFR), ERBB1 variant III (EGFRvIII), ERBB2 (HER2, NEU, CD340), ERBB3 (HER3), ERBB4 (HER4);NCBI gene IDs: 1956, 2064, 2065, 2066); epithelial cell adhesion molecule (EPCAM; NCBI gene ID: 4072); epithelial mitogen (EPGN; NCBI gene ID: 255324); eukaryotic translation elongation factors (e.g., EEF1A2, EEF2; NCBI gene IDs: 1917, 1938); eukaryotic translation initiation factors (e.g., EIF4A1, EIF5A; NCBI gene IDs: 1973, 1984); exportin-1 (XPO1; NCBI gene ID: 7514); farnesoid X receptor (NR1H4, FXR; NCBI gene ID: 9971); Fas ligand (FAS LG, FASL, CD95L, CD178, TNFSF6; NCBI Gene ID: 356); fatty acid amide hydrolase (FAAH; NCBI Gene ID: 2166); fatty acid synthase (FASN; FAS; NCBI Gene ID: 2194); Fc fragments of Ig receptors (e.g., FCER1A, FCGRT, FCGR3A (CD16); NCBI Gene IDs: 2205, 2214, 2217); Fc receptor-like 5 (FCRL5, CD307; NCBI Gene ID: 83416); fibroblast activation protein alpha (FAP; NCBI Gene ID: 2191); fibroblast growth factor receptors (e.g., FG FR1 (CD331), FGFR2 (CD332), FGFR3 (CD333), FGFR4 (CD334); NCBI gene IDs: 2260, 2261, 2263, 2264); fibroblast growth factors (e.g., FGF1 (FGFα), FGF2 (FGFβ), FGF4, FGF5; NCBI gene IDs: 2246, 2247, 2249, 2250); fibronectin 1 (FN1, MSF; NCBI gene ID: 2335); fms-related receptor tyrosine kinases (e.g., FLT1 (VEGFR1), FLT3 (STK1, CD135), FLT4 (VEGFR2); NCBI gene IDs: 2336, 2340, 2341); NCBI Gene ID: 2321, 2322, 2324); fms-related receptor tyrosine kinase 3 ligand (FLT3LG; NCBI Gene ID: 2323); focal adhesion kinase 2 (PTK2, FAK1; NCBI Gene ID: 5747); folate hydrolase 1 (FOLH1, PSMA; NCBI Gene ID: 2346); folate receptor 1 (FOLR1; NCBI Gene ID: 2348); forkhead box protein M1 (FOXM1; NCBI Gene ID: 2305); furin (FURIN, PACE; NCBI Gene ID: 5045); FYN tyrosine kinase (FYN, SYN; NCBI Gene ID: 2534);Galectins (e.g., LGALS3, LGALS8 (PCTA1), LGALS9; NCBI Gene IDs: 3958, 3964, 3965); glucocorticoid receptor (NR3C1, GR; NCBI Gene ID: 2908); glucuronidase beta (GUSB; NCBI Gene ID: 2990); glutamate metabotropic receptor 1 (GRM1; NCBI Gene ID: 2911); glutaminase (GLS; NCBI Gene ID: 2744); glutathione S-transferase Pi (GSTP1; NCBI Gene ID : 2950); glycogen synthase kinase 3β (GSK3B; NCBI Gene ID: 2932); glypican 3 (GPC3; NCBI Gene ID: 2719); gonadotropin-releasing hormone 1 (GNRH1; NCBI Gene ID: 2796); gonadotropin-releasing hormone receptor (GNRHR; NCBI Gene ID: 2798); GPNMB glycoprotein nmb (GPNMB, osteoactivin; NCBI Gene ID: 10457); growth differentiation factor 2 (GDF2, BMP9; NCBI Gene ID: 10457); I gene ID: 2658); growth factor receptor binding protein 2 (GRB2, ASH; NCBI gene ID: 2885); guanylate cyclase 2C (GUCY2C, STAR, MECIL, MUCIL, NCBI gene ID: 2984); H19 imprinted maternally expressed transcript (H19; NCBI gene ID: 283120); HCK proto-oncogene Src family tyrosine kinase (HCK; NCBI gene ID: 3055); heat shock proteins (e.g., HSPA5 (HSP70, BIP, GRP78), HSPB1 (HSP27), HSP90B1 (GP96); NCBI Gene IDs: 3309, 3315, 7184); heme oxygenases (e.g., HMOX1 (HO1), HMOX2 (HO1); NCBI Gene IDs: 3162, 3163); heparanase (HPSE; NCBI Gene ID: 10855); hepatitis A virus cellular receptor 2 (HAVCR2, TIM3, CD366; NCBI Gene ID: 84868); hepatocyte growth factor (HGF; NCBI Gene ID: 3082); HERV-H LTR-associated 2 (HHLA2, B7-H7; NCBI Gene ID: 11148); histamine receptor H2 (HRH2; NCBI Gene ID: 3274); histone deacetylase (e.g., HDAC1, HDAC7, HDAC9; NCBI Gene IDs: 3065, 9734, 51564); HRas proto-oncogene GTPase (HRAS; NCBI Gene ID: 3265); hypoxia-inducible factors (e.g., HIF1A, HIF2A (EPAS1);NCBI Gene IDs: 2034, 3091); I-κ-β kinase (IKKβ; NCBI Gene IDs: 3551, 3553); IKAROS family zinc finger (IKZF1 (LYF1), IKZF3; NCBI Gene IDs: 10320, 22806); Immunoglobulin superfamily member 11 (IGSF11; NCBI Gene ID: 152404); indoleamine 2,3-dioxygenase (e.g., IDO1, IDO2; NCBI Gene IDs: 3620, 169355); inducible T cell costimulator (ICOS, CD278; NCBI Gene ID: 29851); inducible T cell costimulator ligand (ICOSLG, B 7-H2; NCBI Gene ID: 23308); insulin-like growth factor receptors (e.g., IGF1R, IGF2R; NCBI Gene IDs: 3480, 3482); insulin-like growth factors (e.g., IGF1, IGF2; NCBI Gene IDs: 3479, 3481); insulin receptors (INSR, CD220; NCBI Gene ID: 3643); integrin subunits (e.g., ITGA5 (CD49e), ITGAV (CD51), ITGB1 (CD29), ITGB2 (CD18, LFA1, MAC1), ITGB7; NCBI Gene IDs: 3678, 3685, 3688, 3695, 3697); 8); intercellular adhesion molecule 1 (ICAM1, CD54; NCBI gene ID: 3383); interleukin 1 receptor-associated kinase 4 (IRAK4; NCBI gene ID: 51135); interleukin receptors (e.g., IL2RA (TCGFR, CD25), IL2RB (CD122), IL2RG (CD132), IL3RA, IL6R, IL13RA2 (CD213A2), IL22RA1; NCBI gene IDs: 3598, 3559, 3560, 3561, 3563, 3570, 58985); interleukins (e.g., IL1A, IL1B, IL2, IL3, IL6 (HGF), IL7, IL8 ( CXCL8), IL10 (TGIF), IL12A, IL12B, IL15, IL17A (CTLA8), IL18, IL23A, IL24, IL-29 (IFNL1); NCBI gene IDs: 3552, 3553, 3558, 3562, 3565, 3569, 3574, 3586, 3592, 3593, 3600, 3605, 3606, 11009, 51561, 282618; isocitrate dehydrogenase (NADP(+)1) (e.g., IDH1, IDH2; NCBI gene IDs: 3417, 3418); Janus kinases (e.g., JAK1, JAK2, JAK3);NCBI gene IDs: 3716, 3717, 3718); kallikrein-related peptidase 3 (KLK3; NCBI gene ID: 354); killer cell immunoglobulin-like receptor Ig domain and long cytoplasmic tail (e.g., KIR2DL1 (CD158A), KIR2DL2 (CD158B1), KIR2DL3 (CD158B), KIR2DL4 (CD158D), KIR2DL5A (CD158F), KIR2DL5B, KIR3DL1 (CD158E1), KIR3DL2 (CD158K), KIR3DP1 (CD158c), KIR2DS2 (CD158J); NCBI gene ID: 3 802, 3803, 3804, 3805, 3811, 3812, 57292, 553128, 548594, 100132285); killer cell lectin-like receptors (e.g., KLRC1 (CD159A), KLRC2 (CD159c), KLRC3, KLRRC4, KLRD1 (CD94), KLRG1, KLRK1 (NKG2D, CD314); NCBI Gene IDs: 3821, 3822, 3823, 3824, 8302, 10219, 22914); kinase insert domain receptors (KDR, CD309, VEGFR2; NCBI Gene ID: 3791); kinesin family Member 11 (KIF11; NCBI Gene ID: 3832); KiSS-1 metastasis suppressor (KISS1; NCBI Gene ID: 3814); KIT proto-oncogene receptor tyrosine kinase (KIT, C-KIT, CD117; NCBI Gene ID: 3815); KRAS proto-oncogene GTPase (KRAS; NCBI Gene ID: 3845); lactotransferrin (LTF; NCBI Gene ID: 4057); LCK proto-oncogene Src family tyrosine kinase (LCK; NCBI Gene ID: 3932); LDL receptor-related protein 1 (LRP1, CD91, IGFBP3R; NCBI Gene ID: 4035); Leucine repeat-containing protein 15 (LRRC15; NCBI Gene ID: 131578); leukocyte immunoglobulin-like receptors (e.g., LILRB1 (ILT2, CD85J), LILRB2 (ILT4, CD85D); NCBI Gene IDs: 10288, 10859); leukotriene A4 hydrolase (LTA4H; NCBI Gene ID: 4048); adaptor for T cell activation (LAT; NCBI Gene ID: 27040); luteinizing hormone / chorionic gonadotropin receptor (LHCGR; NCBI Gene ID: 3973); LY6 / PLAUR domain-containing 3 (LYPD3; NCBI Gene ID: 27076);Lymphocyte activation 3 (LAG3; CD223; NCBI Gene ID: 3902); lymphocyte antigens (e.g., LY9 (CD229), LY75 (CD205); NCBI Gene IDs: 4063, 17076); LYN proto-oncogene Src family tyrosine kinase (LYN; NCBI Gene ID: 4067); lymphocyte cytoplasmic protein 2 (LCP2; NCBI Gene ID: 3937); lysine demethylase 1A (KDM1A; NCBI Gene ID: 23028); lysophosphatidic acid receptor 1 (LPAR1, EDG2, LPA1, GPR26; NCBI Gene ID: 19 02); lysyl oxidase (LOX; NCBI gene ID: 4015); lysyl oxidase-like 2 (LOXL2; NCBI gene ID: 4017); macrophage migration inhibitory factor (MIF, GIF; NCBI gene ID: 4282); macrophage stimulating 1 receptor (MST1R, CD136; NCBI gene ID: 4486); MAGE family members (e.g., MAGEA1, MAGEA2, MAGEA2B, MAGEA3, MAGEA4, MAGEA5, MAGEA6, MAGEA10, MAGEA11, MAGEC1, MAGEC2, MAGED1, MAGED2; NCBI Gene IDs: 4100, 4101, 4102, 4103, 4104, 4105, 4109, 4110, 9500, 9947, 10916, 51438, 266740); major histocompatibility complex (e.g., HLA-A, HLA-E, HLA-F, HLA-G; NCBI Gene IDs: 3105, 3133, 3134, 3135); major vault protein (MVP, VAULT1; NCBI Gene ID: 9961); MALT1-like caspase (MALT1; NCBI Gene ID: 108 92); MAPK-activated protein kinase 2 (MAPKAPK2; NCBI Gene ID: 9261); MAPK-interacting serine / threonine kinases (e.g., MKNK1, MKNK2; NCBI Gene IDs: 2872, 8569); matrix metalloproteinases (e.g., MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP19, MMP20, MMP21, MMP24, MMP25, MMP26, MMP27, MMP28);NCBI Gene IDs: 4312, 4313, 4314, 4316, 4317, 4318, 4319, 4320, 4321, 4322, 4323, 4324, 4325, 4326, 4327, 9313, 10893, 56547, 64066, 64386, 79148, 118856); MCL1 apoptosis regulator, BCL2 family member (MCL1; NCBI Gene ID: 4170); MDM2 proto-oncogene (MDM2; NCBI Gene ID: 4193); MDM4 regulator of p53 (MDM4; BMFS6; NCBI Gene ID: 4194); rapamycin agonist Mechanistic targets of enzymes (MTOR, FRAP1; NCBI Gene ID: 2475); melanin-A (MLANA; NCBI Gene ID: 2315); melanocortin receptors (MC1R, MC2R; NCBI Gene IDs: 4157, 4148); MER proto-oncogene tyrosine kinase (MERTK; NCBI Gene ID: 10461); mesothelin (MSLN; NCBI Gene ID: 10232); MET proto-oncogene receptor tyrosine kinase (MET, c-Met, HGFR; NCBI Gene ID: 4233); methionyl aminopeptidase 2 (METAP2, MAP2; NCBI Gene ID: 10988); MHC Class I polypeptide-related sequences (e.g., MICA, MICB; NCBI gene IDs: 4277, 100507436); mitogen-activated protein kinases (e.g., MAPK1 (ERK2), MAPK3 (ERK1), MAPK8 (JNK1), MAPK9 (JNK2), MAPK10 (JNK3), MAPK11 (p38β), MAPK12; NCBI gene IDs: 5594, 5595, 5599, 5600, 5601, 5602, 819251); mitogen-activated protein kinase kinase kinases (e.g., MAP3K5 (ASK1), MAP3K8 (TPL2, AURA2); NCBI gene IDs: 4217, 1326 ); mitogen-activated protein kinase kinase kinase kinase kinase 1 (MAP4K1, HPK1; NCBI gene ID: 11184); mitogen-activated protein kinase kinase (e.g., MAP2K1 (MEK1), MAP2K2 (MEK2), MAP2K7 (MEK7); NCBI gene IDs: 5604, 5605, 5609); MPL proto-oncogene thrombopoietin receptor (MPL; NCBI gene ID: 4352); mucins (e.g., MUC1 (including its splice variants (e.g., including MUC1 / A, C, D, X, Y, Z, and REP)), MUC5AC, MUC16 (CA125); NCBI gene IDs: 4582, 4586, 94025);MYC proto-oncogene bHLH transcription factor (MYC; NCBI Gene ID: 4609); myostatin (MSTN, GDF8; NCBI Gene ID: 2660); myristoylated alanine-rich protein kinase C substrate (MARCKS; NCBI Gene ID: 4082); natriuretic peptide receptor 3 (NPR3; NCBI Gene ID: 4883); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7-H6; NCBI Gene ID: 374383); necdin, MAGE family member (NDN; NCBI Gene ID: 4692); nectin cell adhesion molecules (e.g., NECTIN2 (CD112) , PVRL2), NECTIN4 (PVRL4); NCBI Gene IDs: 5819, 81607); neural cell adhesion molecule 1 (NCAM1, CD56; NCBI Gene ID: 4684); neuropilins (e.g., NRP1 (CD304, VEGF165R), NRP2 (VEGF165R2); NCBI Gene IDs: 8828, 8829); neurotrophic receptor tyrosine kinases (e.g., NTRK1 (TRKA), NTRK2 (TRKB), NTRK3 (TRKC); NCBI Gene IDs: 4914, 4915, 4916); NFKB activating protein (NKAP; NCBI Gene ID: 7 9576); NIMA-related kinase 9 (NEK9; NCBI Gene ID: 91754); NLR family pyrin domain-containing protein 3 (NLRP3, NALP3; NCBI Gene ID: 114548); notch receptors (e.g., NOTCH1, NOTCH2, NOTCH3, NOTCH4; NCBI Gene IDs: 4851, 4853, 4854, 4855); NRAS proto-oncogene GTPase (NRAS; NCBI Gene ID: 4893); nuclear factor kappa B (NFKB1, NFKB2; NCBI Gene IDs: 4790, 4791); nuclear factor erythroid 2-like 2 (e.g., NFE2L2; NRF2; NCBI gene ID: 4780); nuclear receptor subfamily 4 group A member 1 (NR4A1; NCBI gene ID: 3164); nucleolin (NCL; NCBI gene ID: 4691); nucleophosmin 1 (NPM1; NCBI gene ID: 4869); nucleotide-binding oligomerization domain-containing protein 2 (NOD2; NCBI gene ID: 64127); nudix hydrolase 1 (NUDT1; NCBI gene ID: 4521); O-6-methylguanine-DNA methyltransferase (MGMT; NCBI gene ID: 4255); opioid receptor delta 1 (OPRD1; NCBI gene ID: 4985); ornithine decarboxylase 1 (ODC1;NCBI Gene ID: 4953); ketoglutarate dehydrogenase (OGDH; NCBI Gene ID: 4967); parathyroid hormone (PTH; NCBI Gene ID: 5741); PD-L1 (CD274; NCBI Gene ID: 29126); periostin (POSTN; NCBI Gene ID: 10631); peroxisome proliferator-activated receptors (e.g., PPARA (PPARα), PPARD (PPARδ), PPARG (PPARγ); NCBI Gene IDs: 5465, 5467, 5468); phosphatase and tensin homolog (PTEN; NCBI Gene ID: 5728); phosphatidylinositol 4,5-bisphosphate 3-kinases (PIK3CA (PI3Kα), PIK3CB (PI3Kβ), PIK3CD (PI3Kδ), PIK3CG (PI3Kγ); NCBI gene IDs: 5290, 5291, 5293, 5294); phospholipases (e.g., PLA2G1B, PLA2G2A, PLA2G2D, PLA2G3, PLA2G4A, PLA2G5, PLA2G7, PLA2G10, PLA2G12A, PLA2G12B, PLA2G15; NCBI gene IDs: 5319, 5320, 5321, 5322, 7941, 8399, 50487, 23659, 26279, 81579, 84 647); Pim proto-oncogenes, serine / threonine kinases (e.g., PIM1, PIM2, PIM3; NCBI Gene IDs: 5292, 11040, 415116); placental growth factor (PGF; NCBI Gene ID: 5228); plasminogen activator, urokinase (PLAU, u-PA, ATF; NCBI Gene ID: 5328); platelet-derived growth factor receptors (e.g., PDGFRA (CD140A, PDGFR2), FDGFRB (CD140B, PDGFR1); NCBI Gene IDs: 5156, 5159); plexin B1 (PLXNB1; NCBI Gene ID: 5364); poliovirus Receptor (PVR) cell adhesion molecule (PVR, CD155; NCBI Gene ID: 5817); Polo-like kinase 1 (PLK1; NCBI Gene ID: 5347); Poly(ADP-ribose) polymerases (e.g., PARP1, PARP2, PARP3; NCBI Gene IDs: 142, 10038, 10039); Polycomb protein EED (EED; NCBI Gene ID: 8726); Porcupine O-acyltransferase (PORCN; NCBI Gene ID: 64840); PRAME nuclear receptor transcriptional regulator (PRAME; NCBI Gene ID: 23532); Premelanosomal protein (PMEL; NCBI Gene ID: 6490);Progesterone receptor (PGR; NCBI Gene ID: 5241); programmed cell death 1 (PDCD1, PD-1, CD279; NCBI Gene ID: 5133); programmed cell death 1 ligand 2 (PDCD1LG2, CD273, PD-L2; NCBI Gene ID: 80380); prominin 1 (PROM1, CD133; NCBI Gene ID: 8842); promyelocytic leukemia (PML; NCBI Gene ID: 5371); prosaposin (PSAP; NCBI Gene ID: 5660); prostaglandin E receptor 4 (PTGER4; NCBI Gene ID: 5734); prostaglandin E synthase (PTGES; NCBI Gene ID: 9536); prostaglandin-endoperoxide synthase (PTGS1 (COX1), PTGS2 (COX2); NCBI Gene IDs: 5742, 5743); proteasome 20S subunit β9 (PSMB9; NCBI Gene ID: 5698); protein arginine phosphate methyltransferases (e.g., PRMT1, PRMT5; NCBI Gene IDs: 3276, 10419); protein kinase N3 (PKN3; NCBI Gene ID: 29941); protein phosphatase 2A (PPP2CA; NCBI Gene ID: 5515); protein tyrosine kinase 7 (inactive) (PTK7; NCBI Gene ID: 5754); protein tyrosine phosphatase receptors (PTPRB (PTPB), PTPRC (CD45R); NCBI Gene IDs: 5787, 5788); prothymosin alpha (PTMA; NCBI Gene ID: 5757); purine nucleoside phosphorylase (PNP; NCBI Gene ID: 4860); purinergic receptor P2X 7 (P2RX7; NCBI Gene ID: 5027); PVR-related immunoglobulin domain-containing (PVRIG, CD112R; NCBI Gene ID: 79037); Raf-1 proto-oncogene serine / threonine kinase (RAF1, c-Raf; NCBI Gene ID: 5894); RAR-related orphan receptor gamma (RORC; NCBI Gene ID: 6097); ras homolog family member C (RHOC; NCBI Gene ID: 389); mTORC1-bound Ra s homolog (RHEB; NCBI Gene ID: 6009); RB transcriptional corepressor 1 (RB1; NCBI Gene ID: 5925); receptor-interacting serine / threonine-protein kinase 1 (RIPK1; NCBI Gene ID: 8737); ret proto-oncogene (RET; NCBI Gene ID: 5979); retinoic acid early transcripts (e.g., RAET1E, RAET1G, RAET1L; NCBI Gene IDs: 135250, 154064, 353091);Retinoic acid receptor alpha (e.g., RARA, RARG; NCBI Gene IDs: 5914, 5916); retinoid X receptor (e.g., RXRA, RXRB, RXRG; NCBI Gene IDs: 6256, 6257, 6258); Rho-associated coiled-coil-containing protein kinase (e.g., ROCK1, ROCK2; NCBI Gene IDs: 6093, 9475); ribosomal protein S6 kinase B1 (RPS6KB1, S6K-β1; NCBI Gene ID: 6198); RING finger protein 128 (RNF128, GRAIL; NCBI Gene ID: 79589); ROS proto-oncogene 1 receptor tyrosine kinase (ROS1; NCBI Gene ID: 79589); Gene ID: 6098); roundabout guidance receptor 4 (ROBO4; NCBI Gene ID: 54538); RUNX family transcription factor 3 (RUNX3; NCBI Gene ID: 864); S100 calcium-binding protein A9 (S100A9; NCBI Gene ID: 6280); secreted frizzled-related protein 2 (SFRP2; NCBI Gene ID: 6423); secreted phosphoprotein 1 (SPP1; NCBI Gene ID: 6696); secretoglobulin family 1A member 1 (SCGB1A1; NCBI Gene ID: 7356); selectins (e.g., SELE, SELL (CD62L), SELP (CD62); NCBI Gene ID: 6401, 6402, 6403); Semaphorin 4D (SEMA4D; CD100; NCBI gene ID: 10507); Sialic acid-binding Ig-like lectins (SIGLEC7 (CD328), SIGLEC9 (CD329), SIGLEC10; NCBI gene IDs: 27036, 27180, 89790); Signal regulatory protein alpha (SIRPA, CD172A; NCBI gene ID: 140885); Signal transducers and activators of transcription (e.g., STAT1, STAT3, STAT5A, STAT5B; NCBI gene IDs: 6772, 6774, 6776, 6777); Longevity protein-3 (S IRT3; NCBI Gene ID: 23410); signaling lymphocyte activation molecule (SLAM) family members (e.g., SLAMF1 (CD150), SLAMF6 (CD352), SLAMF7 (CD319), SLAMF8 (CD353), SLAMF9; NCBI Gene IDs: 56833, 57823, 89886, 114836); SLIT and NTRK-like family member 6 (SLITRK6; NCBI Gene ID: 84189); smoothened frizzled class receptor (SMO; NCBI Gene ID: 6608); soluble epoxide hydrolase 2 (EPHX2; NCBI Gene ID: 2053);Solute carrier family members (e.g., SLC3A2 (CD98), SLC5A5, SLC6A2, SLC10A3, SLC34A2, SLC39A6, SLC43A2 (LAT4), SLC44A4; NCBI gene IDs: 6520, 6528, 6530, 8273, 10568, 25800, 80736, 124935); somatostatin receptors (e.g., SSTR1, SSTR2, SSTR3, SSTR4, SSTR5; NCBI gene IDs: 6751, 6752, 6753, 6754, 6755); sonic hedgehog signaling molecule (SHH; NCBI gene ID: 6469); Sp1 transcription factor (SP1; NCBI gene ID: 6667); sphingosine kinases (e.g., SPHK1, SPHK2; NCBI gene IDs: 8877, 56848); sphingosine-1-phosphate receptor 1 (S1PR1, CD363; NCBI gene ID: 1901); spleen-associated tyrosine kinase (SYK; NCBI gene ID: 6850); splicing factor 3B factor 1 (SF3B1; NCBI gene ID: 23451); SRC proto-oncogene non-receptor tyrosine kinase (SRC; NCBI Gene ID: 6714); stabilin 1 (STAB1, CLEVER-1; NCBI Gene ID: 23166); STEAP family member 1 (STEAP1; NCBI Gene ID: 26872); steroid sulfatase (STS; NCBI Gene ID: 412); stimulator of interferon response cGAMP interacting factor 1 (STING1; NCBI Gene ID: 340061) ); superoxide dismutase 1 (SOD1, ALS1; NCBI gene ID: 6647); suppressor of cytokine signaling (SOCS1 (CISH1), SOCS3 (CISH3); NCBI gene IDs: 8651, 9021); synapsin 3 (SYN3; NCBI gene ID: 8224); syndecan 1 (SDC1, CD138, syndecan; NCBI gene ID: 6382); synuclein alpha (SNCA, PARK1; NCBI gene ID: 6622); T cell immunoglobulin and mucin domain-containing protein 4 (TIMD4, SMUCKLER; NCBI Gene ID: 91937); T cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); tachykinin receptors (e.g., TACR1, TACR3; NCBI Gene IDs: 6869, 6870); TANK-binding kinase 1 (TBK1; NCBI Gene ID: 29110); tankyrase (TNKS; NCBI Gene ID: 8658);TATA-box binding protein-associated factor, RNA polymerase I subunit B (TAF1B; NCBI Gene ID: 9014); T-box transcription factor T (TBXT; NCBI Gene ID: 6862); TCDD-inducible poly (ADP-ribose) polymerase (TIPARP, PAPR7; NCBI Gene ID: 25976); tec protein tyrosine kinase (TEC; NCBI Gene ID: 7006); TEK receptor tyrosine kinase (TEK, CD202B, TIE2; NCBI Gene ID: 7010); telomerase reverse transcriptase (TERT; NCBI Gene ID: 7015); tenascin C (TNC; NCBI Gene ID: 3371 ); triple repair exonucleases (e.g., TREX1, TREX2; NCBI Gene IDs: 11277, 11219); thrombomodulin (THBD, CD141; NCBI Gene ID: 7056); thymidine kinases (e.g., TK1, TK2; NCBI Gene IDs: 7083, 7084); thymidine phosphorylase (TYMP; NCBI Gene ID: 1890); thymidylate synthase (TYMS; NCBI Gene ID: 7298); thyroid hormone receptors (THRA, THRB; NCBI Gene IDs: 7606, 7608); thyroid stimulating hormone receptor (TSHR; NCBI Gene ID: 7253); TNF superfamily members (e.g., For example, TNFSF4 (OX40L, CD252), TNFSF5 (CD40L), TNFSF7 (CD70), TNFSF8 (CD153, CD30L), TNFSF9 (4-1BB-L, CD137L), TNFSF10 (TRAIL, CD253, APO2L), TNFSF 11 (CD254, RANKL2, TRANCE), TNFSF13 (APRIL, CD256, TRAIL2), TNFSF13b (BAFF, BLYS, CD257), TNFSF14 (CD258, LIGHT), TNFSF18 (GITRL); NCBI gene ID: 9 44, 959, 970, 7292, 8600, 8740, 8741, 8743, 8744, 8995); Toll-like receptors (e.g., TLR1 (CD281), TLR2 (CD282), TLR3 (CD283), TLR4 (CD284), TLR5, TLR6 (CD286), TLR7, TLR8 (CD288), TLR9 (CD289), TLR10 (CD290); NCBI Gene IDs: 7096, 7097, 7098, 7099, 10333, 51284, 51311, 54106, 81793); Transferrin (TF; NCBI Gene ID: 7018);Transferrin receptor (TFRC, CD71; NCBI gene ID: 7037); transforming growth factor (e.g., TGFA, TGFB1; NCBI gene IDs: 7039, 7040); transforming growth factor receptor (e.g., TGFBR1, TGFBR2, TGFBR3; NCBI gene IDs: 7046, 7048, 7049); transforming protein E7 (E7; NCBI gene ID: 1489079); transglutaminase 5 (TGM5; NCBI gene ID: 9333); transient receptor potential cation channel subfamily V member 1 (TRPV1, VR1; NCBI gene ID: 7442); containing Transmembrane and immunoglobulin domain protein 2 (TMIGD2, CD28H, IGPR1; NCBI Gene ID: 126259); triggering receptors expressed on myeloid cells (TREM1 (CD354), TREM2; NCBI Gene IDs: 54209, 54210); trophinin (TRO, MAGED3; NCBI Gene ID: 7216); trophoblast glycoprotein (TPBG; NCBI Gene ID: 7162); tryptophan 2,3-dioxygenase (TDO2; NCBI Gene ID: 6999); tryptophan hydroxylases (e.g., TPH1, TPH2; NCBI Gene ID: 716 6, 121278); tumor-associated calcium signal transducer 2 (TACSTD2, TROP2, EGP1; NCBI Gene ID: 4070); tumor necrosis factor (TNF; NCBI Gene ID: 7124); members of the tumor necrosis factor (TNF) receptor superfamily (e.g., TNFRSF1A (CD120a), TNFRSF1B (CD120b), TNFRSF4 (OX40), TNFRSF5 (CD40), TNFRSF6 (CD95, FAS receptor), TNFRSF7 (CD27), TNFRSF8 (CD30), TNFRSF9 (CD137, 4-1BB) ), TNFRSF10A (CD261), TNFRSF10B (TRAIL, DR5, CD262), TNFRSF10C, TNFRSF10D, TNFRSF11A, TNFRSF11B (OPG), TNFRSF12A, TNFRSF13B, TNFR1 3C (CD268, BAFFR), TNFRSF14 (CD270, LIGHTR), TNFRSF16, TNFRSF17 (CD269, BCMA), TNFRSF18 (GITR, CD357), TNFRSF19, TNFRSF21, TNFRSF25;NCBI Gene IDs: 355, 608, 939, 943, 958, 3604, 4804, 4982, 7132, 7133, 7293, 8718, 8764, 8784, 8792, 8793, 8794, 8795, 8797, 23495, 27242, 51330, 55504); tumor protein p53 (TP53; NCBI Gene ID: 7157); tumor suppressor 2 mitochondrial calcium regulator (TUSC2; NCBI Gene ID: 11334); TYRO3 protein tyrosine kinase (TYRO3; BYK; NCBI Gene ID: 7301); tyrosinase (TYR; NCBI Gene ID: 7299); tyrosine hydroxylase (TH; NCBI Gene ID: 7054); tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (e.g., TIE1, TIE1; NCBI Gene ID: 7075); tyrosine-protein phosphatase non-receptor type 11 (PTPN11, SHP2; NCBI Gene ID: 5781); ubiquitin-conjugating enzyme E2 I (UBE2I, UBC9; NCBI Gene ID: 7329); ubiquitin C-terminal hydrolase L5 (UCHL5; NCBI Gene ID: 51377); ubiquitin-specific peptidase 7 (USP7; NCBI Gene ID: 7874); ubiquitin-like modifier activating enzyme 1 (UBA1; NCBI Gene ID: 7317); UL16 binding proteins (e.g., ULBP1, ULBP2, ULBP3; NCBI Gene IDs: 79465, 80328, 80328); valosin-containing proteins (VCP, CDC48; NCBI Gene ID: 7415); vascular cell adhesion molecule 1 (VCAM1, CD106; NCBI Gene ID: 7412); vascular endothelial growth factors (e.g., VEGFA, VEGFB; NCBI Gene IDs: 7422, 7423); vimentin (VIM; NCBI Gene ID: 7431); vitamin D receptor (VDR; NCBI Gene ID: 7421); V-set domain-containing inhibitor of T cell activation 1 (VTCN1, B7-H4; NCBI Gene ID: 79679); V-set immunomodulatory receptors (VSIR, VISTA, B7-H5; NCBI Gene ID: 64115); WEE1 G2 checkpoint kinase (WEE1; NCBI Gene ID: 7465); WRN RecQ-like helicase (WRN; RECQ3; NCBI Gene ID: 7486); WT1 transcription factor (WT1; NCBI Gene ID: 7490); WW domain-containing transcription regulator 1 (WWTR1; TAZ; NCBI Gene ID: 25937); XC motif chemokine ligand 1 (XCL1, ATAC; NCBI Gene ID: 6375);XC motif chemokine receptor 1 (XCR1, GPR5, CCXCR1; NCBI Gene ID: 2829); Yes1-associated transcriptional regulator (YAP1; NCBI Gene ID: 10413); zeta chain-associated protein kinase 70 (ZAP70; NCBI Gene ID: 7535).

