KRA G12D regulatory compound

Abstract

Provided herein are compounds and pharma- ceutically acceptable salts thereof useful as KRAS G12D and / or KRAS G12C inhibitors, methods of making and using them (alone or in combination with additional agents), and pharmaceutical compositions thereof. The KRAS protein, Kirsten Rat Sarcoma 2 Viral Oncogene Homolog ("KRAS"), is a GTPase. KRAS gene mutations have been observed in several conditions, including, for example, pancreatic cancer, endometrial cancer, lung adenocarcinoma, colorectal cancer, rectal cancer, gallbladder cancer, thyroid cancer, cholangiocarcinoma, small cell lung cancer, and non-small cell lung cancer (NSCLC).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 333,347, filed April 21, 2022, U.S. Provisional Patent Application No. 63 / 353,726, filed June 20, 2022, and U.S. Provisional Patent Application No. 63 / 386,651, filed December 8, 2022, which applications are incorporated herein in their entireties for all purposes. [Background technology]

[0002] The KRAS protein, Kirsten Rat Sarcoma 2 Viral Oncogene Homolog ("KRAS"), is a GTPase. KRAS gene mutations have been observed in several conditions, including, for example, pancreatic cancer, endometrial cancer, lung adenocarcinoma, colorectal cancer, rectal cancer, gallbladder cancer, thyroid cancer, cholangiocarcinoma, small cell lung cancer, and non-small cell lung cancer (NSCLC). Thus, there is a need for compounds, pharmaceutical compositions, and methods for inhibiting KRAS (e.g., KRAS G12C and / or KRAS G12D) and treating associated cancers. Summary of the Invention

[0003] In one embodiment, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, X is N, CH, or CR x and R x is (CH2) m CN or halo, m is 0, 1, 2, or 3; R 1 , R 2 , R 3 , and R4 are each independently H or C1-C3 alkyl, L 1 is O, S, or CR 1a R 1b and R 1a and R 1b are each 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 can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; L 2 is CR 2a R 2b and Or, L 2 is O or S, and L 1 is CR 1a R 1b and R 2a and R 2b are each 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 can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; Alternatively, R 1b and R 2b can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; L 3 is a bond or CR 3a R 3b and R 3a and R 3bare each 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 can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; Alternatively, R 2b and R 3b can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; R A is phenyl or naphthyl, and R A is 0, 1, 2, 3, 4, or 5 R A2 is replaced by Each R A2 are independently -OH, C1 to 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, halo, 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), 3-14 membered heterocyclyl, -(C1-C6 alkyl)-(3-14 membered heterocyclyl), C6-C 14 Aryl, -(C1-C6 alkyl)-(C6-C 14 aryl), 5-14 membered heteroaryl, or -(C1-C6 alkyl)-(5-14 membered heteroaryl), and each alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, and haloalkyl is selected from 0, 1, 2, or 3 R A3 and each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl is substituted with 0, 1, 2, or 3 R A4 is replaced by Each R A2a and R A2b are independently H, C1 to C 10 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl; Each R A3 are independently halo, -CN, -OR A3a , -SR A3a , -N(R A3a )(R A3b ), C3-C8 cycloalkyl, or 5-14 membered heteroaryl; Each R A3a and R A3b are independently H, C1 to 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), halo, -CN, -OH, or -N(R A4a )(RA4b ) and Each R A4a and R A4b are independently H or C1-C6 alkyl, Or two R's A2 are combined to form R A On the top two adjacent atoms, C3 to C 10 Cycloalkyl, C6-C 10 can form an aryl, a 3- to 10-membered heterocyclyl, or a 5- to 14-membered heteroaryl; R B is H, -C(O)R B1 , or -C(O)OR B2 and R B1 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 aryl, or 5-14 membered heteroaryl, C3-C8 cycloalkyl, C6-C 14 An aryl or a 5- to 14-membered heteroaryl may have 0, 1, 2, or 3 R B1a is replaced by R B2 is 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 [ka] and C3-C8 cycloalkyl, C6-C 14 An aryl or a 5- to 14-membered heteroaryl may have 0, 1, 2, or 3 R B2a is replaced by R B3 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 aryl, or 5-14 membered heteroaryl, C3-C8 cycloalkyl, C6-C 14 An aryl or a 5- to 14-membered heteroaryl may have 0, 1, 2, or 3 R B3a is replaced by 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 is cycloalkyl, L C is a bond or [ka] and 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 are combined to form C3~C 10 forming a cycloalkyl or a 3- to 10-membered heterocyclyl; R C is 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, 3-14 membered heterocyclyl, C6-C 14 aryl, or 5- to 14-membered heteroaryl, each of C3 to C8 cycloalkyl, 3- to 14-membered heterocyclyl, C6 to C 14 Aryl and 3- to 14-membered heteroaryl can have 0, 1, 2, 3, or 4 R C3 is replaced by Each R C1 is independently selected from C1-C6 alkyl; 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), 3-10 membered heterocyclyl, -(C1-C6 alkyl)-(3-10 membered heterocyclyl), C6-C 10 Aryl, -(C1-C6 alkyl)-(C6-C 10 -(C1-C6 alkyl)-(5-10 membered heteroaryl), or -(C1-C6 alkyl)-(5-10 membered heteroaryl), each alkyl being selected from 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 R C3a2 and each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl is substituted with 0, 1, 2, or 3 halo, —CN, or RC3a2 each alkenyl is substituted with 0, 1, 2, or 3 halo; each alkoxyalkyl and alkynyl is substituted with 0, 1, 2, or 3 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl substituted with 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 to C 10 Alkyl, C1-C6 haloalkyl, C6-C 10 aryl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each aryl and heteroaryl containing 0, 1, 2, or 3 halo, —CN, or R C3a2 is replaced by Alternatively, R C3a and R C3b together with the N to which they are attached form a 3- to 8-membered heterocycle, Each R C3a1 and R C3a2 are independently C1-C3 alkyl, halo, C1-C6 haloalkyl, C3-C8 cycloalkyl, -(C1-C3 alkyl)-(C3-C8 cycloalkyl), 3-10 membered heterocyclyl, -(C1-C3 alkyl)-(3-10 membered heterocyclyl), C6-C 10 Aryl, -(C1-C3 alkyl)-(C6-C 10 aryl), -(C2-C4 alkynyl)-(C6-C 10 cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, alkynyl-aryl, heteroaryl, and alkyl-heteroaryl are substituted with 0, 1, 2, or 3 halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, or SF5; Alternatively, R C3a1 and R C3a2together with the N to which they are attached form a 3- to 8-membered heterocycle, R D is a halo, each heterocyclyl has 1, 2, 3, or 4 heteroatoms selected from N, O, S, and Si; Each heteroaryl has 1, 2, 3, or 4 heteroatoms selected from N, O, and S.

[0004] In one embodiment, the present disclosure provides a compound of formula IA: [ka] or a pharmaceutically acceptable salt thereof, wherein X is N, CH, or CR x and R x is (CH2) m CN or halo, m is 0, 1, 2, or 3; L 1 is O, S, or CR 1a R 1b and R 1a and R 1b are each 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 can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; L 2 is CR 2a R 2b and Or, L 2 is O or S, and L 1 is CR 1a R 1b and R 2a and R 2bare each 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 can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; Alternatively, R 1b and R 2b can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; L 3 is a bond or CR 3a R 3b and R 3a and R 3b are each 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 can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; Alternatively, R 2b and R 3b can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; R A is phenyl or naphthyl, and R A is 0, 1, 2, 3, 4, or 5 R A2 is replaced by Each R A2 are independently -OH, C1 to 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 10Thioalkyl, halo, 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), 3-14 membered heterocyclyl, -(C1-C6 alkyl)-(3-14 membered heterocyclyl), C6-C 14 Aryl, -(C1-C6 alkyl)-(C6-C 14 aryl), 5-14 membered heteroaryl, or -(C1-C6 alkyl)-(5-14 membered heteroaryl), and each alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, and haloalkyl is selected from 0, 1, 2, or 3 R A3 and each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl is substituted with 0, 1, 2, or 3 R A4 is replaced by Each R A2a and R A2b are independently H, C1 to C 10 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl; Each R A3 are independently halo, -CN, -OR A3a , -SR A3a, -N(R A3a )(R A3b ), C3-C8 cycloalkyl, or 5-14 membered heteroaryl; Each R A3a and R A3b are independently H, C1 to 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), halo, -CN, -OH, or -N(R A4a )(R A4b ) and Each R A4a and R A4b are independently H or C1-C6 alkyl, Or two R's A2 are combined to form R A On the top two adjacent atoms, C3 to C 10 Cycloalkyl, C6-C 10 can form an aryl, a 3- to 10-membered heterocyclyl, or a 5- to 14-membered heteroaryl; R B is H, -C(O)R B1 , or -C(O)OR B2 and R B1 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 aryl, or 5-14 membered heteroaryl, C3-C8 cycloalkyl, C6-C 14 An aryl or a 5- to 14-membered heteroaryl may have 0, 1, 2, or 3 R B1a is replaced by R B2 is C1-C6 alkyl, C1-C6 haloalkyl, (C1-C6 alkyl)-OC(O)R B3 , C3-C8 cycloalkyl, C6-C 14aryl, 5- to 14-membered heteroaryl, or [ka] and C3-C8 cycloalkyl, C6-C 14 An aryl or a 5- to 14-membered heteroaryl may have 0, 1, 2, or 3 R B2a is replaced by R B3 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 aryl, or 5-14 membered heteroaryl, C3-C8 cycloalkyl, C6-C 14 An aryl or a 5- to 14-membered heteroaryl may have 0, 1, 2, or 3 R B3a is replaced by 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 is cycloalkyl, L C is a bond or [ka] and 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 are combined to form C3~C 10 forming a cycloalkyl or a 3- to 10-membered heterocyclyl; R Cis 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, 3-14 membered heterocyclyl, C6-C 14 aryl, or 5- to 14-membered heteroaryl, each of C3 to C8 cycloalkyl, 3- to 14-membered heterocyclyl, C6 to C 14 Aryl and 3- to 14-membered heteroaryl may have 0, 1, 2, or 3 R C3 is replaced by Each R C1 is 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), 3-10 membered heterocyclyl, -(C1-C6 alkyl)-(3-10 membered heterocyclyl), C6-C 10 Aryl, -(C1-C6 alkyl)-(C6-C 10-(C1-C6(aryl)-(5-10 membered heteroaryl), or -(C1-C6(alkyl)-(5-10 membered heteroaryl), where each alkyl is selected from 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 R C3a2 and each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl is substituted with 0, 1, 2, or 3 halo, —CN, or R C3a2 each alkenyl is substituted with 0, 1, 2, or 3 halo; each alkoxyalkyl and alkynyl is substituted with 0, 1, 2, or 3 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl substituted with 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 to C 10 Alkyl, C1-C6 haloalkyl, C6-C 10 aryl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each aryl and heteroaryl containing 0, 1, 2, or 3 halo, —CN, or R C3a2 is replaced by Alternatively, R C3a and R C3b together with the N to which they are attached form a 3- to 8-membered heterocycle, Each R C3a1 and R C3a2are independently C1-C3 alkyl, halo, C1-C6 haloalkyl, C3-C8 cycloalkyl, -(C1-C3 alkyl)-(C3-C8 cycloalkyl), 3-10 membered heterocyclyl, -(C1-C3 alkyl)-(3-10 membered heterocyclyl), C6-C 10 Aryl, -(C1-C3 alkyl)-(C6-C 10 aryl), -(C2-C4 alkynyl)-(C6-C 10 aryl), 5-10 membered heteroaryl, -(C1-C3 alkyl)-(5-10 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; Alternatively, R C3a1 and R C3a2 together with the N to which they are attached form a 3- to 8-membered heterocycle, R D is a halo, each heterocyclyl has 1, 2, 3, or 4 heteroatoms selected from N, O, S, and Si; Each heteroaryl has 1, 2, 3, or 4 heteroatoms selected from N, O, and S.

[0005] In one embodiment, the present disclosure provides a compound of formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein X is N, CH, or CR x and R x is (CH2) m CN or halo, m is 0, 1, 2, or 3; L 1 is O or CR 1a R 1b and R 1a and R 1b are each 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 can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; L 2 is CR 2a R 2b and R 2a and R 2b are each 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 can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; Alternatively, R 1b and R 2b can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; R A is phenyl or naphthyl, and R A is 0, 1, 2, 3, 4, or 5 R A2 is replaced by Each R A2 are independently -OH, C1 to 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, halo, 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), 3-14 membered heterocyclyl, -(C1-C6 alkyl)-(3-14 membered heterocyclyl), C6-C 14 Aryl, -(C1-C6 alkyl)-(C6-C 14 aryl), 5-14 membered heteroaryl, or -(C1-C6 alkyl)-(5-14 membered heteroaryl), and each alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, and haloalkyl is selected from 0, 1, 2, or 3 R A3 and each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl is substituted with 0, 1, 2, or 3 R A4 is replaced by Each R A2a and R A2b are independently H, C1 to C 10 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl; Each R A3 are independently halo, -CN, -OR A3a , -SR A3a , -N(R A3a )(R A3b), C3-C8 cycloalkyl, or 5-14 membered heteroaryl; Each R A3a and R A3b are independently H, C1 to 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), halo, -CN, -OH, or -N(R A4a )(R A4b ) and Each R A4a and R A4b are independently H or C1-C6 alkyl, Or two R's A2 are combined to form R A On the top two adjacent atoms, C3 to C 10 Cycloalkyl, C6-C 10 can form an aryl, a 3- to 10-membered heterocyclyl, or a 5- to 14-membered heteroaryl; R B is H, -C(O)R B1 , or -C(O)OR B2 and R B1 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 aryl, or 5-14 membered heteroaryl, C3-C8 cycloalkyl, C6-C 14 An aryl or a 5- to 14-membered heteroaryl may have 0, 1, 2, or 3 R B1a is replaced by R B2 is 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 [ka] and C3-C8 cycloalkyl, C6-C 14 An aryl or a 5- to 14-membered heteroaryl may have 0, 1, 2, or 3 R B2a is replaced by R B3 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 aryl, or 5-14 membered heteroaryl, C3-C8 cycloalkyl, C6-C 14 An aryl or a 5- to 14-membered heteroaryl may have 0, 1, 2, or 3 R B3a is replaced by 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 is cycloalkyl, L C is a bond or [ka] and 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 are combined to form C3~C 10 forming a cycloalkyl or a 3- to 10-membered heterocyclyl; R C is H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, -NH2, -NHRC1 , -N(R C1 )2, C3-C8 cycloalkyl, 3-14 membered heterocyclyl, C6-C 14 aryl, or 5- to 14-membered heteroaryl, each of C3 to C8 cycloalkyl, 3- to 14-membered heterocyclyl, C6 to C 14 Aryl and 3- to 14-membered heteroaryl may have 0, 1, 2, or 3 R C3 is replaced by Each R C1 is 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), 3-10 membered heterocyclyl, -(C1-C6 alkyl)-(3-10 membered heterocyclyl), C6-C 10 Aryl, -(C1-C6 alkyl)-(C6-C 10 -(C1-C6(aryl)-(5-10 membered heteroaryl), or -(C1-C6(alkyl)-(5-10 membered heteroaryl), where each alkyl is selected from 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 R C3a2 and each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl is substituted with 0, 1, 2, or 3 halo, —CN, or R C3a2 each alkenyl is substituted with 0, 1, 2, or 3 halo; each alkoxyalkyl and alkynyl is substituted with 0, 1, 2, or 3 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl substituted with 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 to C 10 Alkyl, C1-C6 haloalkyl, C6-C 10 aryl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each aryl and heteroaryl containing 0, 1, 2, or 3 halo, —CN, or R C3a2 is replaced by Alternatively, R C3a and R C3b together with the N to which they are attached form a 3- to 8-membered heterocycle, Each R C3a1 and R C3a2 are independently C1-C3 alkyl, halo, C1-C6 haloalkyl, C3-C8 cycloalkyl, -(C1-C3 alkyl)-(C3-C8 cycloalkyl), 3-10 membered heterocyclyl, -(C1-C3 alkyl)-(3-10 membered heterocyclyl), C6-C 10 Aryl, -(C1-C3 alkyl)-(C6-C 10 aryl), -(C2-C4 alkynyl)-(C6-C 10aryl), 5-10 membered heteroaryl, -(C1-C3 alkyl)-(5-10 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; Alternatively, R C3a1 and R C3a2 together with the N to which they are attached form a 3- to 8-membered heterocycle, R D is a halo, each heterocyclyl has 1, 2, 3, or 4 heteroatoms selected from N, O, S, and Si; Each heteroaryl has 1, 2, 3, or 4 heteroatoms selected from N, O, and S.

[0006] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient.

[0007] In another embodiment, the present disclosure provides a method for 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.

[0008] 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.

[0009] In another embodiment, the present disclosure provides a method for manufacturing a medicament for treating cancer in a subject in need thereof, wherein a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used.

[0010] In another embodiment, the present disclosure provides a method for manufacturing a medicament for inhibiting cancer metastasis in a subject in need thereof, wherein a compound of the present invention, or a pharmaceutically acceptable salt thereof, is used.

[0011] In another embodiment, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer in a subject.

[0012] In another embodiment, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting cancer metastasis in a subject.

[0013] 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.

[0014] 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.

[0015] In another embodiment, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0016] Also disclosed herein are compounds of subformulas of Formula I, IA, and II, 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), and pharmaceutically acceptable salts thereof. DETAILED DESCRIPTION OF THE INVENTION

[0017] I. Overview This disclosure generally relates to KRAS G12D and / or KRAS G12C The present invention relates to methods and compounds, and pharmaceutically acceptable salts thereof, for inhibiting IL-1. 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 instead is provided as a description of exemplary embodiments.

[0018] II. Definition As used herein, 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.

[0019] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. Dashes before or after chemical groups are for convenience; chemical groups may be shown with or without one or more dashes without losing their ordinary meaning. A wavy line drawn across a line in a structure indicates the point of attachment of the group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which chemical groups are written or named.

[0020] For example, a squiggly line over a chemical group such as shown below, e.g. [ka] indicates a point of attachment, i.e., it indicates a broken bond where a group is attached to another described group.

[0021] As used herein, "a compound of the present disclosure" can mean any 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), and (IIb-2), or a pharmaceutically acceptable salt thereof. Similarly, the phrase "a compound of Formula (number)" means a compound of Formula (number) and a pharmaceutically acceptable salt thereof.

[0022] "C u~ C v " prefix indicates that the following group has u to v carbon atoms. For example, "C1-C8 alkyl" indicates that the alkyl group has 1 to 8 carbon atoms.

[0023] "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 to C6). 20The alkyl group may have 1 to 8 carbon atoms (i.e., C1-C8 alkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3 ), 2-methyl-2-propyl (t-Bu, t-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 (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3 -pentyl (-C(CH3)(CH2CH3)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.

[0024] "Alkenyl" refers to an unbranched or branched hydrocarbon chain containing at least two carbon atoms and at least one carbon-carbon double bond. As used herein, alkenyl refers to an alkyl group having 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 (i.e., C 2~4 Alkenyl can have 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 Alkenyl groups can contain any number of carbons, such as 1, 2, 3, 4, 5, or any range in between. Alkenyl groups can 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, vinyl (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.

[0025] "Alkynyl" refers to an unbranched or branched hydrocarbon chain containing at least one carbon-carbon triple bond. For example, an alkynyl group can be an alkynyl group having 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 (i.e., C 2~6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2~4The term "alkynyl" also includes alkynyl groups having one triple bond and one double bond. 2~6 Examples of alkynyl include, but are not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-4-ynyl, and penta-1,4-diynyl.

[0026] "Alkoxy" means a group having the formula -O-alkyl, where an alkyl group, as defined above, is attached to the parent molecule through an oxygen atom. The alkyl portion of the alkoxy group contains 1 to 20 carbon atoms (i.e., C1 to C6). 20 alkoxy), 1 to 12 carbon atoms (i.e., C1 to C 12 The alkoxy group may have 1 to 8 carbon atoms (i.e., C1-C8 alkoxy), 1 to 6 carbon atoms (i.e., C1-C6 alkoxy), or 1 to 3 carbon atoms (i.e., C1-C3 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), isopropoxy (-O-CH(CH3)2), t-butoxy (-OC(CH3)3 or -OtBu), and the like. Other examples of suitable alkoxy groups include, but are not limited to, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like.

[0027] "Alkoxyalkyl" refers to an alkoxy group linked to an alkoxy group which is linked to the rest of the compound. Alkoxyalkyl has 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 The alkyl group may have any suitable number of carbons, such as alkoxyalkyl. Alkoxy and alkyl are as defined above. Examples of "alkoxyalkyl" include, but are not limited to, methoxymethyl (CH3OCH2-) and methoxyethyl (CH3OCH2CH2).

[0028] "Bridged" means a ring system in which non-adjacent atoms of the rings are joined by a divalent substituent such as an alkylenyl or heteroalkylenyl group, or a single heteroatom.

[0029] "Hydroxyalkyl" refers to a hydroxy group (-OH) linked to an alkyl group which is linked to the rest of the compound, such that the alkyl group is divalent. Hydroxyalkyl is a group having 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 The alkyl group may have any suitable number of carbons, such as hydroxyalkyl, where alkyl is as defined above, where alkyl is divalent.

[0030] As used herein, "halo" or "halogen" refers to fluoro (-F), chloro (-Cl), bromo (-Br), and iodo (I).

[0031] A "haloalkyl" is an alkyl group as defined above in which one or more hydrogen atoms of the alkyl group are replaced with a halogen atom. The alkyl portion of a haloalkyl group has 1 to 20 carbon atoms (i.e., C1 to C6). 20 haloalkyl), 1 to 12 carbon atoms (i.e., C1 to C 12 The alkyl group may have 1 to 8 carbon atoms (i.e., C1-C8 haloalkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). 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.

[0032] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced with halogen atoms. With respect to alkyl groups, haloalkoxy groups include C 1~6 The alkoxy group may have any suitable number of carbon atoms, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or more halogens. When all hydrogens are replaced with halogens, such as fluorine, the compound is persubstituted, e.g., perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, and the like.

[0033] "Thioalkyl" refers to a thio group (-SH) linked to an alkyl group which is linked to the rest of the compound, such that the alkyl group is divalent. A thioalkyl is a group having 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 The alkyl group may have any suitable number of carbons, such as thioalkyl, where alkyl is as defined above, where alkyl is divalent.

[0034] "Haloalkylthio" refers to an alkylthio group, as defined above, in which one or more hydrogen atoms of the alkyl group are replaced by halogen atoms. The alkyl portion of the haloalkylthio group has 1 to 20 carbon atoms (i.e., C1 to C6). 20 haloalkylthio), 1 to 12 carbon atoms (i.e., C1 to C 12 The alkylthio group may have 1 to 8 carbon atoms (i.e., C1-C8 haloalkylthio), 1 to 6 carbon atoms (i.e., C1-C6 alkylthio), or 1 to 3 carbon atoms (i.e., C1-C3 alkylthio). The alkylthio group may be substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9 or more halogens.

[0035] "Heteroalkyl" refers to an unbranched or branched saturated hydrocarbon chain containing 1 to 4 heteroatoms.

[0036] "Cyanoalkyl" refers to a cyano group (-CN) linked to an alkyl group which is linked to the rest of the compound, such that the alkyl group is divalent. A cyanoalkyl is a group having 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 The alkyl group may have any suitable number of carbons, such as cyanoalkyl, where alkyl is as defined above, where alkyl is divalent.

[0037] "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, which may be fused, bridged, spiro, or any combination thereof. As used herein, cycloalkyl refers to a group having 3 to 20 ring carbon atoms (i.e., C 3~20 cycloalkyl), having 3 to 12 ring carbon atoms (i.e., C 3~12 cycloalkyl), having 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl), having 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), or having 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, and include fused ring systems having one aromatic ring and one non-aromatic ring, but not entirely aromatic.

[0038] The term "fused" refers to a ring system in which two or more rings in the system share a pair of adjacent ring atoms.

[0039] "Spiro" refers to at least two rings linked together by one common atom. "Spiro" also refers to ring substituents 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, respectively, are spiro substituents.

[0040] "Alkyl-cycloalkyl" refers to a radical having an alkyl component and a cycloalkyl component, where the alkyl component connects the cycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent alkylene in order to connect the cycloalkyl component and the point of attachment. In some cases, the alkyl component can be absent. The alkyl component can be any of 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 moiety is as defined herein. Exemplary alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, and methyl-cyclohexyl.

[0041] "Heterocycle" or "heterocyclyl" or "heterocycloalkyl" refers to a saturated or unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, sulfur, and silicon. A "heterocyclyl" may be a single ring or multiple rings, such as two, three, four, or more rings, which may be fused, bridged, spiro, or any combination thereof. As used herein, a heterocyclyl has 3 to 20 ring atoms (i.e., a 3-20-membered heterocyclyl), 3 to 12 ring atoms (i.e., a 3-12-membered heterocyclyl), 3 to 10 ring atoms (i.e., a 3-10-membered heterocyclyl), 3 to 8 ring atoms (i.e., a 3-8-membered heterocycle), 4 to 12 ring carbon atoms (i.e., a 4-12-membered heterocyclyl), 4 to 8 ring atoms (i.e., a 4-8-membered heterocyclyl), or 4 to 6 ring atoms (i.e., a 4-6-membered heterocyclyl). Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl.

[0042] "Alkyl-heterocycloalkyl" refers to a radical having an alkyl component and a heterocycloalkyl component, where the alkyl component connects the heterocycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene in order to connect the heterocycloalkyl component and the point of attachment. The alkyl component is selected from the group consisting of 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 be absent. The heterocycloalkyl component is as defined above.

[0043] "Aryl" means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have from 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.

[0044] "Alkyl-aryl" refers to a radical having an alkyl component and an aryl component, where the alkyl component connects the aryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent alkylene in order to connect the aryl component and the point of attachment. The alkyl component is selected from the group consisting of 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 The alkyl group may contain any number of carbons, such as , ...

[0045] "Heteroaryl" refers to aromatic groups, including groups having aromatic tautomers or resonance structures, having monocyclic, polycyclic, or multiple fused rings with at least one heteroatom in the ring, i.e., one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, where the nitrogen or sulfur can 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 groups having 5 to 20 ring atoms (i.e., 5-20-membered heteroaryl), 5 to 12 ring atoms (i.e., 5-12-membered heteroaryl), or 5 to 10 ring atoms (i.e., 5-10-membered heteroaryl), and 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, as well as oxidized forms of the 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, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass and overlap with aryl, as defined above.

[0046] "Alkyl-heteroaryl" refers to a radical having an alkyl component and a heteroaryl component, where the alkyl component connects the heteroaryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent alkylene in order to connect the heteroaryl component and the point of attachment. The alkyl component is selected from the group consisting of 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 5~6In some cases, the alkyl component may be absent. The heteroaryl component is as defined herein.

[0047] "KRAS G12D" refers to the G12D mutation in the KRAS protein, in which aspartic acid replaces glycine at amino acid position 12.

[0048] "KRAS G12D inhibitor" refers to a compound 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). The compound modulates or inhibits some or all of the activity of KRAS G12D.

[0049] "KRAS G12D-associated disease or disorder" refers to a disease or disorder associated with, mediated by, or having a KRAS G12D mutation. Exemplary diseases or disorders include, but are not limited to, KRAS G12D-associated cancers.

[0050] "Oxo" refers to the (=O) or (O) radical.

[0051] Pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, formulations, dosage forms, and other substances that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0052] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts, or, where appropriate, as free bases. Pharmaceutically acceptable salts are non-toxic salts of the free base form of a compound that possesses the desired pharmacological activity of the free base. These salts can be derived from inorganic or organic acids or inorganic or organic 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 sulfate, pyrosulfate, bisulfite, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne, hexyne-1,4-diol, hexyne-2 ... 1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, 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, 21 st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0053] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include alkali metal (e.g., sodium, potassium), alkaline earth metal (e.g., magnesium), ammonium, and NX4 salts. +(X is C1-C4 alkyl). Base addition salts such as sodium or potassium salts are also included.