[0798] In some embodiments, the one or more additional therapeutic agents include, for example, agents that target: 5'-ectonucleotidase (NT5E or CD73; NCBI Gene ID: 4907); adenosine A 2A Receptor (ADORA2A; NCBI Gene ID: 135); Adenosine A 2Breceptor (ADORA2B; NCBI Gene ID: 136); CC motif chemokine receptor 8 (CCR8, CDw198; NCBI Gene ID: 1237); cytokine-inducible SH2-containing protein (CISH; NCBI Gene ID: 1154); diacylglycerol kinase alpha (DGKA, DAGK, DAGK1 or DGK-α; NCBI Gene ID: 1606); fms-like tyrosine kinase 3 (FLT3, CD13 5; NCBI Gene ID: 2322); integrin-associated proteins (IAP, CD47; NCBI Gene ID: 961); interleukin-2 (IL2; NCBI Gene ID: 3558); interleukin-2 receptors (IL2RA, IL2RB, IL2RG; NCBI Gene IDs: 3559, 3560, 3561); Kirsten rat sarcoma virus (KRAS; NCBI Gene ID: 3845; including mutants such as KRAS G12C or G12D); mitogen-activated protein kinase kinase kinase kinase kinase 1 (MAP4K1) (also known as hematopoietic progenitor cell kinase 1 (HPK1), NCBI Gene ID: 11184); regulator of apoptosis in myeloid cell leukemia sequence 1 (MCL1; NCBI Gene ID: 4170); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD; NCBI Gene ID: 5293); programmed death ligand 1 (PD -L1, CD274; NCBI Gene ID: 29126); programmed cell death protein 1 (PD-1, CD279; NCBI Gene ID: 5133); proto-oncogene c-KIT (KIT, CD117; NCBI Gene ID: 3815); signal regulatory protein alpha (SIRPA, CD172A; NCBI Gene ID: 140885); TCDD-inducible poly (ADP-ribose) polymerase (TIPARP, PAR P7; NCBI Gene ID: 25976); T cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); triggering receptor expressed on myeloid cells 1 (TREM1; NCBI Gene ID: 54210); triggering receptor expressed on myeloid cells 2 (TREM2; NCBI Gene ID: 54209); tumor-associated calcium signal transducer 2 (TACSTD2, TROP2, EGP1; NCBI Gene ID: 4070); tumor necrosis factor receptor superfamily member 4 (TNFRSF4, CD134, OX40; NCBI Gene ID: 7293); tumor necrosis factor receptor superfamily member 9 (TNFRSF9, 4-1BB, CD137; NCBI Gene ID: 3604); tumor necrosis factor receptor superfamily member 18 (TNFRSF18, CD357, GITR; NCBI Gene ID: 8784);WRN RecQ-like helicase (WRN; NCBI gene ID: 7486); zinc finger protein Helios (IKZF2; NCBI gene ID: 22807).