[0054] Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, in which 1 to n hydrogen atoms bonded to a carbon atom may be replaced by deuterium atoms or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds may have enhanced resistance to metabolism and thus may be useful for increasing the half-life of the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," TRENDS PHARMACOL. SCI. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0055] Examples of isotopes that can be incorporated into the disclosed compounds 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 can also be mentioned. 11 C. 18 F, 15 O, and 13Substitution with positron-emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of Formulas 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 processes analogous to those illustrated in the Examples set forth below, using the appropriate isotopically labeled reagent in place of the previously employed non-labeled reagent.

[0056] The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, with respect to absolute stereochemistry, as (R)- or (S)-, or for amino acids, as (D)- or (L)-. The present disclosure is meant to include all such possible isomers, as well as 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 and resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, these compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. When compounds are represented in their chiral form, it is understood that embodiments include, but are not limited to, the specific diastereomerically or enantiomerically enriched forms. Where chirality is not specified, it is understood that embodiments are directed to either the specific diastereomerically or enantiomerically enriched forms, or racemic or scalemic mixtures of such compounds. As used herein, a "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0057] A "racemate" refers to a mixture of enantiomers. The mixture may contain equal or unequal amounts of each enantiomer.

[0058] "Stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. Compounds can exist in stereoisomeric forms if they possess one or more asymmetric centers or double bonds with asymmetric substitution and can therefore be produced as individual stereoisomers or mixtures. Unless otherwise specified, the description is intended to include individual stereoisomers and mixtures. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see, for example, Chapter 4 of ADVANCED ORGANIC CHEMISTRY, 4th ed., J. March, John Wiley & Sons, New York, 1992).

[0059] "Subject" or "patient" is meant to describe a vertebrate, including a human or dog, cat, pocket pet, marmoset, horse, cow, pig, sheep, goat, elephant, giraffe, chicken, lion, monkey, owl, rat, squirrel, slender loris, and mouse. "Pocket pet" refers to the group of vertebrates that can fit into a commodity coat pocket, such as, for example, hamsters, chinchillas, ferrets, rats, guinea pigs, gerbils, rabbits, and sugar gliders.

[0060] 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 before or after chemical groups are for convenience; chemical groups may be designated with or without one or more dashes without losing their ordinary meaning. Wavy lines drawn across lines in structures indicate the point of attachment of a group. Dashed lines indicate optional bonds. Unless chemically or structurally required, no directionality is indicated or implied in the order in which chemical groups are written or their point of attachment to the rest of the molecule. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-", and both can be attached in either direction. Similarly, for example, an "arylalkyl" group can be attached to the rest of the molecule at either the aryl or alkyl portion of the group. "C u~ C v " or "(C u ~C v A prefix such as "C" indicates that the following group has u to v carbon atoms. 1~6 "Alkyl" or "C1-C6 alkyl" both indicate that the alkyl group has from 1 to 6 carbon atoms.

[0061] Unless otherwise specified, carbon atoms in 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) are intended to have a valence of 4. In some chemical structure representations, where a carbon atom does not have a sufficient number of variables to produce a valence of 4, the remaining carbon substituents necessary to provide a valence of 4 should be assumed to be hydrogen.

[0062] "Treatment" or "treating" is an approach to obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include one or more of the following: (a) inhibiting the disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition and / or attenuating the severity of the disease or condition), (b) slowing or arresting the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition), and / or (c) palliating the disease, i.e., causing regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or complete remission of the disease or condition, enhancing the effect of another drug, slowing the progression of the disease, improving quality of life, and / or prolonging survival).

[0063] As used herein, the term "therapeutically effective amount" refers to the amount of a compound disclosed herein present in a formulation described herein required to provide a desired level of drug in the subject's secretions and airway and lung tissues, or alternatively, in the bloodstream of a treated subject, that will produce an expected physiological response or desired biological effect when such formulation is administered via a selected route of administration. The exact amount will depend on numerous factors, including the specific compound disclosed herein, the specific activity of the formulation, the delivery device used, the physical properties of the formulation, its intended use, and subjective considerations such as the severity of the disease state and the patient's cooperation, and can be readily determined by one of skill 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 a subject's viral load and / or viral reservoir.

[0064] "Administering" refers to oral administration, administration as a suppository, topical contact, parenteral administration, intravenous administration, intraperitoneal administration, intramuscular administration, intralesional administration, intranasal administration, or subcutaneous administration, intrathecal administration, or implantation of a sustained-release device, e.g., a mini-osmotic pump, to a subject. Administration can be carried out according to a schedule that dictates the frequency of administration, the dosage administered, and other factors.

[0065] As used herein, "co-administration" refers to administration of a unit dose of a compound disclosed herein before or after administration of a unit dose of one or more additional therapeutic agents, e.g., administration of a compound disclosed herein within seconds, minutes, or hours of administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed within seconds or minutes by a unit dose of a compound disclosed herein. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed several hours (e.g., 1-12 hours) later by a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed several hours (e.g., 1-12 hours) later by a unit dose of a compound disclosed herein. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of each agent is present in the patient's body.

[0066] "Subject" refers to animals such as mammals, 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.

[0067] "Disease" or "condition" refers to the physical state 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, inflammatory, cancer, infectious (e.g., viral infection), metabolic, developmental, cardiovascular, liver, intestinal, endocrine, neurological, 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).

[0068] "Cancer" refers to all types of cancer, neoplasm, or malignant tumor found in mammals, including leukemia, lymphoma, melanoma, neuroendocrine tumor, carcinoma, and sarcoma. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include lymphoma, sarcoma, 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 resistant, Herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), Examples of cancers that may be present include ovarian cancer, pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung carcinoma, adenocarcinoma, large cell lung cancer, small cell lung carcinoma, carcinoid, sarcoma), glioblastoma multiforme, glioma, melanoma, prostate cancer, castration-resistant prostate cancer, breast cancer, triple-negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., head, neck, or esophageal), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma, and multiple myeloma.

[0069] Additional examples include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, esophagus, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, or uterus, or cancer of the medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumor, cancer, malignant pancreatic insulinoma, malignant leukemia, and malignant leukemia. thyroid cancer, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, neoplasms of the endocrine or exocrine pancreas, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, Paget's disease of the breast, phyllodes tumor, lobular carcinoma, ductal carcinoma, carcinoma of the pancreatic stellate cells, carcinoma of hepatic stellate cells, or prostate cancer.

[0070] "Leukemia" broadly refers to progressive, malignant diseases of the blood-forming organs and is generally characterized by the abnormal 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 character of the disease: acute or chronic; (2) the type of cells involved: bone marrow (myeloid), lymphocytes (lymphoid), or monocytic; and (3) whether or not there is an increase in the number of abnormal cells in the blood: leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocytic leukemia, and leukocytic leukemia. leukemia), basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelogenous leukemia, cutaneous leukemia, embryonic cell leukemia, eosinophilic leukemia, gross leukemia, hairy cell leukemia, hematoblastic leukemia, hematoblast Cytic cell leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphocytic leukemia leukemia), lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Leder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, or anaplastic cell leukemia.

[0071] "Sarcoma" generally refers to a tumor composed of a substance like embryonic connective tissue and generally composed of closely packed cells embedded in a fibrous or homogeneous substance. Sarcomas that may be treated with the compounds, pharmaceutical compositions, or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid rhabdomyosarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, and idiopathic multiple pigmented hemorrhagic sarcoma. sarcoma), immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer's astrocytic sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0072] "Melanoma" is understood to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0073] "Carcinoma" refers to a malignant neoplasm composed of epithelial cells that tend to infiltrate surrounding tissues and give rise to metastases. Exemplary carcinomas that may be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, lobular carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenoid carcinoma, carcinoma of the adrenal cortex, alveolar carcinoma, basal cell carcinoma, basal cell carcinoma, basaloid carcinoma, basosquamous carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, mucinous carcinoma, comedocarcinoma, uterine carcinoma, cribriform carcinoma, armor carcinoma, skin carcinoma, cylindrical carcinoma, columnar cell carcinoma, ductal carcinoma, ductal carcinoma, scirrhous carcinoma durum, embryonal carcinoma, medullary carcinoma, epidermoid carcinoma, glandular epithelial carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrous carcinoma, colloid carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, adrenal-like carcinoma, childhood embryonal carcinoma, carcinoma in situ, carcinoma in situ in epidermis, carcinoma in situ, Krompecher carcinoma, Klutzycki cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma, mucocytic carcinoma, mucoepidermoid carcinoma, mucinous carcinoma mucosum, mucous carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, medullary carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, cord-like carcinoma, angioectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, nodular carcinoma (carcinoma tuberosum), tubular carcinoma, tuberous carcinoma, verrucous carcinoma, or choriocarcinoma.

[0074] The terms "metastasis," "metastatic," and "metastatic cancer" can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ to another, non-adjacent organ or body part. Cancer begins at a site of origin, e.g., the breast, and that site is called a primary tumor, e.g., primary breast cancer. Some cancer cells within the primary tumor or site of origin acquire the ability to invade and infiltrate surrounding normal tissue in the local area and / or penetrate the walls of the lymphatic or vascular system and spread through that system to other sites and tissues in the body. A second, clinically detectable tumor formed from cancer cells of the primary tumor is called a metastatic tumor or secondary tumor. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, if lung cancer metastasizes to the breast, the secondary tumor in the breast site will consist of abnormal lung cells, not abnormal breast cells. A secondary tumor in the breast is called metastatic lung cancer. Therefore, the term metastatic cancer refers to a disease in which a subject has or has previously had a primary tumor and has one or more secondary tumors.The term non-metastatic cancer or a subject with non-metastatic cancer 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 a subject who has or has a history of a primary lung tumor and has one or more secondary tumors at a second site or multiple sites, for example, in the breast.

[0075] In the context of a substance or the activity or function of a substance related to 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)), "related to" or "related to" means that the substance or the activity or function of the substance causes (in whole or in part) 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) or causes (in whole or in part) a symptom of the disease.

[0076] As used herein, the term "adjacent carbons" refers to consecutive carbon atoms that are directly bonded to each other. For example, [ka] In the formula, 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. [ka] In the example, C1 and C2 are adjacent carbons, C2 and C3 are adjacent carbons, C3 and C4 are adjacent carbons, C4 and C5 are adjacent carbons, C5 and C6 are adjacent carbons, and C6 and C1 are adjacent carbons.

[0077] As used herein, "solvate" refers to the result of the interaction of a solvent with a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0078] As used herein, "prodrug" refers to a derivative of a drug that, upon administration to the human body, is converted into the parent drug through some chemical or enzymatic pathway.

[0079] As used herein, "pharmaceutically acceptable carriers" or "pharmaceutically acceptable excipients" include, but are 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 such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for pharmaceutically active substances is well known in the art. Except as long as any conventional media or agent is incompatible with the active ingredient, its use in therapeutic formulations is contemplated. Supplementary active ingredients can also be incorporated into the formulation. A carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.

[0080] III.Compound Disclosed herein, inter alia, 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). In some embodiments, the disclosure provides compounds of Formula I: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, X is N, CH, or CR x and R x is (CH2) m CN or halo, m is 0, 1, 2, or 3; R 1 , R 2 , R 3 , and R 4 are each independently H or C1-C3 alkyl, L 1 is O, S, or CR 1a R 1b and R 1a and R 1b are each 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 can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; L 2 is CR 2a R 2b and Or, L 2 is O or S, and L 1 is CR 1a R 1b and R 2a and R 2b are each 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 can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; Alternatively, R 1b and R 2b can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; L 3 is a bond or CR 3a R 3b and R 3a and R 3b are each 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 3bcan combine with the atom to which they are attached to form a C3-C6 cycloalkyl; Alternatively, R 2b and R 3b can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; R A is phenyl or naphthyl, and R A is 0, 1, 2, 3, 4, or 5 R A2 is replaced by Each R A2 are independently -OH, C1 to 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, halo, 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), 3-14 membered heterocyclyl, -(C1-C6 alkyl)-(3-14 membered heterocyclyl), C6-C 14Aryl, -(C1-C6 alkyl)-(C6-C 14 aryl), 5-14 membered heteroaryl, or -(C1-C6 alkyl)-(5-14 membered heteroaryl), and each alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, and haloalkyl is selected from 0, 1, 2, or 3 R A3 and each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl is substituted with 0, 1, 2, or 3 R A4 is replaced by Each R A2a and R A2b are independently H, C1 to C 10 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl; Each R A3 are independently halo, -CN, -OR A3a , -SR A3a , -N(R A3a )(R A3b ), C3-C8 cycloalkyl, or 5-14 membered heteroaryl; Each R A3a and R A3b are independently H, C1 to 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), halo, -CN, -OH, or -N(R A4a )(R A4b ) and Each R A4a and R A4b are independently H or C1-C6 alkyl, Or two R's A2 are combined to form R A On the top two adjacent atoms, C3 to C10 Cycloalkyl, C6-C 10 can form an aryl, a 3- to 10-membered heterocyclyl, or a 5- to 14-membered heteroaryl; R B is H, -C(O)R B1 , or -C(O)OR B2 and R B1 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 aryl, or 5-14 membered heteroaryl, C3-C8 cycloalkyl, C6-C 14 An aryl or a 5- to 14-membered heteroaryl may have 0, 1, 2, or 3 R B1a is replaced by R B2 is 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 [ka] and C3-C8 cycloalkyl, C6-C 14 An aryl or a 5- to 14-membered heteroaryl may have 0, 1, 2, or 3 R B2a is replaced by R B3 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 aryl, or 5-14 membered heteroaryl, C3-C8 cycloalkyl, C6-C 14 An aryl or a 5- to 14-membered heteroaryl may have 0, 1, 2, or 3 R B3a is replaced by 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 10is cycloalkyl, L C is a bond or [ka] and 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 are combined to form C3~C 10 forming a cycloalkyl or a 3- to 10-membered heterocyclyl; R C is 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, 3-14 membered heterocyclyl, C6-C 14 aryl, or 5- to 14-membered heteroaryl, each of C3 to C8 cycloalkyl, 3- to 14-membered heterocyclyl, C6 to C 14 Aryl and 3- to 14-membered heteroaryl can have 0, 1, 2, 3, or 4 R C3 is replaced by Each R C1 is 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 )(RC3b ), -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), 3-10 membered heterocyclyl, -(C1-C6 alkyl)-(3-10 membered heterocyclyl), C6-C 10 Aryl, -(C1-C6 alkyl)-(C6-C 10 -(C1-C6(aryl)-(5-10 membered heteroaryl), or -(C1-C6(alkyl)-(5-10 membered heteroaryl), where each alkyl is selected from 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 R C3a2 and each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl is substituted with 0, 1, 2, or 3 halo, —CN, or R C3a2 each alkenyl is substituted with 0, 1, 2, or 3 halo; each alkoxyalkyl and alkynyl is substituted with 0, 1, 2, or 3 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl substituted with 0 or 1 C1-C6 haloalkyl, C6-C 10 substituted with aryl or 5- to 10-membered heteroaryl; Each R C3a and RC3b are independently H, C1 to C 10 Alkyl, C1-C6 haloalkyl, C6-C 10 aryl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each aryl and heteroaryl containing 0, 1, 2, or 3 halo, —CN, or R C3a2 is replaced by Alternatively, R C3a and R C3b together with the N to which they are attached form a 3- to 8-membered heterocycle, Each R C3a1 and R C3a2 are independently C1-C3 alkyl, halo, C1-C6 haloalkyl, C3-C8 cycloalkyl, -(C1-C3 alkyl)-(C3-C8 cycloalkyl), 3-10 membered heterocyclyl, -(C1-C3 alkyl)-(3-10 membered heterocyclyl), C6-C 10 Aryl, -(C1-C3 alkyl)-(C6-C 10 aryl), -(C2-C4 alkynyl)-(C6-C 10 cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, alkynyl-aryl, heteroaryl, and alkyl-heteroaryl are 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 form a 3- to 8-membered heterocycle, R D is a halo, each heterocyclyl has 1, 2, 3, or 4 heteroatoms selected from N, O, S, and Si; Each heteroaryl has 1, 2, 3, or 4 heteroatoms selected from N, O, and S.