[0799] Exemplary Mechanism of Action

[0800] Immune checkpoint modulators

[0801] In some embodiments, provided herein are compounds and one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and / or with one or more stimulators, activators or agonists of one or more stimulatory immune checkpoint proteins or receptors. The blocking or inhibition of inhibitory immune checkpoints can positively regulate T cell or NK cell activation and prevent the immune escape of cancer cells in the tumor microenvironment. The activation or stimulation of stimulatory immune checkpoints can enhance the effect of immune checkpoint inhibitors in cancer treatment. In some embodiments, immune checkpoint proteins or receptors regulate T cell responses (for example, in Xu et al., J Exp Clin Cancer Res. (2018) 37: 110). In some embodiments, immune checkpoint proteins or receptors regulate NK cell responses (for example, in Davis et al., Semin Immunol. (2017) 31: 64-75 and Chiossone et al., Nat Rev Immunol. (2018) 18 (11): 671-688). Inhibition of regulatory T cells (Tregs) or depletion of Tregs can alleviate their suppression of anti-tumor immune responses and have anti-cancer effects (e.g., reviewed in Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77; Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49:1140-1146).

[0802] Examples of immune checkpoint proteins or receptors include CD27 (NCBI gene ID: 939), CD70 (NCBI gene ID: 970); CD40 (NCBI gene ID: 958), CD40LG (NCBI gene ID: 959); CD47 (NCBI gene ID: 961), SIRPA (NCBI gene ID: 140885); CD48 (SLAMF2; NCBI gene ID: 962), transmembrane and immunoglobulin domain-containing 2 (TMIGD2, CD28H; NCBI gene ID: 126259), CD84 (LY9B, SLAMF5; NCBI gene ID: 8832), CD96 (NCBI gene ID: 10225), CD160 (NC NCBI gene ID: 11126), MS4A1 (CD20; NCBI gene ID: 931), CD244 (SLAMF4; NCBI gene ID: 51744); CD276 (B7H3; NCBI gene ID: 80381); V-set domain-containing inhibitor of T cell activation 1 (VTCN1, B7H4); V-set immunomodulatory receptor (VSIR, B7H5, VISTA; NCBI gene ID: 64115); immunoglobulin superfamily member 11 (IGSF11, VSIG3; NCBI gene ID: 152404); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6; NCBI gene ID: 374383); HERV-H LTR-associated 2 (HHLA2, B7H7; NCBI gene ID: 11148); inducible T cell costimulator (ICOS, CD278; NCBI gene ID: 29851); inducible T cell costimulator ligand (ICOSLG, B7H2; NCBI gene ID: 23308); TNF receptor superfamily member 4 (TNFRSF4, OX40; NCBI gene ID: 7293); TNF superfamily member 4 (TNFSF4, OX40L; NCBI gene ID: 7292); TNFRSF8 (CD30; NCBI gene ID: 943), T NFSF8 (CD30L; NCBI Gene ID: 944); TNFRSF10A (CD261, DR4, TRAILR1; NCBI Gene ID: 8797), TNFRSF9 (CD137; NCBI Gene ID: 3604), TNFSF9 (CD137L; NCBI Gene ID: 8744); TNFRSF10B (CD262, DR5, TRAILR2; NCBI Gene ID: 8795), TNFRSF10 (TRAIL; NCBI Gene ID: 8743); TNFRSF14 (HVEM, CD270;NCBI Gene ID: 8764), TNFSF14 (HVEML; NCBI Gene ID: 8740); CD272 (B and T lymphocyte-associated (BTLA); NCBI Gene ID: 151888); TNFRSF17 (BCMA, CD269; NCBI Gene ID: 608), TNFSF13B (BAFF; NCBI Gene ID: 10673); TNFRSF18 (GITR; NCBI Gene ID: 8784), TNFSF18 (GITRL; NCBI Gene ID: 8995); MHC class I polypeptide-related sequence A (MICA; NCBI Gene ID: 100507436); MHC Class I polypeptide-related sequence B (MICB; NCBI Gene ID: 4277); CD274 (CD274, PDL1, PD-L1; NCBI Gene ID: 29126); programmed cell death 1 (PDCD1, PD1, PD-1; NCBI Gene ID: 5133); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152; NCBI Gene ID: 1493); CD80 (B7-1; NCBI Gene ID: 941), CD28 (NCBI Gene ID: 1493); NCBI gene ID: 940); nectin cell adhesion molecule 2 (NECTIN2, CD112; NCBI gene ID: 5819); CD226 (DNAM-1; NCBI gene ID: 10666); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155; NCBI gene ID: 5817); PVR-related immunoglobulin domain-containing (PVRIG, CD112R; NCBI gene ID: 79037); T cells with Ig and ITIM domains. Cellular immune receptor (TIGIT; NCBI gene ID: 201633); T cell immunoglobulin and mucin domain-containing 4 (TIMD4; TIM4; NCBI gene ID: 91937); Hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3; NCBI gene ID: 84868); Galectin 9 (LGALS9; NCBI gene ID: 3965); Lymphocyte activation 3 (LAG3, CD223; NCBI gene ID: 3902); Signal transduction lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150; NCBI gene ID: 6504); lymphocyte antigen 9 (LY9, CD229, SLAMF3; NCBI gene ID: 4063); SLAM family member 6 (SLAMF6, CD352; NCBI gene ID: 114836); SLAM family member 7 (SLAMF7, CD319; NCBI gene ID: 57823); UL16 binding protein 1 (ULBP1;NCBI Gene ID: 80329); UL16 binding protein 2 (ULBP2; NCBI Gene ID: 80328); UL16 binding protein 3 (ULBP3; NCBI Gene ID: 79465); retinoic acid early transcript 1E (RAET1E; ULBP4; NCBI Gene ID: 135250); retinoic acid early transcript 1G (RAET1G; ULBP5; NCBI Gene ID: 353091); retinoic acid early transcript 1L (RAET1L; ULBP6; NCBI Gene ID: 154064); killer cell immunoglobulin-like Receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1; NCBI gene ID: 3811, e.g., lirelumab (IPH-2102, IPH-4102)); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A; NCBI gene ID: 3821); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314; NCBI gene ID: 22914); killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C; NCBI gene ID: 3822); Killer cell lectin-like receptor C3 (KLRC3, NKG2E; NCBI Gene ID: 3823); Killer cell lectin-like receptor C4 (KLRC4, NKG2F; NCBI Gene ID: 8302); Killer cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1; NCBI Gene ID: 3802); Killer cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2; NCBI Gene ID: 3803); Killer cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3 ; NCBI Gene ID: 3804); Killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); Killer cell lectin-like receptor D1 (KLRD1; NCBI Gene ID: 3824); Killer cell lectin-like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1; NCBI Gene ID: 10219); Sialic acid-binding Ig-like lectin 7 (SIGLEC7; NCBI Gene ID: 27036); and Sialic acid-binding Ig-like lectin 9 (SIGLEC9; NCBI Gene ID: 27180).

[0803] In some embodiments, the compounds provided herein are administered with one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. Exemplary T cell inhibitory immune checkpoint proteins or receptors include CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing inhibitor of T cell activation 1 (VTCN1, B7H4); V-set immunomodulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-associated immunoglobulin. protein domains (PVRIG, CD112R); T-cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In some embodiments, the compounds provided herein are administered with one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors.Exemplary T cell stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T cell co-stimulator (ICOS, CD278); inducible T cell co-stimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, e.g., Xu et al., J Exp Clin Cancer Res. (2018) 37:110.

[0804] In some embodiments, the compounds provided herein are administered together with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell cytoplasmic immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor D1 (KLRD1, CD94); killer cell lectin-like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid binding Ig-like lectin 7 (SIGLEC7); and sialic acid binding Ig-like lectin 9 (SIGLEC9). In some embodiments, the compounds provided herein are administered together with one or more agonists or activators of one or more NK cell stimulating immune checkpoint proteins or receptors. Exemplary NK cell stimulatory immune checkpoint proteins or receptors include CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); Killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, for example, Davis et al., Semin Immunol. (2017) 31: 64-75; Fang et al., Semin Immunol. (2017) 31: 37-54; and Chiossone et al., Nat Rev Immunol. (2018) 18 (11): 671-688.

[0805] In some embodiments, one or more immune checkpoint inhibitors include protein (e.g., antibody or fragment thereof or antibody mimic) inhibitors of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, one or more immune checkpoint inhibitors include organic small molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, one or more immune checkpoint inhibitors include protein (e.g., antibody or fragment thereof or antibody mimic) inhibitors of LAG3.

[0806] Examples of CTLA4 inhibitors that can be co-administered include ipilimumab, tremelimumab, BMS-986218, AGEN1181, zevolimab (AGEN1884), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002 (ipilimumab biosimilar), BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, HBM-4003, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

[0807] Examples of inhibitors of PD-L1 (CD274) or PD-1 (PDCD1) that can be co-administered include pembrolizumab, nivolumab, cemiplizumab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, coxilimab (CK-301), saxaluzumab (PF-06801591), tislelizumab (BGB-A317), GLS-010 (WBP-305), and PD-L1 (CD274) or PD-1 (PDCD1) inhibitors. 5), AK-103 (HX-008), AK-105, CS-1003, HLX-10, rivalizumab (MGA-012), BI-754091, batilizumab (AGEN-2034), AMG-404, toripalimab (JS-001), cetrilimab (JNJ-63723283), genoluzumab (CBT-501), LZM-009, palolizumab (BCD-100), lodalizumab (LY-3300054), SHR-1201, and camrelizumab (SHR-1210), Sym-021, budigralizumab (ABBV-181), PD1-PIK, BAT-1306, avelumab (MSB0010718C), CX-072, CBT-502, dotalimumab (TSR-042), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, envolimab (KN-035), sintilimab (IBI-308), HLX-20, KL- A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, sepalizumab (AB122), spartalizumab (PDR-001), and compounds disclosed in WO2018195321, WO2020014643, WO2019160882 or WO2018195321,and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), RO-7247669 (PD-1 / LAG-3), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), RO-7121661 (PD-1 / TIM-3), RG7769 (PD-1 / TIM-3), and TAK-252 (PD-1 / OX40L), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), FS-118 (LAG-3 / PD-L1), FPT-155 (CTLA4 / PD-L1 / CD28), GEN-1046 (PD-L1 / 4-1BB), bintrafuspα (M7824; PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1). In some embodiments, the PD-L1 inhibitor is a small molecule inhibitor such as CA-170, GS-4224, GS-4416, and lazertinib (GNS-1480; PD-L1 / EGFR).

[0808] Examples of TIGIT inhibitors that can be co-administered include tislelizumab (RG-6058), vebolizumab, dunalimab, dunalimab (AB154), AB308, BMS-986207, AGEN-1307, COM-902, or etigilimab.

[0809] Examples of LAG3 inhibitors that may be co-administered include, but are not limited to, elalimumab (LAG525).

[0810] Inhibiting the activity of regulatory T cells (Tregs) or exhausting Tregs can reduce their suppression of anti-tumor immune responses and have anti-cancer effects. See, for example, Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4: 459-77; Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49: 1140-1146. In some embodiments, the compounds provided herein are administered together with one or more Treg activity inhibitors or Treg depletion agents. Treg inhibition or exhaustion can enhance the effect of immune checkpoint inhibitors in cancer therapeutics.

[0811] In some embodiments, the compound provided herein is administered together with one or more Treg inhibitors. In some embodiments, the Treg inhibitor can inhibit Treg migration into the tumor microenvironment. In some embodiments, the Treg inhibitor can reduce the immunosuppressive function of Treg. In some embodiments, the Treg inhibitor can regulate cell phenotype and induce the production of proinflammatory cytokines. Exemplary Treg inhibitors include but are not limited to CCR4 (NCBI gene ID: 1233) antagonists and Ikaros zinc finger protein degraders (e.g., Ikaros (IKZF1; NCBI gene ID: 10320), Helios (IKZF2; NCBI gene ID: 22807), Aiolos (IKZF3; NCBI gene ID: 22806) and Eos (IKZF4; NCBI gene ID: 64375).

[0812] Examples of Helios degraders that may be co-administered include, but are not limited to, 1-57 (Novartis) and compounds disclosed in WO2019038717, WO2020012334, WO20200117759, and WO2021101919.

[0813] In some embodiments, the compound provided herein is administered together with one or more Treg depletion agents. In some embodiments, the Treg depletion agent is an antibody. In some embodiments, the Treg depletion antibody has antibody-dependent cellular cytotoxicity (ADCC) activity. In some embodiments, the Treg depletion antibody is Fc engineered to have enhanced ADCC activity. In some embodiments, the Treg depletion antibody is an antibody-drug conjugate (ADC). Exemplary targets of Treg depleting agents include, but are not limited to, CD25 (IL2RA; NCBI Gene ID: 3559), CTLA4 (CD152; NCBI Gene ID: 1493); GITR (TNFRSF18; NCBI Gene ID: 8784); 4-1BB (CD137; NCBI Gene ID: 3604), OX-40 (CD134; NCBI Gene ID: 7293), LAG3 (CD223; NCBI Gene ID: 3902), TIGIT (NCBI Gene ID: 201633), CCR4 (NCBI Gene ID: 1233), and CCR8 (NCBI Gene ID: 1237).

[0814] In some embodiments, the Treg inhibitor or Treg depleting agent that can be co-administered comprises an antibody or antigen-binding fragment thereof that selectively binds to a cell surface receptor selected from the group consisting of: CC motif chemokine receptor 4 (CCR4), CC motif chemokine receptor 7 (CCR7), CC motif chemokine receptor 8 (CCR8), CXC motif chemokine receptor 4 (CXCR4; CD184), TNFRSF4 (OX40), TNFRSF18 (GITR, CD357), TNFRSF9 (4-1BB, CD137), cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152), programmed cell death 1 (PDCD1, PD-1), sialyl Lewis x (CD15s), CD27, extracellular nucleotide triphosphate diphosphohydrolase 1 (ENTPD1; CD39), protein tyrosine phosphatase receptor type C (PTPRC; CD45), neural cell adhesion molecule 1 (NCAM1; CD56), selectin L (SELL; CD62L), integrin subunit αE (ITGAE; CD103), interleukin 7 receptor (IL7R; CD127), CD40 ligand (CD40LG; CD154), folate receptor α (FOLR1), folate receptor β (FOLR2), leucine-rich repeat-containing protein 32 (LRRC32; GARP), IKAROS family zinc finger 2 (IKZF2; HELIOS), inducible T-cell co-stimulator (ICOS; CD278), lymphocyte activation 3 (LAG3; CD223), transforming growth factor beta 1 (TGFB1), hepatitis A virus cellular receptor 2 (HAVCR2; CD366; TIM3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), TNF receptor superfamily member 1B (CD120b; TNFR2), IL2RA (CD25), or a combination thereof.

[0815] Examples of Treg-depleting anti-CCR8 antibodies that can be administered include, but are not limited to, JTX-1811 (GS-1811) (Jounce Therapeutics, Gilead Sciences), BMS-986340 (Bristol Meyers Squibb), S-531011 (Shionogi), FPA157 (Five Prime Therapeutics), SRF-114 (Surface Oncology), HBM1022 (Harbor BioMed), IO-1 (Oncurious), and antibodies disclosed in WO2021163064, WO2020138489, and WO2021152186.

[0816] Examples of Treg-depleting anti-CCR4 antibodies that can be administered include muglizumab.

[0817] Inhibiting, depleting or reprogramming non-stimulatory myeloid cells in the tumor microenvironment can enhance anti-cancer immune responses (see, e.g., Binnewies et al., Nat. Med. (2018) 24(5):541-550; WO2016049641). Exemplary targets for depleting or reprogramming non-stimulatory myeloid cells include triggering receptors expressed on myeloid cells, TREM-1 (CD354, NCBI gene ID: 54210) and TREM-2 (NCBI gene ID: 54209). In some embodiments, the compounds provided herein are administered together with one or more myeloid cell depleting or reprogramming agents such as anti-TREM-1 antibodies (e.g., PY159; antibodies disclosed in WO2019032624) or anti-TREM-2 antibodies (e.g., PY314; antibodies disclosed in WO2019118513).

[0818] Cluster of differentiation agonists or activators

[0819] In some embodiments, the compounds provided herein are administered together with an agent that targets a cluster of differentiation (CD) marker. Exemplary agents that can be co-administered targeting CD markers include, but are not limited to, A6, AD-IL24, neratinib, tucatinib (ONT 380), mobocertinib (TAK-788), tesevatinib, trastuzumab, and trastuzumab. Trastuzumab biosimilar (HLX-02), margetuximab, BAT-8001, pertuzumab (Perjeta), pegfilgrastim, RG6264, zanidatamab (ZW25), cavatak, AIC-100, tagraxofusp (SL-401), HLA-A2402 / HLA-A0201-restricted epitope peptide vaccine, dasatinib, imatinib, nilotinib, sorafenib, lenvatinib mesylate, ofranergene obadenovec, cabozantinib malate malate), AL-8326, ZLJ-33, KBP-7018, sunitinib malate, pazopanib derivatives, AGX-73, rebastinib, NMS-088, lucitanib hydrochloride, midostaurin, cediranib, duvitinib, sitravatinib, tivozanib, masitinib, regorafenib, olverembatinib dimesylate (HQP-1351), cabozantinib, ponatinib, and famitinib L-malate.L-malate), CX-2029 (ABBV-2029), SCB-313, CA-170, COM-701, CDX-301, GS-3583, asunercept (APG-101), APO-010, and compounds disclosed in the following documents: WO2016196388, WO2016033570, WO2015157386, WO199203459, WO199221766, WO2004080462, WO2005020921, WO2006009755, WO200 7078034, WO2007092403, WO2007127317, WO2008005877, WO2012154480, WO2014100620, WO2014039714, WO2015134536, WO20171671 82. WO2018112136, WO2018112140, WO2019155067, WO2020076105, PCT / US2019 / 063091, WO19173692, WO2016179517, WO2017096179, WO2017096182, WO2017096281, WO2018089628, WO2017096179, WO2018089628, WO2018195321, WO2020014643, WO2019160882, WO201 8195321, WO200140307, ​​WO2002092784, WO2007133811, WO2009046541, WO2010083253, WO2011076781, WO2013056352, WO201513860 0, WO2016179399, WO2016205042, WO2017178653, WO2018026600, WO2018057669, WO2018107058, WO2018190719, WO2018210793, WO2019023347, WO2019042470, WO2019175218, WO2019183266, WO2020013170, WO2020068752, Cancer Discov. 2019 Jan 9(1):8; and Gariepy J. et al. 106th Annu Meet Am Assoc Immunologists (AAI) (May 9-13, San Diego, 2019, Abst 71.5).

[0820] In some embodiments, agents targeting CD markers that can be co-administered include small molecule inhibitors such as PBF-1662, BLZ-945, pemigatinib (INCB-054828), rogaratinib (BAY-1163877), AZD4547, roblitinib (FGF-401), quizartinib dihydrochloride, SX-682, AZD-5069, PLX-9486, avapritinib (BLU-285), ripretinib (DCC-2618), imatinib mesylate, JSP-1 91, BLU-263, CD117-ADC, AZD3229, telatinib, vorolanib, GO-203-2C, AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708, HM-30181A, motixafortide (BL-8040), LY2510924, burixafor (TG-0054), X4P-002, mavorixafor (X4P-001-10), plerixafor, CTX-5861, or REGN-5678 (PSMA / CD28).

[0821] In some embodiments, agents targeting CD markers that may be co-administered include small molecule agonists such as interleukin-2 receptor subunit gamma, eltrombopag, retamod, polyICLC (NSC-301463), Riboxxon, Apoxxim, MCT-465, MCT-475, G100, PEPA-10, eftozanermin alfa (ABBV-621), E-6887, motolimod, resiquimod, selgantolimod (GS-9688), VTX-1463, NKTR-262, AST-008, CMP-001, cobitolimod, tilsotolimod, litenimod, MGN-1601, BB-006, IMO-8400, IMO-9200, agatolimod, DIMS-9054, DV-1079, lefitolimod (MGN-1703), CYT-003, and PUL-042.

[0822] In some embodiments, agents targeting CD markers that can be co-administered include antibodies such as tafasitamab (MOR208; MorphoSys AG), Inebilizumab (MEDI-551), obinutuzumab, IGN-002, rituximab biosimilar (PF-05280586), varlilumab (CDX-1127), AFM-13 (CD16 / CD30), AMG330, otlertuzumab (TRU-016), isatuximab, felzartamab (MOR-202), TAK-079, TAK573, daratumumab TTX-030, selicrelumab (RG7876), APX-005M, ABBV-428, ABBV-927, mitazalimab (JNJ-64457107), lenzilumab, alemtuzuma, emactuzumab, AMG-820, FPA-008 (cabiralizumab), PRS-343 (CD-137 / Her2), AFM-13 (CD16 / CD30), belantamab mafodotin (GSK-2857916), AFM26 (BCMA / CD16A), simlukafusp alfa alfa)(RG7461), urelumab, utomilumab (PF-05082566), AGEN2373, ADG-106, BT-7480, PRS-343 (CD-137 / HER2), FAP-4-IBBL (4-1BB / FAP), ramucirumab, CDX-0158, CDX-0159 and FSI-174, relatlimab (ONO-4482), LAG-525, MK-4280, fianlimab (REGN-3767), INCAGN2385, encelimab (TSR-033), atipotuzumab, BrevaRex (Mab-AR-20.5), MEDI-9447 (oleclumab), CPX-006, IPH-53, BMS-986179, NZV-930, CPI-006, PAT-SC1, lirilumab (IPH-2102), lacutamab (IPH-4102), monalizumab, BAY-1834942, NEO-201 (CEACAM 5 / 6), iodine (131I) apamistamab (131I-BC8 (lomab-B)), MEDI0562 (tavolixizumab), GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, denosumab, BION-1301, MK-4166, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-3 23, CTB-006, INBRX-109, GEN-1029, pepinemab (VX-15), vopratelimab (JTX-2011), GSK3359609, cobolimab (TSR-022), MBG-453, INCAGN-2390, and compounds disclosed in WO2017096179, WO2017096276, WO2017096189, and WO2018089628.

[0823] In some embodiments, co-administered agents targeting CD markers include cell therapies such as CD19-ARTEMIS, TBI-1501, CTL-119 huCART-19 T cells, lisocabtagene maraleucel (JCAR-017), axicabtagene ciloleucel (KTE-C19, ), KTE-X19, US7741465, US6319494, UCART-19, tabelecleucel (EBV-CTL), tisagenlecleucel-T (CTL019), T cells expressing CD19CAR-CD28-CD3ζ-EGFRt, CD19 / 4-1BBL armored CAR T cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-ζT cells, PCAR-019, MatchCART, DSCAR-01, IM19 CAR-T, TC-110, anti-CD19 CAR T cell therapy (B-cell acute lymphoblastic leukemia, Universiti Kebangsaan Malaysia), anti-CD19 CAR T cell therapy (acute lymphoblastic leukemia / non-Hodgkin's lymphoma, University Hospital Heidelberg, Germany), anti-CD19 CAR T cell therapy (silenced IL-6 expression, cancer, Shanghai Unicar-Therapy Bio-medicine Technology), MB-CART2019.1 (CD19 / CD20), GC-197 (CD19 / CD7), CLIC-1901, ET-019003, anti-CD19-STAR-T cells, AVA-001, BCMA-CD19 cCAR (CD19 / APRIL), ICG-134, ICG-132 (CD19 / CD20), CTA-101, WZTL-002, dual anti-CD19 / anti-CD20 CAR T cells (chronic lymphocytic leukemia / B-cell lymphoma), HY-001, ET-019002, YTB-323, GC-012 (CD19 / APRIL), GC-022 (CD19 / CD22), Tn / mem expressing CD19CAR-CD28-CD3ζ-EGFRt, UCAR-011, ICTCAR-014, GC-007F, PTG-01, CC-97540, GC-007G, TC-310, GC-197, Tesaran-T, CART-19, Tesaran (CTL-019)), anti-CD20 CAR T cell therapy (non-Hodgkin's lymphoma), MB-CART2019.1(CD19 / CD20), WZTL-002 dual anti-CD19 / anti-CD20 CAR-T cells, ICG-132(CD19 / CD20), ACTR707 ATTCK-20, PBCAR-20A, LB-1905, CIK-CAR.CD33, CD33CART, dual anti-BCMA / anti-CD38 CAR T cell therapy, CART-ddBCMA, MB-102, IM-23, JEZ-567, UCART-123, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), ICTCAR-052, Tn MUC-1CAR-T, ICTCAR-053, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), AUTO-2, anti-BCMA CART T cell therapy, Descartes-011, anti-BCMA / anti-CD38 CAR T cell therapy, CART-ddBCMA, BCMA-CS1 cCAR, CYAD-01 (NKG2D ligand modulator), KD-045, PD-L1 t-haNK, BCMA-CS1 cCAR, MEDI5083, anti-CD276 CART, and therapies disclosed in WO2012079000 or WO2017049166.

[0824] Cluster of differentiation 47 (CD47) inhibitors

[0825] In some embodiments, the compounds provided herein are administered with an inhibitor of CD47 (IAP, MER6, OA3; NCBI gene ID: 961). Examples of CD47 inhibitors include anti-CD47 mAb (Vx-1004), anti-human CD47 mAb (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibodies or CD47 blockers, NI-1701, NI-1801, RCT-1938, ALX148, SG-404, SRF-231, and TTI-621.Additional exemplary anti-CD47 antibodies include CC-90002, magrolimab (Hu5F9-G4), AO-176 (Vx-1004), letaplimab (IBI-188), lemzoparlimab (TJC-4), SHR-1603, HLX-24, LQ-001, IMC-002, ZL-1201, IMM-01, B6H12, GenSci-059, TAY-018, PT-240, 1F8-GMCSF, SY-102, KD-015, ALX-148, AK- -117, TTI-621, TTI-622, or in WO199727873, WO199940940, WO2002092784, WO2005044857, WO2009046541, WO2010070047, WO2011143624, WO201 2170250, WO2013109752, WO2013119714, WO2014087248, WO2015191861, WO2016022971, WO2016023040, WO2016024021, WO2016081423, WO2016 109415, WO2016141328, WO2016188449, WO2017027422, WO2017049251, WO2017053423, WO2017121771, WO2017194634, WO2017196793, WO2017 215585, WO2018075857, WO2018075960, WO2018089508, WO2018095428, WO2018137705, WO2018233575, WO2019027903, WO2019034895, WO20190 The compounds disclosed in WO2019042285, WO2019042470, WO2019086573, WO2019108733, WO2019138367, WO2019144895, WO2019157843, WO2019179366, WO2019184912, WO2019185717, WO2019201236, WO2019238012, WO2019241732, WO2020019135, WO2020036977, WO2020043188 and WO2020009725.In some embodiments, the CD47 inhibitor is RRx-001, DSP-107, VT-1021, IMM-02, SGN-CD47M, or SIRPa-Fc-CD40L (SL-172154). In some embodiments, the CD47 inhibitor is mololimab.

[0826] In some embodiments, the CD47 inhibitor is a bispecific antibody targeting CD47, such as IBI-322 (CD47 / PD-L1), IMM-0306 (CD47 / CD20), TJ-L1C4 (CD47 / PD-L1), HX-009 (CD47 / PD-1), PMC-122 (CD47 / PD-L1), PT-217, (CD47 / DLL3), IMM-26011 (CD47 / FLT3), 3), IMM-0207(CD47 / VEGF), IMM-2902(CD47 / HER2), BH29xx(CD47 / PD-L1), IMM-03(CD47 / CD20), IMM- 2502 (CD47 / PD-L1), HMBD-004B (CD47 / BCMA), HMBD-004A (CD47 / CD33), TG-1801 (NI-1701) or NI-1801.