[0081] In some embodiments, the present disclosure provides R 1 , R 2 , R 3 , and R 4 is each independently H or methyl. In some embodiments, the present disclosure provides compounds 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 one or two of R 1 and R 2 is methyl. In some embodiments, the present disclosure provides compounds of formula I, wherein R 1 , R 2 , R 3 , and R 4 are each H.

[0082] In some embodiments, the present disclosure provides a compound of formula IA: [ka] or a pharmaceutically acceptable salt thereof, wherein: X is N, CH, or CR x and R x is (CH2) m CN or halo, m is 0, 1, 2, or 3; L 1 is O, S, or CR 1a R 1b and R 1a and R 1b are each 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 can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; L 2is CR 2a R 2b and Or, L 2 is O or S, and L 1 is CR 1a R 1b and R 2a and R 2b are each 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 can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; Alternatively, R 1b and R 2b can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; L 3 is a bond or CR 3a R 3b and R 3a and R 3b are each 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 can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; Alternatively, R 2b and R 3b can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; R A is phenyl or naphthyl, and R A is 0, 1, 2, 3, 4, or 5 R A2 is replaced by Each R A2 are independently -OH, C1 to C 10Alkyl, 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, halo, 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), 3-14 membered heterocyclyl, -(C1-C6 alkyl)-(3-14 membered heterocyclyl), C6-C 14 Aryl, -(C1-C6 alkyl)-(C6-C 14 aryl), 5-14 membered heteroaryl, or -(C1-C6 alkyl)-(5-14 membered heteroaryl), and each alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, and haloalkyl is selected from 0, 1, 2, or 3 R A3 and each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl is substituted with 0, 1, 2, or 3 R A4 is replaced by Each R A2a and R A2b are independently H, C1 to C 10 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl; Each R A3 are independently halo, -CN, -OR A3a , -SR A3a , -N(R A3a )(R A3b ), C3-C8 cycloalkyl, or 5-14 membered heteroaryl; Each R A3a and R A3b are independently H, C1 to 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), halo, -CN, -OH, or -N(R A4a )(R A4b ) and Each R A4a and R A4b are independently H or C1-C6 alkyl, Or two R's A2 are combined to form R A On the top two adjacent atoms, C3 to C 10 Cycloalkyl, C6-C 10 can form an aryl, a 3- to 10-membered heterocyclyl, or a 5- to 14-membered heteroaryl; R B is H, -C(O)R B1 , or -C(O)OR B2 and R B1 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 aryl, or 5-14 membered heteroaryl, C3-C8 cycloalkyl, C6-C 14An aryl or a 5- to 14-membered heteroaryl may have 0, 1, 2, or 3 R B1a is replaced by R B2 is 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 [ka] and C3-C8 cycloalkyl, C6-C 14 An aryl or a 5- to 14-membered heteroaryl may have 0, 1, 2, or 3 R B2a is replaced by R B3 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 aryl, or 5-14 membered heteroaryl, C3-C8 cycloalkyl, C6-C 14 An aryl or a 5- to 14-membered heteroaryl may have 0, 1, 2, or 3 R B3a is replaced by 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 is cycloalkyl, L C is a bond or [ka] and 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 are combined to form C3~C 10 forming a cycloalkyl or a 3- to 10-membered heterocyclyl; R C is 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, 3-14 membered heterocyclyl, C6-C 14 aryl, or 5- to 14-membered heteroaryl, each of C3 to C8 cycloalkyl, 3- to 14-membered heterocyclyl, C6 to C 14 Aryl and 3- to 14-membered heteroaryl may have 0, 1, 2, or 3 R C3 is replaced by Each R C1 is 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), 3-10 membered heterocyclyl, -(C1-C6 alkyl)-(3-10 membered heterocyclyl), C6-C 10 Aryl, -(C1-C6 alkyl)-(C6-C 10 -(C1-C6(aryl)-(5-10 membered heteroaryl), or -(C1-C6(alkyl)-(5-10 membered heteroaryl), where each alkyl is selected from 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 R C3a2 and each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl is substituted with 0, 1, 2, or 3 halo, —CN, or R C3a2 each alkenyl is substituted with 0, 1, 2, or 3 halo; each alkoxyalkyl and alkynyl is substituted with 0, 1, 2, or 3 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl substituted with 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 to C 10 Alkyl, C1-C6 haloalkyl, C6-C 10 aryl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each aryl and heteroaryl containing 0, 1, 2, or 3 halo, —CN, or R C3a2 is replaced by Alternatively, R C3aand R C3b together with the N to which they are attached form a 3- to 8-membered heterocycle, Each R C3a1 and R C3a2 are independently C1-C3 alkyl, halo, C1-C6 haloalkyl, C3-C8 cycloalkyl, -(C1-C3 alkyl)-(C3-C8 cycloalkyl), 3-10 membered heterocyclyl, -(C1-C3 alkyl)-(3-10 membered heterocyclyl), C6-C 10 Aryl, -(C1-C3 alkyl)-(C6-C 10 aryl), -(C2-C4 alkynyl)-(C6-C 10 aryl), 5-10 membered heteroaryl, -(C1-C3 alkyl)-(5-10 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; Alternatively, R C3a1 and R C3a2 together with the N to which they are attached form a 3- to 8-membered heterocycle, R D is a halo, each heterocyclyl has 1, 2, 3, or 4 heteroatoms selected from N, O, S, and Si; Each heteroaryl has 1, 2, 3, or 4 heteroatoms selected from N, O, and S.

[0083] In some embodiments, the present disclosure provides a compound having the structure of formula (I-1): [ka] or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, the present disclosure provides a compound having the structure of formula (I-2): [ka] or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, the present disclosure provides a compound having the structure of formula (I-3): [ka] or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the disclosure provides a compound of Formula I, IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt thereof, where X is N. In some embodiments, the disclosure provides a compound of Formula I, IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt thereof, where X is CH. In some embodiments, the disclosure provides a compound of Formula I, IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt thereof, where X is CR x and R x (CH2) m CN and m is 0, 1, 2, or 3. In some embodiments, the present disclosure provides compounds of formula I, IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt thereof, wherein X is CR x and R x In some embodiments, the present disclosure provides compounds of formula I, IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt thereof, wherein X is CR x and R x is halo, or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the present disclosure provides L 1 is O. In some embodiments, the present disclosure provides compounds of formula I, IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt thereof, wherein: [ka] or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the present disclosure provides L 1 CHR 1b In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, or I-3, 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 is CH. 1 In some embodiments, the present disclosure provides compounds of formula I, IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b is each independently H, C1-C3 alkyl, or halo, or a pharmaceutically acceptable salt thereof. 1b is C1-C3 alkyl, or halo, or a pharmaceutically acceptable salt thereof. 1b is H, or methyl. In some embodiments, the present disclosure provides compounds 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 compounds of formula I, IA, I-1, I-2, or I-3, or a pharmaceutically acceptable salt thereof, wherein R 1b is methyl, or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, the present disclosure provides a compound having the structure of formula (Ib): [ka] or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the present disclosure provides R 2a and R 2b is each independently H, C1-C3 alkyl, halo, or C1-C6 haloalkyl, or a pharmaceutically acceptable salt thereof. 2 CHR 2b In some embodiments, the present disclosure provides a compound of Formula I, IA, I-1, I-2, I-3, (Ia) or (Ib), wherein R 2b is H, or C1-C3 alkyl. In some embodiments, the present disclosure provides compounds of Formula I, IA, I-1, I-2, I-3, (Ia) or (Ib), or a pharmaceutically acceptable salt thereof. 2b is H. In some embodiments, the present disclosure provides compounds 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 compounds of Formula I, IA, I-1, I-2, I-3, (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, wherein R 2b is methyl; or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the present disclosure provides L 3 is 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), wherein R 3a and R 3bis H; or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the present disclosure provides a compound having the structure of formula (Ia-1): [ka] or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, the present disclosure provides a compound having a structure of formula (Ib-1): [ka] or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments, the present disclosure provides a compound having a structure of formula (Ib-2): [ka] or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments, the present disclosure provides a compound having a structure of formula (Ib-3): [ka] or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, the present disclosure provides a compound having a structure of formula (Ib-4): [ka]

[0097] or a pharmaceutically acceptable salt thereof. Disclosed herein, inter alia, are compounds of formula II, (II-1), (IIa), (IIa-1), (IIb), (IIb-1), and (IIb-2). In some embodiments, the disclosure provides compounds of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein: X is N, CH, or CR x and R x is (CH2) m CN or halo, m is 0, 1, 2, or 3; L 1 is O or CR 1a R 1b and R 1a and R 1b are each 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 can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; L 2 is CR 2a R 2b and R 2a and R 2b are each 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 can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; Alternatively, R1b and R 2b can combine with the atom to which they are attached to form a C3-C6 cycloalkyl; R A is phenyl or naphthyl, and R A is 0, 1, 2, 3, 4, or 5 R A2 is replaced by Each R A2 are independently -OH, C1 to 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, halo, 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), 3-14 membered heterocyclyl, -(C1-C6 alkyl)-(3-14 membered heterocyclyl), C6-C 14 Aryl, -(C1-C6 alkyl)-(C6-C 14aryl), 5-14 membered heteroaryl, or -(C1-C6 alkyl)-(5-14 membered heteroaryl), and each alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, and haloalkyl is selected from 0, 1, 2, or 3 R A3 and each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl is substituted with 0, 1, 2, or 3 R A4 is replaced by Each R A2a and R A2b are independently H, C1 to C 10 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl; Each R A3 are independently halo, -CN, -OR A3a , -SR A3a , -N(R A3a )(R A3b ), C3-C8 cycloalkyl, or 5-14 membered heteroaryl; Each R A3a and R A3b are independently H, C1 to 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), halo, -CN, -OH, or -N(R A4a )(R A4b ) and Each R A4a and R A4b are independently H or C1-C6 alkyl, Or two R's A2 are combined to form R A On the top two adjacent atoms, C3 to C 10 Cycloalkyl, C6-C 10can form an aryl, a 3- to 10-membered heterocyclyl, or a 5- to 14-membered heteroaryl; R B is H, -C(O)R B1 , or -C(O)OR B2 and R B1 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 aryl, or 5-14 membered heteroaryl, C3-C8 cycloalkyl, C6-C 14 An aryl or a 5- to 14-membered heteroaryl may have 0, 1, 2, or 3 R B1a is replaced by R B2 is 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 [ka] and C3-C8 cycloalkyl, C6-C 14 An aryl or a 5- to 14-membered heteroaryl may have 0, 1, 2, or 3 R B2a is replaced by R B3 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 aryl, or 5-14 membered heteroaryl, C3-C8 cycloalkyl, C6-C 14 An aryl or a 5- to 14-membered heteroaryl may have 0, 1, 2, or 3 R B3a is replaced by 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 is cycloalkyl, L Cis a bond or [ka] and 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 are combined to form C3~C 10 forming a cycloalkyl or a 3- to 10-membered heterocyclyl; R C is 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, 3-14 membered heterocyclyl, C6-C 14 aryl, or 5- to 14-membered heteroaryl, each of C3 to C8 cycloalkyl, 3- to 14-membered heterocyclyl, C6 to C 14 Aryl and 3- to 14-membered heteroaryl may have 0, 1, 2, or 3 R C3 is replaced by Each R C1 is 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)(RC3b ), -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), 3-10 membered heterocyclyl, -(C1-C6 alkyl)-(3-10 membered heterocyclyl), C6-C 10 Aryl, -(C1-C6 alkyl)-(C6-C 10 -(C1-C6(aryl)-(5-10 membered heteroaryl), or -(C1-C6(alkyl)-(5-10 membered heteroaryl), where each alkyl is selected from 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 R C3a2 and each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl is substituted with 0, 1, 2, or 3 halo, —CN, or R C3a2 each alkenyl is substituted with 0, 1, 2, or 3 halo; each alkoxyalkyl and alkynyl is substituted with 0, 1, 2, or 3 C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl substituted with 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 to C 10Alkyl, C1-C6 haloalkyl, C6-C 10 aryl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, each aryl and heteroaryl containing 0, 1, 2, or 3 halo, —CN, or R C3a2 is replaced by Alternatively, R C3a and R C3b together with the N to which they are attached form a 3- to 8-membered heterocycle, Each R C3a1 and R C3a2 are independently C1-C3 alkyl, halo, C1-C6 haloalkyl, C3-C8 cycloalkyl, -(C1-C3 alkyl)-(C3-C8 cycloalkyl), 3-10 membered heterocyclyl, -(C1-C3 alkyl)-(3-10 membered heterocyclyl), C6-C 10 Aryl, -(C1-C3 alkyl)-(C6-C 10 aryl), -(C2-C4 alkynyl)-(C6-C 10 aryl), 5-10 membered heteroaryl, -(C1-C3 alkyl)-(5-10 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; Alternatively, R C3a1 and R C3a2 together with the N to which they are attached form a 3- to 8-membered heterocycle, R D is a halo, each heterocyclyl has 1, 2, 3, or 4 heteroatoms selected from N, O, S, and Si; Each heteroaryl has 1, 2, 3, or 4 heteroatoms selected from N, O, and S.

[0098] In some embodiments, the present disclosure provides a compound having the structure of formula (II-1): [ka] or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, the present disclosure provides a compound having a structure of formula (II-2): [ka] or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, the present disclosure provides a compound having a structure of formula (II-3): [ka] or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, the disclosure provides a compound of Formula II, II-1, II-2, or II-3, or a pharmaceutically acceptable salt thereof, wherein X is N. In some embodiments, the disclosure provides a compound of Formula II, II-1, II-2, or II-3, or a pharmaceutically acceptable salt thereof, wherein X is CH. In some embodiments, the 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 and R x (CH2) m CN and m is 0, 1, 2, or 3. 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 and 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 CR x and R xIn 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 halo. 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 C—Cl.

[0102] In some embodiments, the present disclosure provides L 1 is O. 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 [ka] or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments, the present disclosure provides L 1 CHR 1b In some embodiments, the present disclosure provides a compound of Formula II, II-1, II-2, or II-3, wherein L 1 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 is CH. 1 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 is each independently H, C1-C3 alkyl, or halo, or a pharmaceutically acceptable salt thereof. 1b is C1-C3 alkyl, or halo, or a pharmaceutically acceptable salt thereof. 1bis methyl, or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the present disclosure provides a compound having the structure of formula (IIb): [ka] or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments, the present disclosure provides R 2a and R 2b is each independently H, C1-C3 alkyl, halo, or C1-C6 haloalkyl, or a pharmaceutically acceptable salt thereof. 2 CHR 2b In some embodiments, the present disclosure provides a compound of Formula II, II-1, II-2, II-3, (IIa) or (IIb), wherein R 2b is H, or C1-C3 alkyl. In some embodiments, the present disclosure provides compounds of Formula II, II-1, II-2, II-3, (IIa) or (IIb), or pharmaceutically acceptable salts 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 is C1-C3 alkyl. In some embodiments, the present disclosure provides compounds of Formula II, II-1, II-2, II-3, (IIa) or (IIb), or pharmaceutically acceptable salts thereof, wherein R 2b is methyl; or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the present disclosure provides a compound having the structure of formula (IIa-1): [ka] or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the present disclosure provides a compound having the structure of formula (IIb-1): [ka] or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the present disclosure provides a compound having a structure of formula (IIb-2): [ka] or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments, the present disclosure provides 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), wherein R is phenyl substituted with A , 0, 1, 2, 3, 4 or 5 R A2or a pharmaceutically acceptable salt thereof.

[0110] 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 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), where each alkenyl is selected from 0, 1, 2, or 3 R A3 and each R A2a are independently C1-C6 haloalkyl or C3-C8 cycloalkyl, and each R A3 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 a pharmaceutically acceptable salt thereof, wherein each R A2 are independently Me, -OH, -C(Cl)=CH2, -CH=CHF2, [ka] F, Cl, —CH2CF3, —OCF3, —O-cyclopropyl, —SCF3, or —CH2-cyclopropyl.

[0111] 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 a pharmaceutically acceptable salt thereof, wherein R A teeth, [ka] is.

[0112] 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 a pharmaceutically acceptable salt thereof, wherein R A teeth, [ka] is.

[0113] 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 teeth, [ka] is.

[0114] 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 teeth, [ka] is.

[0115] In some embodiments, the present disclosure provides R B is H; or a pharmaceutically acceptable salt thereof.

[0116] 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 is -C(O)R B1 , or -C(O)OR B2 and R B1 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 aryl, or 5-14 membered heteroaryl, C3-C8 cycloalkyl, C6-C 14 An aryl or a 5- to 14-membered heteroaryl may have 0, 1, 2, or 3 R B1a is replaced by R B2is 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 [ka] and C3-C8 cycloalkyl, C6-C 14 An aryl or a 5- to 14-membered heteroaryl may have 0, 1, 2, or 3 R B2a is replaced by R B3 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 14 aryl, or 5-14 membered heteroaryl, C3-C8 cycloalkyl, C6-C 14 An aryl or a 5- to 14-membered heteroaryl may have 0, 1, 2, or 3 R B3a is replaced by 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 It is cycloalkyl.

[0117] In some embodiments, the present disclosure provides L C is a bond; or a pharmaceutically acceptable salt thereof.

[0118] 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 teeth, [ka] and Y is C or Si, n is 0 or 1, q is 0 or 1, and R Y1 is H or C1-C3 alkyl, and R Y2 is H or C1-C3 alkyl, or R Y1 and R Y2 combine to form a C3-C6 cycloalkyl.

[0119] 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 teeth, [ka] and Y is C or Si, n is 0 or 1, q is 0 or 1, and R Y1 is H or Me, and R Y2 is H or Me, or R Y1 and R Y2 combine to form a cyclopropyl.

[0120] 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, 2 or 3 R C3 3- to 14-membered heterocyclyl substituted with Each R C3 are independently C1-C6 alkyl, halo, C1-C6 haloalkyl, =CH2, -OR C3a or -(C1-C6 alkyl)-(5-10 membered heteroaryl), where each alkyl is 1-OC(O)N(R C3a1 )(R C3a2 ), -OR C3a1 or N3, Each R C3a are independently C1-C6 haloalkyl, Each R C3a1 and R C3a2 are independently C1-C3 alkyl, C1-C6 haloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, each aryl or heteroaryl being 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 N to which they are attached form a 3- to 8-membered heterocycle.

[0121] 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, 2 or 3 RC3 3- to 14-membered heterocyclyl substituted with Each R C3 are independently C1-C6 alkyl, halo, C1-C6 haloalkyl, =CH2, -OR C3a or -(C1-C6 alkyl)-(5-10 membered heteroaryl), where each alkyl is 1-OC(O)N(R C3a1 )(R C3a2 ), -OR C3a1 or N3, Each R C3a are independently C1-C6 haloalkyl, Each R C3a1 and R C3a2 are independently C1-C3 alkyl, C1-C6 haloalkyl, or C6-C 10 aryl, each aryl being substituted with one SF5; Alternatively, R C3a1 and R C3a2 together with the N to which they are attached form a 3- to 8-membered heterocycle.

[0122] 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 teeth, [ka] and Y is C, n is 0, q is 0, and R Y1 is H and R Y2 is H. In some embodiments, the present disclosure provides Cis —CH—; or a pharmaceutically acceptable salt thereof.

[0123] 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 an 8- to 14-membered heterocyclyl and 0, 1, 2, or 3 R C3 is replaced by Each R C3 are independently C1-C6 alkyl, halo, =CH2, -OR C3a or -(C1-C6 alkyl)-(5-10 membered heteroaryl), Each alkyl is one -OC(O)N(R C3a1 )(R C3a2 ), -OR C3a1 or N3, Each R C3a are independently C1-C6 haloalkyl, Each R C3a1 and R C3a2 are independently C1-C3 alkyl, C1-C6 haloalkyl, or C6-C 10 aryl, each aryl being substituted with one SF5; Alternatively, R C3a1 and R C3a2 together with the N to which they are attached form a 3- to 8-membered heterocycle.

[0124] 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 teeth, [ka] and Y is C or Si, n is 1, q is 1, and R Y1 is Me and R Y2 is Me, or 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 and each R is a 3- to 7-membered heterocyclyl substituted with C3 is independently halo or C1-C6 haloalkyl.

[0125] In some embodiments, the 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 -CH2OR C3a1 , or F and R C3a1is a 5-6 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 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 -CH2OR C3a1 and R C3a1 is a 6-membered heteroaryl substituted with one C 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 -CH2OR C3a1 and R C3a1 is a pyridazine, pyrimidine, or pyrazine, wherein the pyridazine, pyrimidine, or pyrazine is substituted with one CF3.

[0126] 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 -CH2- and R C is one R C3 3- to 14-membered heterocyclyl substituted with R C3 is one -OR C3a1 , or -SR C3a1 C1-C6 alkyl substituted with R C3a1 is a 5-10 membered heteroaryl substituted with 0, 1, or 2 C1-C3 haloalkyl, or C1-C3 haloalkoxy. 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 -CH2- and R C is one R C3 4-8 membered heterocyclyl substituted with R C3 is -CH2OR C3a1 and R C3a1 is a pyrimidine, which is substituted with one trifluoromethyl group.

[0127] 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 The part is [ka] [ka] [ka] is.

[0128] 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 The part is [ka] [ka] is.

[0129] 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 The part is [ka] is.

[0130] 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 The part is [ka] [ka] [ka] is.

[0131] 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 The part is [ka] is.

[0132] In some embodiments, the present disclosure provides 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. Dis F; or a pharmaceutically acceptable salt thereof.

[0133] 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 N, CH, or CR x and R x is a halo, L 1 is O or CR 1a R 1b and R 1a and R 1b are each independently H, (C1-C3) alkyl, or halo; L 2 is CR 2a R 2b and R 2a and R 2b are each independently H, C1-C3 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl; L 3 is a bond or CR 3a R 3b and R 3a and R 3b are each independently H or C1-C3 alkyl, R 1 , R 2 , R 3 , and R 4 are H, respectively, R A is naphthyl and R A is 0, 1, 2, 3, 4, or 5 R A2 is replaced by Each R A2are independently -OH, C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 thioalkyl, halo, C1-C6 haloalkyl, -OR A2a , -SR A2a , -N(R A2a )(R A2b ), or -(C1-C6 alkyl)-(C3-C8 cycloalkyl), and each alkyl, alkenyl, alkynyl, alkoxy, and haloalkyl is selected from 0, 1, 2, or 3 R A3 is replaced by Each R A2a and R A2b are independently H, C1-C6 haloalkyl, or C3-C8 cycloalkyl; Each R A3 are independently haloes, R B is H, L C is a bond or [ka] and 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, R C is a 3- to 14-membered heterocyclyl, and each 3- to 14-membered heterocyclyl is selected from 0, 1, 2, 3, or 4 R C3 is replaced by Each R C3 are independently C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxyalkyl, halo, C1-C6 haloalkyl, =CH2, -OR C3a and each alkyl is selected from 0, 1, 2, or 3 -OC(O)N(R C3a1)(R C3a2 ), -OR C3a1 , -SR C3a1 or N3, R C3a is C1-C6 alkyl, C1-C6 haloalkyl, or 5-10 membered heteroaryl, and heteroaryl is selected from the group consisting of one R C3a2 is replaced by R C3a1 and R C3a2 are each independently C1-C3 alkyl, C1-C6 haloalkyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is substituted with 1 or 2 halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, or SF5; Alternatively, R C3a1 and R C3a2 together with the N to which they are attached form a 3- to 8-membered heterocycle, R D is F.

[0134] 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 N, CH, or C—Cl; L 1 is O, CH2, CHCH3, CHCH2CH3, CHF, or CF2, L 2 is CH2, CHCH3, CHCH2CH3, CHCHF2, or [ka] and L 3 is a bond, CH2, or CHCH3, R 1 , R 2 , R 3 , and R 4 are H, respectively, R A teeth, [ka] and R B is H, -OL C -R C The part is [ka] [ka] [ka] and R D is F.

[0135] 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 is CH2, CHCH3, CHCH2CH3, CHF, or CF2.

[0136] In some embodiments, the present disclosure provides L 3 is CH2 or CHCH3; or a pharmaceutically acceptable salt thereof.

[0137] 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 teeth, [ka] is.

[0138] 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 N, R 1 , R 2 , R 3 , and R 4 are H, respectively, L 1 is CR 1a R 1b and R 1a and R 1b are each independently H or C1-C3 alkyl, L 2 is CR 2a R 2b and R 2a and R 2b are H, respectively, L 3 is CR 3a R 3b and R 3a and R 3b are H, respectively, R A is naphthyl and R A is two R A2 is replaced by Each R A2 are independently C2-C6 alkynyl or halo, R B is H, L C teeth, [ka] and 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 heterocyclyl, and the 3- to 14-membered heterocyclyl is C3 is replaced by R C3 is C1-C6 alkyl, halo, or C1-C6 haloalkyl, and alkyl is selected from one -OR C3a1 is replaced by R C3a1 is a 5-10 membered heteroaryl, wherein the heteroaryl is substituted with one C1-C3 haloalkyl; R D is F.

[0139] 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 N, R 1 , R 2 , R 3 , and R 4 are H, respectively, L 1 is CH2 or CHCH3, L 2 is CH2, L 3 is CH2, R A teeth, [ka] and R B is H, -OL C -R C The part is [ka] and R D is F.

[0140] In some embodiments, the 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): [ka] wherein R 1b is H or methyl, R C3 is -CH2OR C3a1 , or F, R C3a1 is a 5-6 membered heteroaryl substituted with one halo, or C1-C2 haloalkyl.

[0141] In some embodiments, the 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): [ka] wherein R 1b is H or methyl, R C3 is -CH2OR C3a1 , or F, R C3a1 is a 5-6 membered heteroaryl substituted with one halo, or C1-C2 haloalkyl.