[0827] SIRPa targeting agents

[0828] In some embodiments, the compounds provided herein are administered with a SIRPα targeting agent (NCBI gene ID: 140885; UniProt P78324). Examples of SIRPα targeting agents include SIRPα inhibitors (such as AL-008, RRx-001, and CTX-5861) and anti-SIRPα antibodies (such as FSI-189 (GS-0189), ES-004, BI-765063, ADU1805, CC-95251, Q-1801 (SIRPα / PD-L1)). Additional SIRPα targeting agents of use are described, for example, in WO200140307, ​​WO2002092784, WO2007133811, WO2009046541, WO2010083253, WO2011076781, WO2013056352, WO2015138600, WO2016179399, WO2016205042, W 02017178653, WO2018026600, WO2018057669, WO2018107058, WO2018190719, WO2018210793, WO2019023347, WO2019042470, WO2019175218, WO2019183266, WO2020013170 and WO2020068752.

[0829] FLT3R agonists

[0830] In some embodiments, the compound provided herein is administered together with a FLT3R agonist. In some embodiments, the compound provided herein is administered together with a FLT3 ligand. In some embodiments, the compound provided herein is administered together with a FLT3L-Fc fusion protein (e.g., as described in WO2020263830). In some embodiments, the compound provided herein is administered together with GS-3583 or CDX-301. In some embodiments, the compound provided herein is administered together with GS-3583.

[0831] TNF receptor superfamily (TNFRSF) member agonists or activators

[0832] In some embodiments, the compounds provided herein are administered with an agonist of one or more TNF receptor superfamily (TNFRSF) members, such as an agonist of one or more of the following: TNFRSF1A (NCBI gene ID: 7132), TNFRSF1B (NCBI gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI gene ID: 7293), TNFRSF5 (CD40; NCBI gene ID: 958), TNFRSF6 (FAS, NCBI gene ID: 3 55), TNFRSF7 (CD27, NCBI gene ID: 939), TNFRSF8 (CD30, NCBI gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID: 8795), TNFRSF10C (CD263, TRAILR3 , NCBI gene ID: 8794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI gene ID: 8792), TNFRSF11B (NCBI gene ID: 4982), TNFRSF12A (CD266, NCBI gene ID: 51330), TNFRSF13B (CD267, NCBI gene ID: 23495), TNFRSF13C (CD268, NCBI gene ID: 23496), and TNFRSF14A (CD269, NCBI gene ID: 23507). ID: 115650), TNFRSF16 (NGFR, CD271, NCBI gene ID: 4804), TNFRSF17 (BCMA, CD269, NCBI gene ID: 608), TNFRSF18 (GITR, CD357, NCBI gene ID: 8784), TNFRSF19 (NCBI gene ID: 55504), TNFRSF21 (CD358, DR6, NCBI gene ID: 27242) and TNFRSF25 (DR3, NCBI gene ID: 8718).

[0833] Exemplary anti-TNFRSF4 (OX40) antibodies that can be co-administered include MEDI6469, MEDI6383, Tavolizumab (MEDI0562), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0834] Exemplary anti-TNFRSF5 (CD40) antibodies that can be co-administered include RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0835] In some embodiments, the anti-TNFRSF7 (CD27) antibody varilutumab (CDX-1127) is co-administered.

[0836] Exemplary anti-TNFRSF9 (4-1BB, CD137) antibodies that can be co-administered include usurelumab, utolumab (PF-05082566), AGEN-2373, and ADG-106.

[0837] In some embodiments, the anti-TNFRSF17 (BCMA) antibody GSK-2857916 is co-administered.

[0838] Exemplary anti-TNFRSF18 (GITR) antibodies that can be co-administered include MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO2017096179, WO2017096276, WO2017096189, and WO2018089628. In some embodiments, antibodies or fragments thereof that co-target TNFRSF4 (OX40) and TNFRSF18 (GITR) are co-administered. Such antibodies are described, for example, in WO2017096179 and WO2018089628.

[0839] Bispecific antibodies targeting TNFRSF family members that can be co-administered include PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), AFM-13 (CD16 / CD30), odronextamab (REGN-1979; CD20 / CD3), AMG-420 (BCMA / CD3), INHIBRX-105 (4-1BB / PDL1), FAP-4-IBBL (4-1BB / FAP), plamotamab (XmAb-13676; CD3 / CD20), RG-7828 (CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), and IMM-0306 (CD47 / CD20).

[0840] Bispecific T cell engagers

[0841] In some embodiments, the compounds provided herein are administered together with a bispecific T cell engager (e.g., without Fc) or an anti-CD3 bispecific antibody (e.g., with Fc). Exemplary anti-CD3 bispecific antibodies or BiTEs that can be co-administered include duvortuxizumab (JNJ-64052781; CD19 / CD3), AMG-211 (CEA / CD3), AMG-160 (PSMA / CD3), RG7802 (CEA / CD3), ERY-974 (CD3 / GPC3), PF-06671008 (cadherin / CD3), APVO436 (CD123 / CD3), flotetuzumab (CD123 / CD3), onituzumab (odronextamab)(REGN-1979; CD20 / CD3), MCLA-117(CD3 / CLEC12A), JNJ-0819(heme / CD3), JNJ-7564(CD3 / heme), AMG-757(DLL3-C D3), ​​AMG-330(CD33 / CD3), AMG-420(BCMA / CD3), AMG-427(FLT3 / CD3), AMG-562(CD19 / CD3), AMG-596(EGFRvIII / CD3), AMG-673(CD3 3 / CD3), AMG-701(BCMA / CD3), AMG-757(DLL3 / CD3), AMG-211(CEA / CD3), blinatumomab(CD19 / CD3), huGD2-BsAb(CD3 / GD2 ), ERY974(GPC3 / CD3), GEMoab(CD3 / PSCA), RG6026(CD20 / CD3), RG6194(HER2 / CD3), PF-06863135(BCMA / CD3), SAR440234(CD3 / CDw 123), JNJ-9383 (MGD-015), AMG-424 (CD38 / CD3), tidutamab (XmAb-18087 (SSTR2 / CD3)), JNJ-63709178 (CD123 / CD3), MGD-0 07 (CD3 / gpA33), MGD-009 (CD3 / B7H3), IMCgp100 (CD3 / gp100), XmAb-14045 (CD123 / CD3), XmAb-13676 (CD3 / CD20) Titumumab (XmAb-18087;

[0015] The present invention relates to a novel anti-CD3 binding bispecific molecule comprising: a monoclonal antibody ... Exemplary bispecific T cell engagers that can be co-administered target CD3 and a tumor-associated antigen as described herein, including, for example, CD19 (e.g., blinatumomab); CD33 (e.g., AMG330); CEA (e.g., MEDI-565); receptor tyrosine kinase-like orphan receptor 1 (ROR1) (Gohil et al., Oncoimmunology. (2017) May 17;6(7):e1326437); PD-L1 (Horn et al., Oncotarget. 2017 Aug 3;8(35):57964-57980); and EGFRvIII (Yang et al., Cancer Lett. 2017 Sep 10;403:224-230).

[0842] Bispecific and trispecific natural killer (NK) cell engagers

[0843] In some embodiments, the compounds provided herein are administered with a bispecific NK cell engager (BiKE) or a trispecific NK cell engager (TriKE) (e.g., without Fc) or a bispecific antibody (e.g., with Fc) against NK cell activating receptors, such as CD16A, C-type lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), natural cytotoxicity receptors (NKp30, NKp44, and NKp46), killer cell C-type lectin-like receptors (NKp65, NKp80), Fc receptors FcγR (which mediate antibody-dependent cellular cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Exemplary anti-CD16 bispecific antibodies, BiKEs, or TriKEs that can be co-administered include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). Depending on the circumstances, the anti-CD16 binding bispecific molecule may or may not have an Fc. Exemplary co-administered bispecific NK cell engagers target CD16 and one or more tumor-associated antigens as described herein, including, for example, CD19, CD20, CD22, CD30, CD33, CD123, EGFR, EpCAM, ganglioside GD2, HER2 / neu, HLA class II, and FOLR1. BiKE and TriKE are described, for example, in Felices et al., Methods Mol Biol. (2016) 1441: 333-346; Fang et al., Semin Immunol. (2017) 31: 37-54.

[0844] MCL1 apoptosis regulator, BCL2 family member (MCL1) inhibitor

[0845] In some embodiments, the compounds provided herein are administered with an inhibitor of an MCL1 apoptosis regulator (BCL2 family member) (MCL1, TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcl1 / EAT; NCBI gene ID: 4170). Examples of MCL1 inhibitors include tapotoclax (AMG-176), AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, PRT-1419, GS-9716, and those described in WO2018183418, WO2016033486, and WO2017147410.

[0846] SHP2 inhibitors

[0847] In some embodiments, the compounds provided herein are administered with an inhibitor of protein tyrosine phosphatase non-receptor type 11 (PTPN11; BPTP3, CFC, JMML, METCDS, NS1, PTP-1D, PTP2C, SH-PTP2, SH-PTP3, SHP2; NCBI gene ID: 5781). Examples of SHP2 inhibitors include TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630, and those described in WO2018172984 and WO2017211303.

[0848] Hematopoietic progenitor kinase 1 (HPK1) inhibitors and degraders

[0849] In some embodiments, the compounds provided herein are administered together with an inhibitor of mitogen-activated protein kinase kinase kinase kinase kinase 1 (MAP4K1, HPK1; NCBI gene ID: 11184). Examples of hematopoietic progenitor kinase 1 (HPK1) inhibitors include, but are not limited to, those described in WO2020092621, WO2018183956, WO2018183964, WO2018167147, WO2018049152, WO2020092528, WO2016205942, WO2016090300, WO2018049214, WO2018049200, WO2018049191, WO2018102366, WO2018049152, and WO2016090300.

[0850] Apoptosis signal-regulating kinase (ASK) inhibitors

[0851] In some embodiments, the compounds provided herein are administered with an inhibitor of ASK, e.g., mitogen-activated protein kinase kinase kinase 5 (MAP3K5; ASK1, MAPKKK5, MEKK5; NCBI gene ID: 4217). Examples of ASK1 inhibitors include those described in WO2011008709 (Gilead Sciences) and WO 2013112741 (Gilead Sciences).

[0852] Bruton's tyrosine kinase (BTK) inhibitors

[0853] In some embodiments, the compounds provided herein are administered with an inhibitor of Bruton's tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI gene ID: 695). Examples of BTK inhibitors include (S)-6-amino-9-(1-(but-2-ynyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, HM71224, ibrutinib, M-2951 (Ibrutinib), and PD-1 inhibitors. evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, PCI-32765, and TAS-5315.

[0854] Cyclin-dependent kinase (CDK) inhibitors

[0855] In some embodiments, the compounds provided herein are combined with inhibitors of cyclin-dependent kinase 1 (CDK1, CDC2; CDC28A; p34CDC2; NCBI gene ID: 983); cyclin-dependent kinase 2 (CDK2, CDKN2; p33 (CDK2); NCBI gene ID: 1017); cyclin-dependent kinase 3 (CDK3; NCBI gene ID: 1018); cyclin-dependent kinase 4 (CDK4, CMM3; PSK-J3; NCBI gene ID: 1020); The cells were treated with an inhibitor of a cyclin-dependent kinase (CDK), a cyclin-dependent kinase (CA ... Inhibitors of CDK 1, 2, 3, 4, 6, 7, and / or 9 include abemaciclib, alvocidib (HMR-1275, flavopiridol), AT-7519, dinaciclib, ibrance, FLX-925, LEE001, palbociclib, samuraciclib, ribociclib, rigosertib, selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, milciclib, trilaciclib, simurosertib hydrate (TAK931), and TG-02.

[0856] Discoidin domain receptor (DDR) inhibitors

[0857] In some embodiments, the compounds provided herein are administered in combination with an inhibitor of discoidin domain receptor tyrosine kinase 1 (DDR1, CAK, CD167, DDR, EDDR1, HGK2, MCK10, NEP, NTRK4, PTK3, PTK3A, RTK6, TRKE; NCBI Gene ID: 780); and / or an inhibitor of discoidin domain receptor tyrosine kinase 2 (DDR2, MIG20a, NTRKR3, TKT, TYRO10, WRCN; NCBI Gene ID: 4921). Examples of DDR inhibitors include dasatinib and those disclosed in WO 2014 / 047624 (Gilead Sciences), US 2009-0142345 (Takeda Pharmaceutical), US 2011-0287011 (Oncomed Pharmaceuticals), WO 2013 / 027802 (Chugai Pharmaceutical), and WO 2013 / 034933 (Imperial Innovations).

[0858] Targeting E3 ligase ligand conjugates

[0859] In some embodiments, the compounds provided herein are administered together with a targeting E3 ligase ligand conjugate. Such conjugates have a target protein binding portion and an E3 ligase binding portion (e.g., inhibitor of apoptosis protein (IAP) (e.g., XIAP, c-IAP1, c-IAP2, NIL-IAP, Bruce and survivin) E3 ubiquitin ligase binding portion, Von Hippel-Lindau E3 ubiquitin ligase (VHL) binding portion, cereblon E3 ubiquitin ligase binding portion, mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding portion) and can be used, for example, to promote or increase degradation of the targeted protein via the ubiquitin pathway. In some embodiments, the targeting E3 ligase ligand conjugate comprises: a targeting or binding portion that targets or binds to a protein described herein, and an E3 ligase ligand or binding portion. In some embodiments, the targeted E3 ligase ligand conjugate comprises a targeting or binding portion that targets or binds to a protein selected from the group consisting of: Cbl proto-oncogene B (CBLB; Cbl-b, Nbla00127, RNF56; NCBI gene ID: 868) and an inhibitor of hypoxia-inducible factor 1 subunit alpha (HIF1A; NCBI gene ID: 3091). In some embodiments, the targeted E3 ligase ligand conjugate comprises a kinase inhibitor (e.g., a small molecule kinase inhibitor, such as BTK and a small molecule kinase inhibitor of an E3 ligase ligand or binding portion). See, for example, WO2018098280. In some embodiments, the targeted E3 ligase ligand conjugate comprises: a binding portion that targets or binds to interleukin-1 (IL-1) receptor-associated kinase-4 (IRAK-4); rapidly accelerated fibrosarcoma (RAF, such as c-RAF, A-RAF and / or B-RAF), c-Met / p38 or BRD protein; and an E3 ligase ligand or binding portion. See, for example, WO2019099926, WO2018226542, WO2018119448, WO2018223909, WO2019079701. Additional targeted E3 ligase ligand conjugates that can be co-administered are described, for example, in WO2018237026, WO2019084026, WO2019084030, WO2019067733, WO2019043217, WO2019043208, and WO2018144649.

[0860] Histone deacetylase (HDAC) inhibitors

[0861] In some embodiments, the compounds provided herein are administered with an inhibitor of a histone deacetylase, such as an inhibitor of histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID: 9734). Examples of HDAC inhibitors include abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), resminostat, ricolinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, and entinostat.

[0862] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

[0863] In some embodiments, the compounds provided herein are administered with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include BLV-0801, epacadostat, linrodostat (F-001287, BMS-986205), GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

[0864] Janus kinase (JAK) inhibitors

[0865] In some embodiments, the compounds provided herein are administered with an inhibitor of Janus kinase 1 (JAK1, JAK1A, JAK1B, JTK3; NCBI Gene ID: 3716); Janus kinase 2 (JAK2, JTK10; THCYT3; NCBI Gene ID: 3717); and / or Janus kinase 3 (JAK3, JAK-3, JAK3_HUMAN, JAKL, L-JAK, LJAK; NCBI Gene ID: 3718). Examples of JAK inhibitors include AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), lestaurtinib, momelotinib (CYT0387), igatinib maleate (NS-018), pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly known as tasocitinib citrate), INCB052793, and XL019.

[0866] Lysyl oxidase-like protein (LOXL) inhibitors

[0867] In some embodiments, the compounds provided herein are administered with inhibitors of LOXL proteins, such as LOXL1 (NCBI Gene ID: 4016), LOXL2 (NCBI Gene ID: 4017), LOXL3 (NCBI Gene ID: 84695), LOXL4 (NCBI Gene ID: 84171), and / or LOX (NCBI Gene ID: 4015). Examples of LOXL2 inhibitors include the antibodies described in WO 2009017833 (Arresto Biosciences), WO 2009035791 (Arresto Biosciences), and WO 2011097513 (Gilead Biologics).