[0142] In some embodiments, the 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 the compound has the following structure: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0143] In some embodiments, the 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 the compound has the structure: [ka] It has.

[0144] In some embodiments, the 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), wherein the compound has the structure: [ka] It has.

[0145] In some embodiments, the 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 the compound has the structure: [ka] It has.

[0146] In some embodiments, the 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), wherein the compound has the structure: [ka] It has.

[0147] In some embodiments, the 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 the compound has the structure: [ka] It has.

[0148] In some embodiments, the 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), wherein the compound has the structure: [ka] It has.

[0149] In some embodiments, the 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 the compound has the structure: [ka] It has.

[0150] In some embodiments, the 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), wherein the compound has the structure: [ka] It has.

[0151] In some embodiments, the 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 the compound has the structure: [ka] It has.

[0152] In some embodiments, the 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), wherein the compound has the structure: [ka] It has.

[0153] Also included within the scope of this specification are in vivo metabolic products of the compounds described herein. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily through enzymatic processes. Thus, included are novel and unobvious compounds produced by a process comprising contacting a compound with a mammal for a period of time sufficient to yield metabolic products thereof. Such products are typically radiolabeled (e.g., 14 C or 3 H) Compounds are prepared and identified by administering them to animals, such as rats, mice, guinea pigs, monkeys, or humans, at detectable doses (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism (typically about 30 seconds to 30 hours), and isolating the transformation products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by using antibodies capable of binding to epitopes surviving in the metabolites). Metabolite structures are determined in conventional manner, for example, by MS or NMR analysis. Metabolite analysis is generally performed in the same manner as conventional drug metabolism studies. Transformation products are useful in diagnostic assays for therapeutic administration of compounds, even if they do not possess their own HSV antiviral activity unless otherwise found in vivo.

[0154] Recipes and methods for determining the stability of compounds in surrogate gastrointestinal secretions are known. A compound is defined herein as stable in the gastrointestinal tract if less than about 50 mole percent of the protecting groups are deprotected in surrogate intestinal or gastric fluids when incubated at 37°C for 1 hour. Just because a compound is stable to the gastrointestinal tract does not mean that it cannot be hydrolyzed in vivo. Prodrugs are typically stable in the digestive system, but can be substantially hydrolyzed to the parent drug in the digestive lumen, liver, lungs, or other metabolic organs, or generally within cells. As used herein, a prodrug is understood to be a compound chemically designed to efficiently release the parent drug after overcoming a biological barrier to oral delivery.

[0155] IV. Pharmaceutical Compositions Also disclosed herein is a pharmaceutical composition 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), (IIa), (IIa-1), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. Also provided herein is a pharmaceutical composition 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.

[0156] The compounds disclosed herein can be formulated with conventional carriers and excipients. Tablets can include, for example, excipients, glidants, fillers, binders, or combinations thereof. Aqueous formulations are prepared in sterile form and, if intended for delivery by other than oral administration, are generally isotonic. Exemplary excipients include, but are not limited to, those described in the "HANDBOOK OF PHARMACEUTICAL EXCIPIENTS" (1986). Excipients can include, for example, ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and combinations thereof. In some embodiments, the formulation is basic. 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 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, 2 to 9, 2 to 10, 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 4 to 5, 4 to 6, 4 to 7, 4 to 8, 4 to 9, 4 to 10, 4 to 11, 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, 5 to 11, 6 to 7, 6 to 8, 6 to 9, 6 to 10, 6 to 11, 7 to 8, 7 to 9, 7 to 10, 7 to 11, 8 to 9, 8 to 10, 8 to 11, 9 to 10, or 9 to 11).

[0157] In some embodiments, the compounds disclosed herein have pharmacokinetic properties (e.g., oral bioavailability) suitable for oral administration of the compounds. Formulations suitable for oral administration can be presented, for example, as discrete units such as capsules, cachets, 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 or water-in-oil liquid emulsion. The active ingredient can also be administered, for example, as a bolus, electuary, or paste.

[0158] Tablets may be made by compression or molding, optionally with at least one accessory ingredient. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, dispersant, or a combination thereof. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. Tablets may optionally be coated or scored, and may optionally be formulated to provide slow or controlled release of the active ingredient therefrom.

[0159] For infections of the eye or other external tissues (e.g., mouth and skin), formulations may be applied as a topical ointment or cream containing the active ingredient in an amount, for example, 0.075-20% w / w (including active ingredient in ranges of 0.1% to 20% in 0.1% w / w increments, such as 0.6% w / w, 0.7% w / w, etc.), 0.2-15% w / w, or 0.5-10% w / w. When formulated in an ointment, the active ingredient may, in some embodiments, be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base.

[0160] 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 polyhydric alcohol, 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 include, for example, a compound that enhances 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 contain water.

[0161] The oily phase of the emulsion can be composed of known ingredients in a known manner. In some embodiments, the phase comprises only an emulsifier (otherwise known as an emulgent). In some embodiments, the phase comprises a mixture of at least one emulsifier with a fat, an oil, or a combination thereof. In some embodiments, a hydrophilic emulsifier is included along with a lipophilic emulsifier that functions as a stabilizer. Taken together, the emulsifiers, with or without stabilizers, constitute the so-called emulsifying waxes, which, together with oils and fats, constitute the so-called emulsifying ointment bases that can form the oily dispersed phase of a cream formulation.

[0162] Emulgents and emulsion stabilizers suitable for use in the formulation may include, for example, but are not limited to, TWEEN® 60, TWEEN® 80, SPAN® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, and combinations thereof.

[0163] The selection of suitable oils or fats for the formulation can be based on achieving the desired aesthetic properties. In some embodiments, the cream can be a non-greasy, non-staining, and washable product with a suitable consistency to avoid leakage from tubes or other containers. In some embodiments, the ester can include, for example, linear or branched, mono- or dibasic alkyl esters, such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, CRODAMOL® CAP, or a blend of branched esters known as such, or a combination thereof. In some embodiments, a high-melting lipid, such as white soft paraffin and / or liquid paraffin or other mineral oil, can be included.

[0164] In some embodiments, a compound disclosed herein is administered alone. In some embodiments, a compound disclosed herein is administered in a pharmaceutical composition. In some embodiments, the pharmaceutical composition is for veterinary use. In some embodiments, the pharmaceutical composition is for human use. In some embodiments, a pharmaceutical composition disclosed herein comprises at least one additional therapeutic agent. In some embodiments, a pharmaceutical composition disclosed herein comprises one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are independently a chemotherapeutic agent, an immunotherapeutic agent, a hormonal agent, an antihormonal agent, a targeted therapy agent, or an antiangiogenic agent.

[0165] The pharmaceutical compositions disclosed herein may be in any form suitable for the intended method of administration. The pharmaceutical compositions disclosed herein may be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Exemplary techniques and formulations may be found, for example, in REMINGTON'S PHARMACEUTICAL SCIENCES (MACK PUBLISHING CO., EASTON, PA). Such methods may include the step of bringing into association a compound disclosed herein with the carrier, which constitutes at least one accessory ingredient. In general, the formulations may be prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0166] For oral use, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups, or elixirs can be prepared. Preparations intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such preparations can contain at least one agent, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients suitable for tablet manufacture are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia, and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or they may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action 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.

[0167] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0168] Aqueous suspensions contain the active substance in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients may include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, as well as dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids, and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain at least one preservative, such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, one or more sweeteners (e.g., sucrose or saccharin), or mixtures thereof. Further non-limiting examples of suspending agents include cyclodextrins, hi some embodiments, the suspending agent is sulfobutylether beta-cyclodextrin (SEB-beta-CD), such as CAPTISOL®.

[0169] Oil suspensions can be formulated by suspending the active ingredients in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, coconut oil, or a combination thereof) or in a mineral oil such as liquid paraffin, or a combination thereof. Oral suspensions can contain a thickening agent such as, for example, beeswax, hard paraffin, cetyl alcohol, or a combination thereof. In some embodiments, sweetening agents, such as those set forth above, and / or flavoring agents can be added to provide a palatable oral preparation. In some embodiments, the formulations disclosed herein are preserved by the addition of an antioxidant, such as ascorbic acid.

[0170] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water can provide the active ingredient in a mixture with a dispersing or wetting agent, a suspending agent, a preservative, or combinations thereof. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, can also be present.

[0171] The pharmaceutical composition may be in the form of an oil-in-water emulsion. The oil phase may 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 acacia and gum tragacanth, naturally occurring phosphatides such as soybean 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 may also contain sweeteners and flavoring agents. Syrups and elixirs may be formulated with sweeteners such as glycerol, sorbitol, or sucrose. Such formulations may also contain, for example, demulcents, preservatives, flavorings, coloring agents, or combinations thereof.

[0172] The pharmaceutical compositions may be in the form of a sterile injectable or intravenous preparation, for example, a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as described 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 vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, solid oils may be used as solvents or suspending media. For this purpose, any solvent-free solid oil, including synthetic monoglycerides or diglycerides, may be used. Additionally, fatty acids such as oleic acid may also be used in the preparation of injectables. Acceptable vehicles 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.

[0173] The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. For example, a sustained-release formulation intended for oral administration to humans may contain from about 1 mg to 2000 mg of active ingredient, compounded with an appropriate and convenient amount of carrier material, which may vary from 5% to 95% (weight:weight) of the total formulation. For example, a sustained-release formulation intended for oral administration to humans may contain from about 1 mg to 1000 mg of active ingredient, compounded with an appropriate and convenient amount of carrier material, which may vary from 5% to 95% (weight:weight) of the total formulation. Pharmaceutical compositions can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from 3 μg to 500 μg of active ingredient per milliliter of solution to allow infusion of a suitable volume at a rate of about 30 mL / hour.

[0174] Formulations suitable for topical administration to the eye also include eye drops wherein 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).

[0175] Formulations suitable for topical administration to the mouth include lozenges, which may contain the active ingredient (i.e., a compound disclosed herein and / or additional therapeutic agent) in a flavored base, usually sucrose and acacia or tragacanth; pastilles, which contain the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes, which contain the active ingredient in a suitable liquid carrier.

[0176] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0177] 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.

[0178] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which 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.

[0179] The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind described above. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, of the active ingredient, or an appropriate fraction thereof.

[0180] It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents standard in the art having regard to the type of formulation in question; for example, those suitable for oral administration may include flavoring agents.

[0181] Additionally, there is provided a veterinary formulation comprising a compound disclosed herein together with a carrier for veterinary use.

[0182] A veterinary carrier is a substance useful for the purpose of administering the formulation and may be a solid, liquid, or gaseous substance that is otherwise inert or acceptable in veterinary art and compatible with the active ingredient. These veterinary formulations may be administered orally, parenterally, or by any other desired route.

[0183] The compounds herein are used to provide controlled-release pharmaceutical compositions ("controlled-release formulations") comprising one or more of the compounds as active ingredients, the release of which can be controlled and regulated to allow for less frequent dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0184] The effective dose of active ingredient will depend, at least in part, on the nature of the condition being treated, toxicity, whether the compound is used prophylactically (low doses) or against an active viral infection, the delivery method, and the pharmaceutical composition, and will be determined by the clinician using conventional dose-escalation studies. In some embodiments, the effective dose is 0.0001 to 100 mg / kg body weight per day, e.g., about 10 to about 30 mg / kg body weight per day, 15 to 25 mg / kg body weight per day, 10 to 15 mg / kg body weight per day, or 20 to 30 mg / kg body weight per day. For example, a daily candidate dose for an adult weighing approximately 70 kg can range 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 can take the form of a single or multiple doses. For example, the daily candidate dose for an adult human weighing approximately 70 kg may range from 1 mg to 1000 mg (eg, 5 mg to 500 mg) and may take the form of single or multiple doses.

[0185] V. Kit Also provided herein are kits comprising the compounds disclosed herein, or pharmaceutically acceptable salts thereof. In some embodiments, the kits described herein may include a label and / or instructions for using the compound in treating 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.

[0186] In some embodiments, the kit may also include one or more additional therapeutic agents and / or instructions for using the additional therapeutic agents in combination with the compounds disclosed herein in the treatment of a disease or condition in a subject (e.g., a human) in need thereof.

[0187] In some embodiments, the kits provided herein contain individual dosage units of a compound 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, pre-filled syringes or syringe cartridges, IV bags, inhalers, nebulizers, etc., each of which may contain a therapeutically effective amount of the compound of interest, 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 other multiple dosage units, such as the number of dosage units required for a particular regimen or time period.

[0188] Also provided is an article 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 article of manufacture container is a vial, bottle, ampoule, pre-filled syringe, blister package, tin, can, bottle, box, intravenous bag, inhaler, or nebulizer.

[0189] VI. Administration 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). It will be understood 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.

[0190] The compounds of the disclosure (also referred to herein as the active ingredients) can be administered by any route appropriate to the condition to be treated.

[0191] Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be understood 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.

[0192] The compounds of the present disclosure can be administered to an individual according to an effective dosing regimen for any desired period or duration, 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 more, in some embodiments, the compounds are administered on a daily or intermittent schedule for the duration of the individual's life.

[0193] The dosage or frequency of administration of a compound of the present disclosure may be adjusted over the course of treatment, based on the judgment of the administering physician.

[0194] The compound can be administered to an individual (e.g., a human) in an effective amount. In some embodiments, the compound is administered once daily.

[0195] The compound can be administered by any useful route and means, such as oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of the compound can include about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, for example, about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or for example, about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or for example, about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or for example, about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day, or for example, about 0.3 mg to about 30 mg per day, or for example, about 30 mg to about 300 mg per day.

[0196] The compounds of the present disclosure can be combined with one or more additional therapeutic agents at any dosage of the compound of the present disclosure (e.g., about 1 mg to about 1000 mg of compound). Therapeutically effective amounts can include about 1 mg per dose to about 1000 mg per dose, for example, about 50 mg per dose to about 500 mg per dose, or for example, about 100 mg per dose to about 400 mg per dose, or for example, about 150 mg per dose to about 350 mg per dose, or for example, about 200 mg per dose to about 300 mg per dose. Other therapeutically effective amounts of the compounds of the present disclosure are about 100, about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, about 475, or about 500 mg per dose. Other therapeutically effective amounts of the compounds of the present disclosure are about 100 mg per dose, or about 125, about 150, about 175, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, or about 500 mg per dose. Dose can be administered hourly, daily, or weekly. For example, a dose may be administered about once every 1, 2, 3, 4, 6, 8, 12, or 16 hours, or about once every 24 hours. A dose may also be administered about once every 1, 2, 3, 4, 5, or 6 days, or about once every 7 days. A dose may also be administered about once every 1, 2, 3, or 4 weeks, or about once every 4 weeks. In some embodiments, a dose may be administered about once every week. A dose may also be administered about once every month.

[0197] Other therapeutically effective amounts of the compounds of the present disclosure are about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, or about 100 mg per dose.

[0198] The frequency of administration of the compounds of the present disclosure can be determined by the needs of an individual patient, and can be, for example, once a day, twice a day, or more frequently. Administration of the compound continues as long as necessary to treat the disease or condition. For example, the compound can be administered to a human with cancer for a period of about 20 to about 180 days, or for example, for a period of about 20 to about 90 days, or for example, for a period of about 30 to about 60 days.

[0199] Administration can be intermittent, with the patient receiving a daily dose of a compound of the present disclosure for a period of several days or more, followed by a period of several days or more during which the patient does not receive a daily dose of the compound. For example, the patient can receive a dose of the compound every other day or three times per week. As a further example, the patient can be administered a dose of the compound daily for a period of about 1 to about 14 days, followed by a period of about 7 to about 21 days during which the patient does not receive a dose of the compound, followed by a subsequent period (e.g., about 1 to about 14 days) during which the patient again receives a daily dose of the compound. The alternating periods of compound administration followed by non-administration of the compound can be repeated as clinically needed to treat the patient.

[0200] In some embodiments, a pharmaceutical composition is provided that includes a compound of the present disclosure or a pharmaceutically acceptable salt thereof in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents, and a pharmaceutically acceptable excipient.

[0201] 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., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents.

[0202] 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 may be selected from different classes of therapeutic agents.

[0203] In some embodiments, when a compound of the present disclosure is combined with one or more additional therapeutic agents described herein, the components of the composition are administered simultaneously or as a sequential regimen. When administered sequentially, the combination may be administered in two or more doses.

[0204] In some embodiments, compounds of the present disclosure are combined with one or more additional therapeutic agents in a unit dosage form for simultaneous administration to a patient, for example, as a solid dosage form for oral administration.

[0205] In some embodiments, a compound of the present disclosure is co-administered with one or more additional therapeutic agents.

[0206] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. In this case, the rate of absorption of the compound depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0207] VII.How to use The present disclosure further relates to the use of the compounds disclosed herein for the treatment and / or prevention of diseases and / or conditions through the inhibition of KRAS G12D and / or G12C. The present disclosure further relates to the use of the compounds for the preparation of a medicament for the treatment and / or prevention of cancer.

[0208] The medicaments referred to herein can be prepared by conventional processes comprising combining a compound according to the present disclosure with a pharmaceutically acceptable carrier.

[0209] In some embodiments, provided herein is a method of inhibiting KRAS G12D protein in a subject in need thereof, comprising administering a therapeutically effective amount 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), or a pharmaceutically acceptable salt thereof. and administering to a subject a pharmaceutical composition comprising an acceptable salt or 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).

[0210] In some embodiments, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to a subject a therapeutically effective amount 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). 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).

[0211] In some embodiments, provided herein are methods of treating and / or preventing cancer.

[0212] In some embodiments, provided herein are methods of treating and / or preventing KRAS G12D-associated cancer.

[0213] In some embodiments, provided herein are methods of reducing proliferation of a cell, 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).

[0214] In some embodiments, the KRAS G12D-associated disease or condition comprises cancer. In some embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a malignant tumor. In some embodiments, the cancer comprises a metastatic cancer. In some embodiments, the cancer is resistant or refractory to one or more anti-cancer therapies. In some embodiments, more than about 50% of the cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., so-called "hot" cancers or tumors). In some embodiments, more than about 1% and less than about 50% of the cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., so-called "warm" cancers or tumors). In some embodiments, less than about 1% of the cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., so-called "cold" cancers or tumors).

[0215] In some embodiments, the KRAS G12D-associated disease or condition is a hematological cancer, e.g., a leukemia (e.g., acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), B-cell ALL, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), anaplastic leukemia, lymphoma (e.g., small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), T-cell lymphoma, B-cell lymphoma, diffuse large ... These include: large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL), primary macroglobulinemia (Waldestrom's macroglobulinemia (WM), and / or myeloma (e.g., multiple myeloma (MM)).

[0216] In some embodiments, the KRAS G12D-associated disease or condition is an epithelial tumor (e.g., carcinoma, squamous cell carcinoma, basal cell carcinoma, squamous intraepithelial neoplasia), a ductal tumor (e.g., adenocarcinoma, adenoma, adenomyoma), a mesenchymal or soft tissue tumor (e.g., sarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, dermatofibrosarcoma, neurofibrosarcoma, fibrous histiocytoma, angiosarcoma, angiomyxoma, leiomyoma, chondroma, chondrosarcoma, alveolar soft part sarcoma, epithelioid hemangioendothelioma, Spitz tumor, synovial sarcoma), and lymphoma.

[0217] In some embodiments, the KRAS G12D-associated disease or condition includes a solid tumor in or arising from a tissue or organ, for example, Bone (e.g., ameloblastoma, aneurysmal bone cyst, angiosarcoma, chondroblastoma, chondroma, chondromyxofibroma, chondrosarcoma, chordoma, dedifferentiated chondrosarcoma, enchondroma, epithelioid hemangioendothelioma, fibrous dysplasia, giant cell tumor of bone, hemangioma and related lesions, osteoblastoma, osteochondroma, osteosarcoma, osteoid, osteoma, periosteal chondroma, desmoid, Ewing's sarcoma); 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 gland adenoid cystic carcinoma, salivary gland mucoepidermoid carcinoma, salivary gland Warthin's tumor); Esophagus (e.g., Barrett's esophagus, dysplasia, and adenocarcinoma); Gastrointestinal tract (including stomach (e.g., gastric adenoma, primary gastric lymphoma, gastrointestinal stromal tumor (GIST), metastatic deposits, gastric carcinoid, gastric sarcoma, neuroendocrine carcinoma, primary gastric squamous cell carcinoma, gastric adenocarcinoma), small intestine and smooth muscle (e.g., intravenous leiomyomatosis), colon (e.g., colorectal adenocarcinoma), rectum, and anus); Pancreas (e.g., serous neoplasms (including microcystic or macrocystic serous cystadenoma, solid serous cystadenoma, von Hippel-Lindau (VHL)-associated serous cystic neoplasm, and serous cystadenocarcinoma); mucinous cystic neoplasm (MCN), intraductal papillary mucinous neoplasm (IPMN), intraductal oncocytic papillary neoplasm (IOPN), intraductal tubular neoplasm, cystic acinar neoplasm (including acinar cell cystadenoma, acinar cell cystadenocarcinoma, and pancreatic adenocarcinoma), invasive ductal adenocarcinoma (including tubular adenocarcinoma, adenomatous adenocarcinoma, and adenocarcinoma of the pancreas) including squamous cell carcinoma), mucinous carcinoma, medullary carcinoma, hepatocarcinoma-like carcinoma, signet ring cell carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, acinar cell carcinoma, neuroendocrine tumor, neuroendocrine microadenoma, neuroendocrine tumor (NET), neuroendocrine carcinoma (NEC) (including small cell or large cell NEC), islet cell adenoma, gastrinoma, glucagonoma, serotoninoma, somatostatinoma, VIPoma, solid pseudopapillary tumor (SPN), pancreatoblastoma); Gallbladder (e.g., carcinoma of the gallbladder and extrahepatic bile duct, intrahepatic cholangiocarcinoma); Neuroendocrine (e.g., adrenocortical carcinoma, carcinoid tumor, pheochromocytoma, pituitary adenoma); Thyroid gland (e.g., poorly differentiated (anaplastic) carcinoma, medullary carcinoma, oncocytic tumor, papillary carcinoma, adenocarcinoma); Liver (e.g., adenoma, mixed hepatocellular and cholangiocarcinoma, fibrolamellar carcinoma, hepatoblastoma, hepatocellular carcinoma, mesenchymal tumor, nested stromal epithelial tumor, undifferentiated carcinoma; hepatocellular carcinoma, intrahepatic cholangiocarcinoma, cholangiocyst adenocarcinoma, epithelioid hemangioendothelioma, angiosarcoma, embryonal sarcoma, rhabdomyosarcoma, solitary fibrous tumor, teratoma, yolk sac tumor, carcinosarcoma, rhabdoid tumor); Kidney (e.g., ALK-rearranged renal cell carcinoma, chromophobe renal cell carcinoma, renal clear cell carcinoma, clear cell sarcoma, metanephric adenoma, metanephric adenofibroma, renal mucinous tubular spindle cell carcinoma, renal neoplasm, nephroblastoma (Wilms' tumor), papillary adenoma, papillary renal cell carcinoma, renal oncocytoma, renal cell carcinoma, succinate dehydrogenase-deficient renal cell carcinoma, collecting duct carcinoma); Breast (e.g., invasive ductal carcinoma (including but not limited to acinic cell carcinoma, adenoid cystic carcinoma, apocrine adenocarcinoma, cribriform carcinoma, glycogen-rich / clear cell, inflammatory carcinoma, lipid-rich carcinoma, medullary carcinoma, metaplastic carcinoma, micropapillary carcinoma, mucinous carcinoma, neuroendocrine carcinoma, malignant oncocytoma, papillary carcinoma, sebaceous carcinoma, secretory carcinoma, tubular carcinoma); lobular carcinoma including but not limited to pleomorphic carcinoma, signet ring cell carcinoma; · Peritoneum (e.g., mesothelioma; primary peritoneal cancer); Ovarian (e.g., choriocarcinoma, epithelial tumor, germ cell tumor, sex cord-stromal tumor), fallopian tube (e.g., serous adenocarcinoma, mucinous carcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma, undifferentiated carcinoma, Mullerian tumor, adenosarcoma, leiomyosarcoma, teratoma, germ cell tumor, choriocarcinoma, trophoblastic tumor), uterus (e.g., cervical cancer, endometrial polyp, endometrial hyperplasia, carcinoma in situ (EIC)), endometrial cancer (e.g., endometrioid carcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, squamous cell carcinoma, transitional cell carcinoma, female genital tissues, including endometrial carcinoma, small cell carcinoma, undifferentiated carcinoma, mesenchymal neoplasm), leiomyoma (e.g., endometrial stromal nodule, leiomyosarcoma, endometrial stromal sarcoma (ESS), mesenchymal tumor), mixed epithelial and mesenchymal tumor (e.g., adenofibroma, carcinoma fibroma, adenosarcoma, carcinosarcoma (malignant mixed mesodermal sarcoma MMMT)), endometrial stromal tumor, malignant mixed Mullerian tumor of the endometrium, gestational trophoblastic tumor (partial hydatidiform mole, complete hydatidiform mole, invasive hydatidiform mole, placental enthesal tumor), vulva, vagina); Male reproductive tissues, including the prostate, testes (e.g., germ cell tumors, spermatocytic seminomas), and penis; Bladder (e.g., squamous cell carcinoma, urothelial carcinoma, bladder urothelial carcinoma); Brain (e.g., gliomas (e.g., astrocytoma (including non-invasive, low-grade, poorly differentiated, glioblastoma; oligodendroglioma, ependymoma)), meningioma, ganglioglioma, schwannoma (neurinoma), craniopharyngioma, chordoma, non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, pituitary tumors); Eyes (e.g., retinoma, retinoblastoma, intraocular melanoma, posterior uveal melanoma, iris hamartoma); Head and neck (e.g., nasopharyngeal carcinoma, endolymphatic sac tumor (ELST), epidermoid carcinoma, laryngeal carcinoma (including squamous cell carcinoma (SCC) (e.g., glottic carcinoma, supraglottic carcinoma, subglottic carcinoma, and combined laryngeal carcinoma), carcinoma in situ, verrucous, spindle cell, and basaloid SCC, undifferentiated carcinoma, laryngeal adenocarcinoma, adenoid cystic carcinoma, neuroendocrine carcinoma, and laryngeal sarcoma)), head and neck paraganglioma (e.g., carotid body paraganglioma, vagus nerve paraganglioma); · Thymus (e.g., thymoma); Heart (e.g. cardiac myxoma); · 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); Lymphatic (e.g., lymphomas (including Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL), and refractory iNHL), Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (including B-cell lymphoma and T-cell lymphoma (e.g., Burkitt's lymphoma); large B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, indolent B-cell lymphoma, low-grade B-cell lymphoma, fibrin-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; and systemic T-cell lymphoma), lymphangioleiomyomatosis); · Central nervous system (CNS) (e.g., gliomas (astrocytomas (e.g., pilocytic astrocytoma, pilocytic myxoid astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, diffuse astrocytoma, fibrous astrocytoma, large round cell astrocytoma, protoplasmic astrocytoma, undifferentiated astrocytoma) cysts, glioblastomas (e.g. giant cell glioblastoma, gliosarcoma, glioblastoma multiforme), and gliomatosis cerebri), oligodendrogliomas (e.g. oligodendroglioma, anaplastic oligodendroglioma), oligoastrocytic tumors (e.g. oligoastrocytoma, anaplastic oligoastrocytoma), ependymal tumors (e.g. Subependymomas, myxopapillary ependymomas, ependymomas (e.g., cellular, papillary, clear cell, elongated ependymal cell), poorly differentiated ependymomas), optic gliomas, and non-gliomas (including, 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, and astrocytic region tumors); neurofibromas, meningiomas, peripheral nerve sheath tumors, neuroblastoma group tumors (neuroblastoma, ganglioneuroblastoma, ganglioneuromatosis), and trisomy 19 ependymomas; Neuroendocrine tissues (e.g., the preganglionic system, including the adrenal medulla (pheochromocytoma) and extra-adrenal paraganglia (extra-adrenal paraganglioma)); Skin (including, for example, clear cell hidradenoma, cutaneous benign fibrous histiocytoma, cylindroma, hidradenoma, melanoma (cutaneous melanoma, mucosal melanoma), pilomatricoma, and Spitz tumor); and Soft tissue (e.g., invasive angiomyxoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, angiofibroma, angiomatoid fibrous histiocytoma, synovial sarcoma, biphasic synovial sarcoma, clear cell sarcoma, dermatofibrosarcoma protuberans, desmoid fibromatosis, small round cell tumor, desmoplastic small round cell tumor, elastoma, embryonal rhabdomyosarcoma, Ewing's sarcoma / neurectodermal tumor (PNET), extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, paraspinal sarcoma, inflammatory myofibroblastic tumor, lipoblastic tumor) The patient has a solid tumor arising from a tissue or organ selected from the group consisting of: rhabdomyosarcoma, lipoma, chondroid lipoma, liposarcoma / malignant lipoma-like tumor, liposarcoma, myxoid liposarcoma, fibromyxoid sarcoma, lymphangioleiomyoma, malignant myoepithelioma, malignant melanoma of soft tissue, myoepithelial carcinoma, myxoinflammatory fibroblastic sarcoma, undifferentiated sarcoma, hemangiopericytoma, rhabdomyosarcoma, non-rhabdomyosarcomatous soft tissue sarcomas (NRSTS), soft tissue leiomyosarcoma, undifferentiated sarcoma, and well-differentiated liposarcoma.