[0868] Matrix metalloproteinase (MMP) inhibitors

[0869] In some embodiments, the compounds provided herein are administered with an inhibitor of a matrix metalloproteinase (MMP), such as an inhibitor of MMP1 (NCBI gene ID: 4312), MMP2 (NCBI gene ID: 4313), MMP3 (NCBI gene ID: 4314), MMP7 (NCBI gene ID: 4316), MMP8 (NCBI gene ID: 4317), MMP9 (NCBI gene ID: 4318), MMP10 (NCBI gene ID: 4319), MMP11 (NCBI gene ID: 4320), MMP12 (NCBI gene ID: 4321), MMP13 (NCBI gene ID: 4322), MMP14 (NCBI gene ID: 4323), MMP15 (NCBI gene ID: 4324), MMP16 (NCBI gene ID: 4325), MMP17 (NCBI gene ID: 4326), MMP18 (NCBI gene ID: 4327), MMP19 (NCBI gene ID: 4330), MMP20 (NCBI gene ID: 4331), MMP21 (NCBI gene ID: 4332), MMP22 (NCBI gene ID: 4333), MMP23 (NCBI gene ID: 4334), MMP24 (NCBI gene ID: 4335), MMP25 (NCBI gene ID: 4336), MMP26 (NCBI gene ID: 4337), MMP27 (NCBI gene ID: 4338), MMP28 (NCBI gene ID: 4339), MMP30 (NCBI gene ID: 4340), MMP31 (NCBI gene ID: 4341), MMP32 (NCBI gene ID: 4342), MMP33 (NCBI gene ID: 4343), MMP34 (NCBI gene ID: 4344), MMP35 (NCBI gene MMP14 (NCBI gene ID: 4323), MMP15 (NCBI gene ID: 4324), MMP16 (NCBI gene ID: 4325), MMP17 (NCBI gene ID: 4326), MMP19 (NCBI gene ID: 4327), MMP20 (NCBI gene ID: 9313), MMP21 (NCBI gene ID: 118856), MMP24 (NCBI gene ID: 10893), MMP25 (NCBI gene ID: 64386), MMP26 (NCBI gene ID: 56547), MMP27 (NCBI gene ID: 64066) and / or MMP28 (NCBI gene ID: 79148). Examples of MMP9 inhibitors include marimastat (BB-2516), siimastat (Ro 32-3555), GS-5745 (andecaliximab), and those described in WO 2012027721 (Gilead Biologics).

[0870] RAS and RAS pathway inhibitors

[0871] In some embodiments, the compounds provided herein are administered to KRAS proto-oncogene GTPases (KRAS; also known as NS; NS3; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; CK-RAS; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; c-Ki-ras2; NCBI Gene ID: 3845); NRAS proto-oncogene GTPases (NRAS; also known as NS6; CMNS ; NCMS; ALPS4; N-ras; NRAS1; NCBI Gene ID: 4893) or HRAS proto-oncogene GTPase (HRAS; also known as CTLO; KRAS; HAMSV; HRAS1; KRAS2; RASH1; RASK2; Ki-Ras; p21ras; CH-RAS; cK-ras; H-RASIDX; c-Ki-ras; C-BAS / HAS; C-HA-RAS1; NCBI Gene ID: 3265). Ras inhibitors can inhibit Ras at the polynucleotide (e.g., transcription inhibitor) or polypeptide (e.g., GTPase inhibitor) level. In some embodiments, the inhibitor targets one or more proteins in the Ras pathway, for example, inhibiting one or more of EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT, and mTOR. Exemplary K-Ras inhibitors that can be co-administered include sotorasib (AMG-510), COTI-219, ARS-3248, WDB-178, BI-3406, BI-1701963, SML-8-73-1 (G12C), adagrasib (MRTX-849), ARS-1620 (G12C), SML-8-73-1 (G12C), compound 3144 (G12D), Kobe0065 / 2602 (Ras GTP), RT11, MRTX-849 (G12C) and K-Ras (G12D) selective inhibitory peptides, including KRpep-2 and KRpep-2d. Exemplary KRAS mRNA inhibitors include anti-KRAS U1 aptamers, AZD-4785, siG12D-LODER TMand siG12D exosomes. Exemplary MEK inhibitors that can be co-administered include binimetinib, cobimetinib, PD-0325901, pimasertib, RG-7304, selumetinib, trametinib, and those described below and herein. Exemplary Raf dimer inhibitors that can be co-administered include BGB-283, HM-95573, LXH-254, LY-3009120, RG7304, and TAK-580. Exemplary ERK inhibitors that can be co-administered include LTT-462, LY-3214996, MK-8353, ravoxertinib, and ulixertinib. Exemplary Ras GTPase inhibitors that can be co-administered include reglucose. Illustrative PI3K inhibitors that may be co-administered include ideliximab Aboliciib, bupariciib, pictilisib, inavolisib (RG6114), ASN-003. Exemplary AKT inhibitors that can be co-administered include capasitinib and GSK2141795. Exemplary PI3K / mTOR inhibitors that can be co-administered include dactolisib, omipalisib, voxtalisib, gedatolisib, GSK2141795, GSK-2126458, inavolisib (RG6114), sapanisertib, ME-344, sirolimus (oral nanoamorphous formulation, cancer), racemic tyrosine (TYME-88 (mTOR / cytochrome P450 3A4)), temsirolimus ( CCI-779), CC-115, onatasertib (CC-223), SF-1126, and PQR-309 (bimiralisib). In some embodiments, Ras-driven cancers (e.g., NSCLC) with CDKN2A mutations can be inhibited by co-administering the MEK inhibitor selumetinib and the CDK4 / 6 inhibitor palbociclib. See, e.g., Zhou et al., Cancer Lett. 2017 Nov 1; 408: 130-137. Furthermore, K-RAS and mutant N-RAS can be reduced by the irreversible ERBB1 / 2 / 4 inhibitor neratinib. See, e.g., Booth et al., Cancer Biol Ther. 2018 Feb 1; 19(2): 132-137.

[0872] Mitogen-activated protein kinase (MEK) inhibitors

[0873] In some embodiments, the compounds provided herein are administered with an inhibitor of mitogen-activated protein kinase kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI gene ID: 5609). Examples of MEK inhibitors include antroquinonol, bimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib + trametinib, PD-0325901, pimacitinib, LTT462, AS703988, CC-90003, and refametinib.

[0874] Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0875] In some embodiments, the compounds provided herein are combined with an inhibitor of the following: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA, CLAPO, CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-α, p110-α; NCBI gene ID: 5290); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB, P110BETA, PI3K, PI3KBETA, PIK3C1; NCBI Gene ID: 5291); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG, PI3CG, PI3K, PI3Kγ, PIK3, p110γ, p120-PI3K; Gene ID: 5494); and / or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD, APDS, IMD14, P110DELTA, PI3K, p110D, NCBI Gene ID: 5293). In some embodiments, the PI3K inhibitor is a pan-PI3K inhibitor. Examples of PI3K inhibitors include ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY 10824391, BEZ235, buparizib (BKM120), BYL719 (arbolixib), CH5132799, copanlixib (BAY 80-6946), duvelixib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, idelixib INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604, reglucoserti, RP5090, RP6530, SRX3177, taselixib, TG100115, TGR-1202 (umbralisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, wortmannin, ZSTK474, and in WO2005113556 (ICOS), WO 2013 / 052699 (Gilead Calistoga), WO2013116562 (Gilead Calistoga), WO2014100765 (Gilead Calistoga), WO2014100767 (Gilead Calistoga) and WO2014201409 (Gilead Sciences).

[0876] Spleen tyrosine kinase (SYK) inhibitors

[0877] In some embodiments, the compounds provided herein are administered with an inhibitor of spleen-associated tyrosine kinase (SYK, p72-Syk, NCBI Gene ID: 6850). Examples of SYK inhibitors include 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine, BAY-61-3606, cerdulatinib (PRT-062607), entospletinib, fostamatinib (R788), HMPL-523, NVP-QAB 205AA, R112, R343, tamatinib (R406), gusacitinib (ASN-002), and those described in US8450321 (Gilead Connecticut) and US20150175616.

[0878] Toll-like receptor (TLR) agonists

[0879] In some embodiments, the compounds provided herein are administered with an agonist of a toll-like receptor (TLR), such as an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and / or TLR10 (NCBI Gene ID: 81793).Exemplary TLR7 agonists that can be co-administered include DS-0509, GS-9620 (visamod), visamod analogs, LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7795, BDB-001, DSP-0509, and US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences). Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014056953 (Janssen), WO2014076221 (Ja nssen), WO2014128189(Janssen), US20140350031(Janssen), WO2014023813(Janssen), US20080234251(Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), and US20130251673 (Novira Therapeutics). The TLR7 / TLR8 agonist that can be co-administered is NKTR-262.Exemplary TLR8 agonists that can be co-administered include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics) and US20130251673 (Novira Therapeutics). Example TLR9 agonists that can be co-administered include AST-008, CMP-001, IMO-2055, IMO-2125, litenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), CYT-003, CYT-003-QbG10, and PUL-042. Examples of TLR3 agonists include retadalafil, polyICLC, and . Apoxxim, IPH-33, MCT-465, MCT-475, and ND-1.1.

[0880] Tyrosine kinase inhibitors (TKIs)

[0881] In some embodiments, the compound provided herein is used together with a tyrosine kinase inhibitor (TKI). TKI can target the receptors of epidermal growth factor receptor (EGFR) and fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). The example of TKI includes but is not limited to afatinib, ARQ-087 (drazantinib), asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, cediranib, clenobutane, dacomitinib, dasatinib, dovitinib, E-6201, erdatinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, tinib, KX2-391 (Src), lapatinib, lestaurinib, lenvatinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rociletinib, surufatinib (HMPL-012), sunitinib, famitinib L-malate (MAC-4), tivolanib, TH-4000, and MEDI-575 (anti-PDGFR antibody). Exemplary agents targeting EGFR include neratinib, tucatinib (ONT-380), tevatinib, mobotinib (TAK-788), DZD-9008, valitinib, abivertinib (ACEA-0010), EGF816 (nazartinib), olmutinib (BI-1482694), osimertinib (AZD-9291), AMG-596 (EGFRvIII / CD3), lifirafenib (BGB-283), vectibix, lazertinib and compounds disclosed in Booth et al., Cancer Biol Ther. 2018 Feb 1;19(2):132-137. Antibodies targeting EGFR include, but are not limited to, modotuximab, cetuximab sarotalocan (RM-1929), seribantumab, nesimumab, depatuxizumab mafodotin (ABT-414), tomozotuximab, depatuxizumab (ABT-806), and cetuximab.

[0882] chemotherapeutic agents

[0883] In some embodiments, the compounds provided herein are administered with a chemotherapeutic or anti-tumor agent.

[0884] As used herein, the term "chemotherapeutic agent" or "chemotherapeutic agent" (or "chemotherapy" in the case of treatment with a chemotherapeutic agent) is intended to encompass any non-proteinaceous (e.g., non-peptide) compound that can be used to treat cancer. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide. Alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodepa, carboquinone, metodepa, and uredepa; ethyleneimines and methylmelamines, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimemylolomelamine; lactones, such as brassic acid and brassinone; camptothecins, including the synthetic analogue topotecan; bryostatin, callystatin; CC-1065, including its synthetic analogues adolesine, carzelesin, and biszelesin; nostoc, especially nostoc 1 and nostoc 8; caudate; duocarmycins, including the synthetic analogue KW-2 189 and CBI-TMI; eleutherobin; 5-azacytidine; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, naphthone mustard, cyclophosphamide, glufosfamide, ivophosphamide, bendamustine, estramustine, ifosfamide, dichloromethyldiethylamine, dichloromethyldiethylamine hydrochloride, melphalan, nembixin, phenylephrine, prednimustine, trolofosamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as ene Diyne antibiotics (e.g., calicheamicins, particularly calicheamicin gamma II and calicheamicin phi II), daptomycins (including daptomycin A), bisphosphonates (such as clodronate), espamimicins, neostatin chromophores and related chromogenic protein enediyne antibiotic chromophores, aclarubicin, dactinomycin, anthramycin, azaserine, bleomycin, dactinomycin, carabicin, carrninomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detoxibacin, 6-diazo-5-oxo-L-norleucine , doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolo-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, mexilomycin, mitomycins (such as mitomycin C), mycophenolic acid, nogamycin, olivomycin, peplomycin, porfibrinomycin, puromycin, quinamycin, rhodorubicin, streptomycin, streptozotocin, tuberculin, ubenimex, zoloft and daunorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as normethopterin, methotrexate, pteropterin and trimetrexate; purine analogs such as cladribine, pentostatin, fludarabine, 6-mercaptopurine, thiaprine and thioguanine;Pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as captestosterone, drostanolone propionate, cyclothiocarbamate, melastane, and testolactone; antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; radiotherapeutic agents such as radium-223; trichothecenes, particularly T-2 toxin, verracurin A, roridin A, and anguidine; taxanes such as paclitaxel; Albumin-bound paclitaxel (abraxane), docetaxel Cabazitaxel, BIND-014, tesetaxel; sabizabulin (Veru-111); platinum analogs such as cisplatin and carboplatin, NC-6004 nanoplatin; acetoglucuronolide; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene; edatrexate; defosfamide; colcemid; diacrazoxane; elformthine; elliptonium acetate; epothilone; etoglucose; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansine alkaloids such as maytansine and anserine streptozotocin; mitoxantrone; mopidarol; diamine nitrazepam; pentostatin; methambucil; pirarubicin; losoxantrone; fluoropyrimidines; folinic acid; podophyllic acid; 2-ethylhydrazide; procarbazine; polysaccharide-K (PSK); razoxane; rhizoxin; sizolan; spirogermanamine; tricholomanic acid; trabectedin, triazinon; 2,2',2"-trichlorotrimethylamine; carbamates; vindesine; dacarbazine; mannomustine; dibromomannitol; dibromodulanol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; chlorambucil; gemcitabine 6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine Novolin; Teniposide; Edatrexate; Daunomycin; Aminopterin; Xeoloda; Ibandronate; CPT-11; Topoisomerase inhibitor RFS2000; Difluoromethylornithine (DFMO); Retinoids such as retinoic acid; Capecitabine; NUC-1031; FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin); FOLFIRI (folinic acid, 5-fluorouracil, irinotecan); FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin) and pharmaceutically acceptable salts, acids or derivatives of any of the above substances. Such agents can be conjugated to antibodies or any targeting agent described herein to form antibody-drug conjugates (ADCs) or targeted drug conjugates.

[0885] Antihormonal agents

[0886] Also included within the definition of "chemotherapeutic agent" are antihormonal agents such as antiestrogens and selective estrogen receptor modulators (SERMs), aromatase inhibitors, antiandrogens, and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing, which are used to modulate or inhibit the effects of hormones on tumors.

[0887] Examples of antiestrogens and SERMs include tamoxifen (including NOLVADEX™), raloxifene, droloxifene, 4-hydroxytamoxifen, troloxifene, raloxifene hydrochloride, LY117018, onapristone, and toremifene.

[0888] Aromatase inhibitors regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazole, aminoglutethimide, megestrol acetate Exemestane, formestane, fadrozole, vorazole Letrozole and anastrozole

[0889] Examples of antiandrogens include apalutamid...

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, in X is N, CH or CR x ; R x For (CH2) m CN or halide; m is 0, 1, 2 or 3; R 1 , R 2 , R 3 and R 4 Each independently is H or C1-C3 alkyl; L 1 O, S or CR 1a R 1b ; R 1a and R 1b Each is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, C1-C3 cyanoalkyl or C3-C6 cycloalkyl; Alternatively, R 1a and R 1b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups; L 2 CR 2a R 2b ; Alternatively, L 2 is O or S, and L 1 CR 1a R 1b ; R 2a and R 2b Each is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, C1-C3 cyanoalkyl or C3-C6 cycloalkyl; Alternatively, R 2a and R 2b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups; Alternatively, R 1b and R 2b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups; L 3 key or CR 3a R 3b ; R 3a and R 3b Each is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -CN, C1-C3 cyanoalkyl or C3-C6 cycloalkyl; Alternatively, R 3a and R 3b Capable of combining with the atoms to which they are attached to form C3-C6 cycloalkyl groups; Alternatively, R 2b and R 3b Capable of combining with the atoms to which they are attached to form a C3-C6 cycloalkyl group; R A is phenyl or naphthyl, wherein R A 0, 1, 2, 3, 4 or 5 R A2 replace; Each R A2 are independently -OH, C1-C 10 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C 10 Alkoxy, C1-C 10 Hydroxyalkyl, C2-C 10 Alkoxyalkyl, C1-C6 alkyl-N(R A2a )(R A2b )、C1-C 10 Thioalkyl, halogen, C1-C6 haloalkyl, -CN, -C(O)R A2a 、-C(O)OR A2a 、-OC(O)R A2a 、-OC(O)OR A2a 、-C(O)N(R A2a )(R A2b )、-N(R A2a )C(O)(R A2b )、-OC(O)N(R A2a )(R A2b )、-N(R A2a )C(O)(OR A2b ), oxo, -OR A2a 、-SR A2a 、-S(O)2R A2a 、-S(O)2OR A2a 、-N(R A2a )(R A2b )、-(C0-C3 alkyl)-SF5、-OP(O)(OR A2a )(OR A2b ), C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C3-C8 cycloalkyl), 3- to 14-membered heterocyclic group, -(C1-C6 alkyl)-(3- to 14-membered heterocyclic group), C6-C 14 Aryl, -(C1-C6 alkyl)-(C6-C 14 aryl), 5- to 14-membered heteroaryl, or -(C1-C6 alkyl)-(5- to 14-membered heteroaryl), wherein each alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl and haloalkyl is replaced by 0, 1, 2 or 3 R A3 substituted, and wherein each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl and alkyl-heteroaryl is substituted by 0, 1, 2 or 3 R A4 replace; Each R A2a and R A2b are independently H, C1-C 10 Alkyl, C1-C6 haloalkyl or C3-C8 cycloalkyl; Each R A3 are independently halogen, -CN, -OR A3a 、-SR A3a 、-N(R A3a )(R A3b ), C3-C8 cycloalkyl or 5- to 14-membered heteroaryl; Each R A3a and R A3b are independently H, C1-C 10 Alkyl, C1-C6 haloalkyl or C3-C8 cycloalkyl; Each R A4 are independently C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkylthio, C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C6-C 10 aryl), halogen, -CN, -OH or -N(R A4a )(R A4b ); Each R A4a and R A4b are independently H or C1-C6 alkyl; Alternatively, in R A On two adjacent atoms, two R A2 Can combine to form C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3- to 10-membered heterocyclyl, or 5- to 14-membered heteroaryl; R B is H, -C(O)R B1 or -C(O)OR B2 ; R B1 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 aryl or 5- to 14-membered heteroaryl, wherein the C3-C8 cycloalkyl, the C6-C 14 The aryl group or the 5- to 14-membered heteroaryl group is replaced by 0, 1, 2 or 3 R B1a replace; R B2 C1-C6 alkyl, C1-C6 haloalkyl, (C1-C6 alkyl)-OC(O)R B3 , C3-C8 cycloalkyl, C6-C 14 aryl, 5- to 14-membered heteroaryl, or wherein the C3-C8 cycloalkyl, the C6-C 14 The aryl group or the 5- to 14-membered heteroaryl group is replaced by 0, 1, 2 or 3 R B2a replace; R B3 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 aryl or 5- to 14-membered heteroaryl, wherein the C3-C8 cycloalkyl, the C6-C 14 The aryl group or the 5- to 14-membered heteroaryl group is replaced by 0, 1, 2 or 3 R B3a replace; Each R B1a , R B2a and R B3a are independently C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkoxyalkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, oxo, -OH, -CN or C3-C 10 Cycloalkyl; L C For key or Y is C or Si; n is 0, 1, 2 or 3; q is 0, 1, 2, or 3; R Y1 is H or C1-C3 alkyl; R Y2 is H or C1-C3 alkyl; Alternatively, R Y1 and R Y2 Combine to form C3-C 10 Cycloalkyl or 3- to 10-membered heterocyclic group; R C H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, -NH2, -NHR C1 、-N(R C1 )2, C3-C8 cycloalkyl, 3- to 14-membered heterocyclic group, C6-C 14 aryl or 5- to 14-membered heteroaryl, wherein each C3-C8 cycloalkyl, 3- to 14-membered heterocyclyl, C6-C 14 Aryl and 3- to 14-membered heteroaryl are substituted with 0, 1, 2, 3 or 4 R C3 replace; Each R C1 Independently selected from C1-C6 alkyl; Each R C3 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C8 alkynyl, C1-C6 alkoxyalkyl, C1-C6 hydroxyalkyl, halo, C1-C6 haloalkyl, C1-C6 heteroalkyl, -(C1-C6 alkyl)-N(R C3a )(R C3b )、-CN、-C(O)R C3a 、-C(O)OR C3a 、-C(O)N(R C3a )(R C3b )、-N(R C3a )C(O)(R C3b )、-OC(O)N(R C3a )(R C3b )、-N(R C3a )C(O)(OR C3b ), =CH2, =CF2, oxo, -OR C3a 、-SR C3a 、-N(R C3a )(R C3b ), -N3, SF5, C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C3-C8 cycloalkyl), 3- to 10-membered heterocyclic group, -(C1-C6 alkyl)-(3- to 10-membered heterocyclic group), C6-C 10 Aryl, -(C1-C6 alkyl)-(C6-C 10 aryl), 5- to 10-membered heteroaryl, or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), Each alkyl group is replaced by 0, 1, 2 or 3 -CN, -C(O)OR C3a1 、-C(O)N(R C3a1 )(R C3a2 )、-N(R C3a1 )C(O)(R C3a2 )、-OC(O)N(R C3a1 )(R C3a2 ),-OR C3a1 、-SR C3a1 , N3, SF5 or 0, 1, 2 or 3 3R C3a2 substituted 3- to 10-membered heterocyclyl, each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl and alkyl-heteroaryl being replaced by 0, 1, 2 or 3 halo, -CN or R C3a2 substituted, each alkenyl is substituted by 0, 1, 2 or 3 halo groups, and each alkoxyalkyl and alkynyl is substituted by 0, 1, 2 or 3 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl substituted by 0 or 1 C1-C6 haloalkyl, C6-C 10 substituted with aryl or 5- to 10-membered heteroaryl; Each R C3a and R C3b are independently H, C1-C 10 Alkyl, C1-C6 haloalkyl, C6-C 10 Aryl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein each aryl and heteroaryl is substituted by 0, 1, 2 or 3 halogen, -CN or R C3a2 replace; Alternatively, R C3a and R C3b Together with the nitrogen to which they are attached, they form a 3- to 8-membered heterocyclic ring; Each R C3a1 and R C3a2 are independently C1-C3 alkyl, halo, C1-C6 haloalkyl, C3-C8 cycloalkyl, -(C1-C3 alkyl)-(C3-C8 cycloalkyl), 3- to 10-membered heterocyclyl, -(C1-C3 alkyl)-(3- to 10-membered heterocyclyl), C6-C 10 Aryl, -(C1-C3 alkyl)-(C6-C 10 Aryl), -(C2-C4 alkynyl)-(C6-C 10 aryl), 5- to 10-membered heteroaryl, -(C1-C3 alkyl)-(5- to 10-membered heteroaryl), or SF5, wherein each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, alkynyl-aryl, heteroaryl and alkyl-heteroaryl is substituted with 0, 1, 2 or 3 halo, C1-C3 haloalkyl, C1-C3 haloalkoxy or SF5; Alternatively, R C3a1 and R C3a2 Together with the N to which they are attached, they form a 3- to 8-membered heterocyclic ring; R D is a halogen group; Each heterocyclyl has 1, 2, 3 or 4 heteroatoms selected from N, O, S and Si; and Each heteroaryl group has 1, 2, 3 or 4 heteroatoms selected from N, O and S.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 and R 4 Each is H.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, which has the structure of formula (I-1):

4. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, which has the structure of formula (I-2):

5. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, which has the structure of formula (I-3): 6 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is N.

7. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein X is CH.

8. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein X is C-Cl.

9. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein L 1 is O.

10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, which has the structure of formula (IIa):

11. A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein L 1 For CHR 1b .

12. A compound according to any one of claims 1 to 8 or 11, or a pharmaceutically acceptable salt thereof, wherein L 1 For CH2.

13. A compound according to any one of claims 1 to 8 or 11, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b Each is independently H, C1-C3 alkyl or halo.

14. A compound according to any one of claims 1 to 8, 11 or 13, or a pharmaceutically acceptable salt thereof, wherein R 1b It is a C1-C3 alkyl group or a halogen group.

15. A compound according to any one of claims 1 to 8, 11 or 13 to 14, or a pharmaceutically acceptable salt thereof, wherein R 1b It is methyl.

16. A compound according to any one of claims 1 to 8 or 11 to 13 or a pharmaceutically acceptable salt thereof, which has the structure of formula (IIb):

17. A compound according to any one of claims 1 to 8 or 11 to 13 or a pharmaceutically acceptable salt thereof, which has the structure of formula (Ib):

18. A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b Each is independently H, C1-C3 alkyl, halo or C1-C6 haloalkyl.

19. A compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, wherein L 2 For CHR 2b .

20. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein R 2b It is H or C1-C3 alkyl.

21. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 2b For H.

22. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 2b It is a C1-C3 alkyl group.

23. A compound according to any one of claims 1 to 20 or 22, or a pharmaceutically acceptable salt thereof, wherein R 2b It is methyl.

24. A compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein L 3 is the key.

25. A compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein L 3 CR 3a R 3b .

26. A compound according to any one of claims 1 to 23 or 25, or a pharmaceutically acceptable salt thereof, wherein R 3a and R 3b For H.

27. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, which has the structure of formula (IIa-1):

28. A compound according to any one of claims 1 to 9, 11 to 13 or 16 to 21 or a pharmaceutically acceptable salt thereof, which has the structure of formula (IIb-1):

29. A compound according to any one of claims 1 to 3, 5 to 8, 11 to 13, 16 to 21 or 24, or a pharmaceutically acceptable salt thereof, having the structure of formula (IIb-2):

30. A compound according to any one of claims 1 to 8, 11 to 13, 17 to 21 or 25 to 26, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib-1):

31. A compound according to any one of claims 1 to 4, 6 to 8, 11 to 13, 17 to 21 or 25 to 26, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib-2):

32. A compound according to any one of claims 1 to 8, 11 to 15, 17 to 21 or 25 to 26, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib-3):

33. A compound according to any one of claims 1 to 4, 6 to 8, 11 to 15, 17 to 21 or 25 to 26, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib-4):

34. A compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein R A 0, 1, 2, 3, 4 or 5 R A2 Substituted naphthyl.

35. A compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof, wherein Each R A2 are independently C1-C6 alkyl, -OH, C2-C6 alkenyl, C2-C6 alkynyl, halo, C1-C6 haloalkyl, -OR A2a 、-SR A2a or -(C1-C6 alkyl)-(C3-C8 cycloalkyl), wherein each alkenyl group is replaced by 0, 1, 2 or 3 R A3 replace; Each R A2 are independently C1-C6 haloalkyl or C3-C8 cycloalkyl; and Each R A3 are independently halo.

36. A compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein each R A2 are independently Me, -OH, -C(Cl)=CH2, -CH=CHF2, -C≡CH, F, Cl, -CH2CF3, -OCF3, -O-cyclopropyl, -SCF3 or -CH2-cyclopropyl.

37. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R A for 38. A compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R A for 39. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein R A for 40. A compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R B For H.

41. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein L C for Y is C or Si; n is 0 or 1; q is 0 or 1; R Y1 is H or Me; and R Y2 is H or Me; Alternatively, R Y1 and R Y2 Combine to form a cyclopropyl group.

42. A compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt thereof, wherein R C 0, 1, 2 or 3 R C3 substituted 3- to 14-membered heterocyclic group; Each R C3 are independently C1-C6 alkyl, halo, C1-C6 haloalkyl, =CH2, -OR C3a or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), wherein each alkyl is replaced by one -OC(O)N(R C3a1 )(R C3a2 ),-OR C3a1 or N3 substitution; Each R C3a are independently C1-C6 haloalkyl; and Each R C3a1 and R C3a2 are independently C1-C3 alkyl, C1-C6 haloalkyl, C6-C 10 Aryl or 5- to 10-membered heteroaryl, wherein each aryl or heteroaryl is substituted with 0, 1, 2, 3 or 4 halo, C1-C3 haloalkyl, C1-C3 haloalkoxy or SF5; Alternatively, R C3a1 and R C3a2 Together with the nitrogen to which they are attached, they form a 3- to 8-membered heterocyclic ring.

43. A compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein R C 0, 1, 2 or 3 R C3 substituted 3- to 14-membered heterocyclic group; Each R C3 are independently C1-C6 alkyl, halo, C1-C6 haloalkyl, =CH2, -OR C3a or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), wherein each alkyl is replaced by one -OC(O)N(R C3a1 )(R C3a2 ),-OR C3a1 or N3 substitution; Each R C3a are independently C1-C6 haloalkyl; and Each R C3a1 and R C3a2 are independently C1-C3 alkyl, C1-C6 haloalkyl or C6-C 10 Aryl, wherein each aromatic group is substituted by 1 SF5; Alternatively, R C3a1 and R C3a2 Together with the nitrogen to which they are attached, they form a 3- to 8-membered heterocyclic ring.

44. A compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein L C It is -CH2-.

45. A compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R C is an 8- to 14-membered heterocyclic group, substituted by 0, 1, 2 or 3 R C3 replace; Each R C3 are independently C1-C6 alkyl, halo, =CH2, -OR C3a or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), Each alkyl group is replaced by a -OC(O)N(R C3a1 )(R C3a2 ),-OR C3a1 or N3 substitution; Each R C3a are independently C1-C6 haloalkyl; and Each R C3a1 and R C3a2 are independently C1-C3 alkyl, C1-C6 haloalkyl or C6-C 10 Aryl, wherein each aromatic group is substituted by 1 SF5; Alternatively, R C3a1 and R C3a2 Together with the nitrogen to which they are attached, they form a 3- to 8-membered heterocyclic ring.

46. ​​A compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein L C for Y is C or Si; n is 1; q is 1; R Y1 for me; and R Y2 It's Me; Alternatively, R Y1 and R Y2 Combine to form a cyclopropyl group.

47. A compound according to any one of claims 1 to 43 or 46, or a pharmaceutically acceptable salt thereof, wherein R C is 0, 1 or 2 R C3 substituted 3- to 7-membered heterocyclyl; and Each R C3 are independently halogen or C1-C6 haloalkyl.

48. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein L C is -CH2-; R C For 1 R C3 substituted 3- to 14-membered heterocyclic group; R C3 To be a -OR C3a1 or -SR C3a1 Substituted C1-C6 alkyl; and R C3a1 is a 5- to 10-membered heteroaryl group substituted by 0, 1 or 2 C1-C3 haloalkyl or C1-C3 haloalkoxy groups.

49. The compound according to claim 48 or a pharmaceutically acceptable salt thereof, wherein L C is -CH2-; R C For 1 R C3 substituted 4- to 8-membered heterocyclic group; R C3 -CH2OR C3a1 ;and R C3a1 is a pyrimidine, wherein the pyrimidine is substituted with 1 trifluoromethyl group.

50. A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein -OL C -R C Part of 51. A compound according to any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof, wherein said -OL C -R C Part of 52. A compound according to any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof, wherein said -OL C -R C Part of 53. A compound according to any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof, wherein said -OL C -R C Part of 54. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, wherein R D For F.

55. A compound according to any one of claims 1 and 3 to 5, or a pharmaceutically acceptable salt thereof, wherein X is N, CH or CR x ; R x is a halogen group; L 1 O or CR 1a R 1b ; R 1a and R 1b Each is independently H, C1-C3 alkyl or halo; L 2 CR 2a R 2b ; R 2a and R 2b Each is independently H, C1-C3 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl; L 3 key or CR 3a R 3b ; R 3a and R 3b Each independently is H or C1-C3 alkyl; R 1 , R 2 , R 3 and R 4 Each is H; R A is naphthyl, wherein R A 0, 1, 2, 3, 4 or 5 R A2 replace; Each R A2 are independently -OH, C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 sulfanyl, halo, C1-C6 haloalkyl, -OR A2a 、-SR A2a 、-N(R A2a )(R A2b ) or -(C1-C6 alkyl)-(C3-C8 cycloalkyl), wherein each alkyl, alkenyl, alkynyl, alkoxy and haloalkyl group is replaced by 0, 1, 2 or 3 R A3 replace; Each R A2a and R A2b are independently H, C1-C6 haloalkyl or C3-C8 cycloalkyl; Each R A3 are independently halo; R B is H; L C For key or Y is C or Si; n is 0 or 1; q is 0 or 1; R Y1 is H or C1-C3 alkyl; R Y2 is H or C1-C3 alkyl; Alternatively, R Y1 and R Y2 Combine to form a C3-C8 cycloalkyl group; R C is a 3- to 14-membered heterocyclic group, wherein each 3- to 14-membered heterocyclic group is substituted by 0, 1, 2, 3 or 4 R C3 replace; Each R C3 are independently C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxyalkyl, halo, C1-C6 haloalkyl, =CH2, -OR C3a , wherein each alkyl group is replaced by 0, 1, 2 or 3 -OC(O)N(R C3a1 )(R C3a2 ),-OR C3a1 、-SR C3a1 or N3 substitution; R C3a is C1-C6 alkyl, C1-C6 haloalkyl or 5- to 10-membered heteroaryl, wherein the heteroaryl is replaced by 1 R C3a2 replace; Each R C3a1 and R C3a2 are independently C1-C3 alkyl, C1-C6 haloalkyl, C6-C 10 Aryl or 5- to 10-membered heteroaryl, wherein the aryl or heteroaryl is substituted with 1 or 2 halogen groups, C1-C3 haloalkyl groups, C1-C3 haloalkoxy groups or SF5; Alternatively, R C3a1 and R C3a2 Together with the nitrogen to which they are attached, they form a 3- to 8-membered heterocyclic ring; and R D For F.

56. A compound according to any one of claims 1 and 3 to 5, or a pharmaceutically acceptable salt thereof, wherein X is N, CH or C-Cl; L 1 is O, CH2, CHCH3, CHCH2CH3, CHF or CF2; L 2 is CH2, CHCH3, CHCH2CH3, CHCHF2 or L 3 is a bond, CH2 or CHCH3; R 1 , R 2 , R 3 and R 4 Each is H; R A for R B is H; The-ol C -R C Part of and R D For F.

57. The compound according to claim 56 or a pharmaceutically acceptable salt thereof, wherein L 1 It is CH2, CHCH3, CHCH2CH3, CHF or CF2.

58. The compound according to claim 56 or 57, or a pharmaceutically acceptable salt thereof, wherein L 3 It is CH2 or CHCH3.

59. A compound according to any one of claims 56 to 58, or a pharmaceutically acceptable salt thereof, wherein R A for 60. A compound according to any one of claims 1 and 3 to 5, or a pharmaceutically acceptable salt thereof, wherein X is N; R 1 , R 2 , R 3 and R 4 Each is H; L 1 CR 1a R 1b ; R 1a and R 1b Each independently is H or C1-C3 alkyl; L 2 CR 2a R 2b ; R 2a and R 2b Each is H; L 3 CR 3a R 3b ; R 3a and R 3b Each is H; R A is naphthyl, wherein R A By 2 R A2 replace; Each R A2 are independently C2-C6 alkynyl or halo; R B is H; L C for Y is C; n is 0; q is 0; R Y1 is H; R Y2 is H; R C is a 3- to 14-membered heterocyclic group, wherein the 3- to 14-membered heterocyclic group is replaced by 1 R C3 replace; R C3 is C1-C6 alkyl, halogen or C1-C6 haloalkyl, wherein the alkyl is replaced by one -OR C3a1 replace; R C3a1 is a 5- to 10-membered heteroaryl group, wherein the heteroaryl group is substituted with 1 C1-C3 haloalkyl group; and R D For F.

61. A compound according to any one of claims 1 and 3 to 5, or a pharmaceutically acceptable salt thereof, wherein X is N; R 1 , R 2 , R 3 and R 4 Each is H; L 1 is CH2 or CHCH3; L 2 is CH2; L 3 is CH2; R A for R B is H; The-ol C -R C Part of and R D For F.

62. A compound according to any one of claims 1, 3 to 5, 17 and 30 to 33, or a pharmaceutically acceptable salt thereof, having a structure of Formula (Ib-5) or Formula (Ib-6): in R 1b is H or methyl; R C3 -CH2OR C3a1 or F; and R C3a1 It is a 5- to 6-membered heteroaryl group substituted by one halogen group or C1-C2 haloalkyl group.

63. A compound according to any one of claims 1, 3 to 5, 17 and 30 to 33, or a pharmaceutically acceptable salt thereof, having a structure of Formula (Ib-7) or Formula (Ib-8): in R 1b is H or methyl; R C3 -CH2OR C3a1 or F; and R C3a1 It is a 5- to 6-membered heteroaryl group substituted by one halogen group or C1-C2 haloalkyl group.

64. A compound according to any one of claims 1 to 63, or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

65. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the following structure:

66. The compound according to claim 1, having the following structure:

67. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the following structure:

68. The compound according to claim 1, having the following structure:

69. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the following structure:

70. The compound according to claim 1, having the following structure:

71. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the following structure:

72. The compound according to claim 1, having the structure:

73. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the following structure:

74. The compound according to claim 1, having the structure:

75. A pharmaceutical composition comprising a compound according to any one of claims 1 to 74 and a pharmaceutically acceptable excipient.

76. The pharmaceutical composition of claim 75, further comprising one or more additional therapeutic agents.

77. A method of inhibiting KRAS G12D protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 74 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 75 or 76.

78. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 74, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 75 or 76.

79. The method of claim 78, wherein the cancer is a KRAS G12D-associated cancer.

80. The method of claim 78 or 79, wherein the cancer is a blood cancer selected from the group consisting of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), B-cell ALL, myelodysplastic syndrome (MDS), myeloproliferative disorders (MPD), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), undifferentiated leukemia, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM), and multiple myeloma (MM).

81. The method of any one of claims 78 to 80, wherein the cancer is a solid tumor and is selected from lung cancer, colorectal cancer, gastric cancer, kidney cancer, ovarian cancer, testicular cancer, uterine cancer, bladder cancer, breast cancer, prostate cancer, cervical cancer, pancreatic cancer, and head and neck cancer.

82. The method of any one of claims 78 to 81, wherein the cancer is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, uterine cancer, gastric cancer, bile duct cancer, testicular cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain cancer, bone cancer, soft tissue sarcoma, non-small cell lung cancer, small cell lung cancer, myelodysplastic syndrome, thyroid cancer, or colon cancer.

83. The method of any one of claims 78 to 82, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, endometrial cancer, endometrial carcinoma, bile duct cancer, testicular germ cell cancer, cervical squamous cell carcinoma, or myelodysplastic syndrome.

84. The method of any one of claims 78 to 83, wherein the cancer is myelodysplastic syndrome.

85. The method of any one of claims 78 to 84, wherein the cancer is high-risk myelodysplastic syndrome or low-risk myelodysplastic syndrome.

86. The method of any one of claims 78 to 85, wherein the cancer is high-risk myelodysplastic syndrome.

87. The method of any one of claims 78 to 85, wherein the cancer is low-risk myelodysplastic syndrome.

88. The method of any one of claims 78 to 83, wherein the cancer is colorectal cancer.

89. The method of any one of claims 78 to 83, wherein the cancer is non-small cell lung cancer.

90. The method of any one of claims 78 to 83, wherein the cancer is pancreatic cancer.

91. The method of any one of claims 78 to 83, wherein the cancer is endometrial cancer.

92. The method of any one of claims 78 to 83, wherein the cancer is endometrial cancer.

93. The method of any one of claims 78 to 83, wherein the cancer is testicular germ cell cancer.

94. The method of any one of claims 78 to 83, wherein the cancer is cervical squamous cell carcinoma.

95. The method of any one of claims 78 to 83, wherein the cancer is cholangiocarcinoma.

96. The method of any one of claims 78 to 95, wherein the compound, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more additional therapeutic agents or therapeutic modalities.

97. The pharmaceutical composition of claim 76, or the method of claim 96, wherein the one or more additional therapeutic agents or the additional therapeutic modalities comprise one, two, three, or four additional therapeutic agents and / or therapeutic modalities.

98. The pharmaceutical composition or method of claim 97, wherein the additional therapeutic agent or the therapeutic modality is selected from an immune checkpoint regulator, an antibody-drug conjugate (ADC), an anti-apoptotic agent, a targeted anti-cancer therapeutic agent, a chemotherapeutic agent, surgery, or radiotherapy.

99. A pharmaceutical composition or method according to claim 98, wherein the immune checkpoint regulator is selected from anti-PD-(L)1 antibodies, anti-TIGIT antibodies, anti-CTLA4 antibodies, anti-CCR8 antibodies, anti-TREM1 antibodies, anti-TREM2 antibodies, CD47 inhibitors, DGKα inhibitors, HPK1 inhibitors, FLT3 agonists, adenosine receptor antagonists, CD39 inhibitors, CD73 inhibitors, IL-2 variants (IL-2v) and CAR-T cell therapy.

100. The pharmaceutical composition or method of claim 99, wherein the anti-PD-(L)1 antibody is selected from pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivolimab, batilizumab, toripalimab, sitrilimab, genoluzumab, palolizumab, lodalizumab, carrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab and sepalizumab.

101. The pharmaceutical composition or method of claim 99, wherein the anti-TIGIT antibody is selected from tisleliumab, vebrolimumab, dunalimab, AB308, AK127, BMS-986207, and etilizumab.

102. The pharmaceutical composition or method of claim 99, wherein the anti-CTLA4 antibody is selected from ipilimumab, tremelimumab, and zeflalimab.

103. The pharmaceutical composition or method of claim 99, wherein the CD47 inhibitor is selected from mololimab, letaprilimab, leszolimab, AL-008, RRx-001, CTX-5861, FSI-189 (GS-0189), ES-004, BI-765063, ADU1805, CC-95251, and Q-1801.

104. The pharmaceutical composition or method of claim 99, wherein the adenosine receptor antagonist is edradinan (AB928), taminadonan, TT-10, TT-4, or M1069.

105. The pharmaceutical composition or method of claim 99, wherein the CD39 inhibitor is TTX-030.

106. The pharmaceutical composition or method of claim 99, wherein the CD73 inhibitor is quelicustat (AB680), ulelimab, mopalimab, ORIC-533, ATG-037, PT-199, AK131, NZV930, BMS-986179, or olelumab.

107. The pharmaceutical composition or method of claim 99, wherein the IL-2v is aldesleukin (Proleukin), bempeline aldesleukin (NKTR-214), nemvaleukin alfa (ALKS-4230), THOR-202 (SAR-444245), BNT-151, ANV-419, XTX-202, RG-6279 (RO-7284755), NL-201, STK-012, SHR-1916 or GS-4528.

108. The pharmaceutical composition or method of claim 99, wherein the ADC is selected from gosartuzumab, datopotamusab, derutec, venetosumab, and detrastuzumab.

109. The pharmaceutical composition or method of claim 99, wherein the additional therapeutic agent is selected from idelalisib, gosartuzumab, mololimab, GS-0189, GS-3583, sepalizumab, GS-4224, GS-9716, GS-6451, GS-1811 (JTX-1811), quilibrium (AB680), etrametinam (AB928), dunalimab, AB308, PY159, PY314, AGEN-1223, AGEN-2373, akinumab, and briginumab.

110. The pharmaceutical composition or method of claim 97, wherein the one or more additional therapeutic agents are independently a chemotherapeutic agent, an immunotherapeutic agent, a hormonal agent, an anti-hormonal agent, a targeted therapeutic agent, or an anti-angiogenic agent.

111. The pharmaceutical composition or method of claim 97, wherein the one or more additional therapeutic agents are independently SNS-301, 5-FU+leucovorin+oxaliplatin+irinotecan, 5-FU+nano-liposomal irinotecan, 5-FU, afatinib, Aflibercept Aflibercept + FOLFIRI, nab-paclitaxel, alectinib Anastrozole Atezolizumab, avelumab, azacitidine Bevacizumab Bevacizumab + carboplatin + nab-paclitaxel, bevacizumab + carboplatin + pemetrexed, bevacizumab + FOLFIRI, bevacizumab + FOLFOX, bevacizumab + FOLFOXIRI, bevacizumab + leucovorin + 5-FU + oxaliplatin (FOLFOX), bevacizumab + XELOX, bevacizumab, BGB324, bimetinib + connefenib + cetuximab, brigatinib, cabozantinib, canakinumab, capecitabine, carboplatin + nab-paclitaxel, carboplatin + pemetrexed, carboplatin, cemiplimab, cetuximab Cetuximab + FOLFIRI, cisplatin + gemcitabine, cisplatin + pemetrexed, cisplatin, crizotinib Cytarabine + daunorubicin, cytarabine + idarubicin, cytarabine, dabrafenib Dabrafenib + trametinib, daptomycin (DS-1062), daptomycin + durvalumab, daptomycin + pembrolizumab, daunorubicin, decitabine Docetaxel, dunalimab, dotalimumab Doxorubicin, DSP-7888, Durvalumab + Tremelimumab, Durvalumab, Ensidipine, Vientumab Entrectinib Erlotinib, etoposide, exemestane Fluorouracil, FOLFIRI, FOLFIRINOX, FOLFOXIRI, gefitinib Gemcitabine + nab-paclitaxel, gemcitabine, sabatolizumab, idarubicin, ifosfamide, imelastatin, irinotecan, ivosidenib, LB-100, lenalidomide Lenalidomide, Lenvatinib Letrozole Leucovorin + nanoliposomal irinotecan, leucovorin, Lonsurf Rotacept, nab-paclitaxel Nabucacin + FOLFIRI + bevacizumab, nivolumab Nivolumab + docetaxel, nivolumab + ipilimumab, norgeleukin α (N-803) + pembrolizumab, norgeleukin α, osperlimumab + tislelizumab, osperlimumab, osimertinib Oxaliplatin (FOLFOX), paclitaxel, panitumumab, pembrolizumab Pembrolizumab + carboplatin + nab-paclitaxel, pembrolizumab + carboplatin + pemetrexed, pembrolizumab + lenvatinib + pemetrexed, pembrolizumab + olaparib, pembrolizumab + pemetrexed + carboplatin, pemetrexed Pemetrexed + cisplatin + carboplatin, pevonestat, progesterone, ramucirumab Ramucirumab + docetaxel, regorafenib Regosacer, Nordisk, Sabatolimumab, Selinexor, Tiselizumab + Atezolizumab, Tiselizumab, Trametinib Trametinib + dabrafenib + panitumumab, trastuzumab + pertuzumab, detrastuzumab Trastuzumab, vandetanib, vemurafenib, venetoclax, vembrolizumab plus pembrolizumab, vembrolizumab, vinblastine, vinorelbine, XELOX, or aflibercept.

112. A method for manufacturing a medicament for treating cancer in a subject in need thereof, characterized in that Use is made of a compound according to any one of claims 1 to 74 or a pharmaceutically acceptable salt thereof.

113. A method for manufacturing a medicament for inhibiting cancer metastasis in a subject in need thereof, characterized in that Use is made of a compound according to any one of claims 1 to 74 or a pharmaceutically acceptable salt thereof.

114. Use of a compound according to any one of claims 1 to 74, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.

115. Use of a compound according to any one of claims 1 to 74, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting cancer metastasis in a subject.

116. A compound according to any one of claims 1 to 74, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof.

117. A compound according to any one of claims 1 to 74, or a pharmaceutically acceptable salt thereof, for use in inhibiting cancer metastasis in a subject in need thereof.

118. A compound according to any one of claims 1 to 74, or a pharmaceutically acceptable salt thereof, for use in therapy.

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