[0218] 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.

[0219] 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.

[0220] In some embodiments, the KRAS G12D-associated disease or condition 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.

[0221] In some embodiments, the KRAS G12D-associated disease or condition is pancreatic cancer, colorectal cancer, non-small cell lung cancer, endometrial cancer, uterine endometrical carcinoma, cholangiocarcinoma, testicular germ cell cancer, cervical squamous cell carcinoma, or myelodysplastic syndrome cancer.

[0222] In some embodiments, the cancer is a myelodysplastic syndrome. In some embodiments, the cancer is a high-risk myelodysplastic syndrome or a low-risk myelodysplastic syndrome. In some embodiments, the cancer is a high-risk myelodysplastic syndrome. In some embodiments, the cancer is a high-risk myelodysplastic syndrome.

[0223] 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 uterine endometrical carcinoma. 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 cholangiocarcinoma.

[0224] The effective dosage of the active ingredient used may vary depending on the particular compound used, the mode of administration, the condition being treated, and the severity of the condition being treated, and such dosage may be readily ascertained by one skilled in the art.

[0225] When used to treat or prevent KRAS G12D-related diseases or conditions requiring the compounds of the present disclosure, satisfactory results are generally obtained when the compounds of the present disclosure are administered at a daily dose of about 0.1 milligrams to about 300 milligrams per kilogram of animal body weight. In some embodiments, the compounds of the present disclosure are administered as a single daily dose, in divided doses two to six times daily, or in sustained-release form. For most large mammals, the total daily dosage is about 1 milligram to about 1000 milligrams, or about 1 milligram to about 50 milligrams. For a 70 kg adult human, the total daily dose is generally about 0.1 milligram to about 200 milligrams. This dosage regimen can be adjusted to provide the optimal therapeutic response. In some embodiments, the total daily dose is from about 1 milligram to about 900 milligrams, from about 1 milligram to about 800 milligrams, from about 1 milligram to about 700 milligrams, from about 1 milligram to about 600 milligrams, from about 1 milligram to about 400 milligrams, from about 1 milligram to about 300 milligrams, from about 1 milligram to about 200 milligrams, from about 1 milligram to about 100 milligrams, from about 1 milligram to about 50 milligrams, from about 1 milligram to about 20 milligrams, or from about 1 milligram to about 10 milligrams.

[0226] The compounds of the present application or compositions thereof can be administered once, twice, three times, or four times daily using any suitable method described above. Administration or treatment with the compounds can continue for several days; for example, treatment typically lasts for at least 7, 14, or 28 days per treatment cycle. Treatment cycles alternate periodically, with rest periods of about 1 to 28 days, typically about 7 days or about 14 days, between cycles. Treatment cycles can also be continuous in other embodiments.

[0227] In some embodiments, the method includes administering to a subject an initial daily dose of about 1 to 800 mg of a compound described herein, and increasing the dose in increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dose can be increased daily, every other day, twice a week, or once a week.

[0228] 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 modalities.

[0229] In some embodiments, the present disclosure provides pharmaceutical compositions or methods wherein the one or more further additional therapeutic agents or additional therapeutic modalities comprises one, two, three, or four additional therapeutic agents and / or therapeutic modalities.

[0230] In some embodiments, the present disclosure provides pharmaceutical compositions or methods, wherein the additional therapeutic agent or treatment modality is selected from an immune checkpoint modulator, an antibody-drug conjugate (ADC), an anti-apoptotic agent, a targeted anti-cancer therapeutic agent, a chemotherapeutic agent, surgery, or radiation therapy.

[0231] In some embodiments, the disclosure provides pharmaceutical compositions or methods wherein the immune checkpoint modulator is selected from an anti-PD-(L)1 antibody, an anti-TIGIT antibody, an anti-CTLA4 antibody, an anti-CCR8 antibody, an anti-TREM1 antibody, an anti-TREM2 antibody, a CD47 inhibitor, a DGKα inhibitor, an HPK1 inhibitor, an FLT3 agonist, an adenosine receptor antagonist, a CD39 inhibitor, a CD73 inhibitor, an IL-2 variant (IL-2v), and a CAR-T cell therapy.

[0232] In some embodiments, the disclosure provides pharmaceutical compositions or methods wherein the anti-PD-(L)1 antibody is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimuzumab, prorugolimab, lodapolimab, camrelizumab, budigalimab, avelumab, dostarimab, embafolimab, sintilimab, and zimvelerimab.

[0233] In some embodiments, the present disclosure provides pharmaceutical compositions or methods, wherein the anti-TIGIT antibody is selected from tiragolumab, vibostolimab, donvanalimab, AB308, AK127, BMS-986207, and etigilimab.

[0234] In some embodiments, the present disclosure provides pharmaceutical compositions or methods wherein the anti-CTLA4 is selected from ipilimumab, tremelimumab, and zalifrelimab.

[0235] In some embodiments, the disclosure provides pharmaceutical compositions or methods wherein the CD47 inhibitor is selected from magrolimab, retaplimab, lemzoparimab, AL-008, RRx-001, CTX-5861, FSI-189 (GS-0189), ES-004, BI-765063, ADU1805, CC-95251, and Q-1801.

[0236] In some embodiments, the disclosure provides pharmaceutical compositions or methods wherein the adenosine receptor antagonist is etramadanth (AB928), taminadenant, TT-10, TT-4, or M1069.

[0237] In some embodiments, the present disclosure provides a pharmaceutical composition or method wherein the CD39 inhibitor is TTX-030.

[0238] In some embodiments, the disclosure provides pharmaceutical compositions or methods wherein the CD73 inhibitor is chemliglustat (AB680), uriledolimab, mupadrimab, ORIC-533, ATG-037, PT-199, AK131, NZV930, BMS-986179, or oleculab.

[0239] In some embodiments, the disclosure provides pharmaceutical compositions or methods wherein the IL-2v is aldesleukin (Proleukin), bempegaldesleukin (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.

[0240] In some embodiments, the disclosure provides pharmaceutical compositions or methods wherein the ADC is selected from sacituzumab govitecan, datopotamab deruxtecan, enfortumab vedotin, and trastuzumab deruxtecan.

[0241] In some embodiments, the disclosure provides pharmaceutical compositions or methods, wherein the additional therapeutic agent is selected from idelalisib, sacituzumab govitecan, magrolimab, GS-0189, GS-3583, dimverelimab, GS-4224, GS-9716, GS-6451, GS-1811 (JTX-1811), quemlicustat (AB680), etrumadenant (AB928), domvanalimab, AB308, PY159, PY314, AGEN-1223, AGEN-2373, axicabtadin ciloleucel, and brexcabutadine autoleucel.

[0242] In some embodiments, the method includes administering one or more additional therapeutic agents. The one or more additional therapeutic agents may be one or more of the therapeutic agents described below. In some embodiments, the one or more additional therapeutic agents are independently a chemotherapeutic agent, an immunotherapeutic agent, a hormonal agent, an antihormonal agent, a targeted therapy agent, or an antiangiogenic agent.

[0243] In some embodiments, the one or more additional therapeutic agents comprise 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 comprise a therapeutic agent used to treat high-risk myelodysplastic syndrome (HR MDS). In some embodiments, the one or more additional therapeutic agents comprise azacitidine (Vidaza®), decitabine (Dacogen®), lenalidomide (Revlimid®), cytarabine, idarubicin, daunorubicin, cytarabine plus daunorubicin, cytarabine plus idarubicin, pevonedistat, venetoclax, sabatolimab, guadecitabine, rigosertib, ivosidenib, enazidenib, selinexor, BGB324, DSP-7888, or SNS-301.

[0244] In some embodiments, the one or more additional therapeutic agents comprise a therapeutic agent used to treat lower-risk myelodysplastic syndromes (LR MDS). In some embodiments, the one or more additional therapeutic agents comprise lenalidomide, azacitidine, roxadustat, raspatercept, imetelstat, LB-100, or rigosertib.

[0245] In some embodiments, the one or more additional therapeutic agents comprise a therapeutic agent used to treat colorectal cancer. In some embodiments, the one or more additional therapeutic agents comprise bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab, ziv-aflibercept, bevacizumab (Avastin®), leucovorin, 5-FU, oxaliplatin (FOLFOX), pembrolizumab (Keytruda®), FOLFIRI, regorafenib (Stivarga®), aflibercept (Zaltrap®), cetuximab (Erbitux®), Lonsurf®, or the like. (Orcantas®), XELOX, FOLFOXIRI, bevacizumab plus leucovorin plus 5-FU plus oxaliplatin (FOLFOX), bevacizumab plus FOLFIRI, bevacizumab plus FOLFOX, aflibercept plus FOLFIRI, cetuximab plus FOLFIRI, bevacizumab plus XELOX, bevacizumab plus FOLFOXIRI, binimetinib plus encorafenib plus cetuximab, trametinib plus dabrafenib plus panitumumab, trastuzumab plus pertuzumab, napabucasin plus FOLFIRI plus bevacizumab, or nivolumab plus ipilimumab.

[0246] In some embodiments, the one or more additional therapeutic agents comprise a therapeutic agent used to treat non-small cell lung cancer (NSCLC). In some embodiments, the one or more additional therapeutic agents comprise afatinib, albumin-bound paclitaxel, alectinib, atezolizumab, bevacizumab, cabozantinib, carboplatin, cisplatin, crizotinib, dabrafenib, docetaxel, erlotinib, etoposide, gemcitabine, nivolumab, paclitaxel, pembrolizumab, pemetrexed, ramucirumab, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine, vinorelbine, alectinib (Ale censa®), dabrafenib (Tafinlar®), trametinib (Mekinist®), osimertinib (Tagrisso®), entrectinib (Tarceva®), crizotinib (Xalkori®), pembrolizumab (Keytruda®), carboplatin, pemetrexed (Alimta®), nab-paclitaxel (Abraxane®), ramucirumab (Cyramza®), Docetaxel, bevacizumab (Avastin®), brigatinib, gemcitabine, cisplatin, afatinib (Gilotrif®), nivolumab (Opdivo®), gefitinib (Iressa®), dabrafenib + trametinib, pembrolizumab + carboplatin + pemetrexed, pembrolizumab + carboplatin + nab-paclitaxel, ramucirumab + docetaxel, bevacizumab + carboplatin + pemetrexed, pembrolizumab + pemetrexed docetaxel, cisplatin, pemetrexed, bevacizumab, carboplatin, cisplatin, gemcitabine, nivolumab, docetaxel, carboplatin, pemetrexed, carboplatin, nab-paclitaxel, or pemetrexed, cisplatin, and carboplatin, datopotamab deruxtecan (DS-1062), trastuzumab deruxtecan (Enhertu®), enfortumumab vedotin (Padcev®), durvalumab, canakinumab,These include cemiplimab, nogapendequin alfa, avelumab, tiragolumab, donbanalimab, vibostolimab, osipellimab, datopotamab deruxtecan + pembrolizumab, datopotamab deruxtecan + durvalumab, durvalumab + tremelimumab, pembrolizumab + lenvatinib + pemetrexed, pembrolizumab + olaparib, nogapendequin alfa (N-803) + pembrolizumab, tiragolumab + atezolizumab, vibostolimab + pembrolizumab, or osipellimab + tislelizumab.

[0247] In some embodiments, the one or more additional therapeutic agents comprise a therapeutic agent used to treat pancreatic cancer, hi some embodiments, the one or more additional therapeutic agents comprise 5-FU, leucovorin, oxaliplatin, irinotecan, gemcitabine, nab-paclitaxel (Abraxane®), FOLFIRINOX, 5-FU + leucovorin + oxaliplatin + irinotecan, 5-FU + nanoliposomal irinotecan, leucovorin + nanoliposomal irinotecan, or gemcitabine + nab-paclitaxel.

[0248] In some embodiments, the one or more additional therapeutic agents comprise a therapeutic agent used to treat endometrial cancer, hi some embodiments, the one or more additional therapeutic agents comprise carboplatin, paclitaxel, cisplatin, doxorubicin, ifosfamide, progesterone, anastrozole (Arimidex®), letrozole (Femara®), exemestane (Aromasin®), pembrolizumab (Keytruda®), lenvatinib (Lenvima®), or dostarimab (Jemperli®).

[0249] In some embodiments, the one or more additional therapeutic agents are independently selected from the group consisting of SNS-301, 5-FU + leucovorin + oxaliplatin + irinotecan, 5-FU + nanoliposomal irinotecan, 5-FU, afatinib (Gilotrif®), aflibercept (Zaltrap®), aflibercept + FOLFIRI, albumin-bound paclitaxel, alectinib (Alecensa®), anastrozole (Arimidex®), atezolizumab, avelumab, azacitidine (Vidaza®), ribozyme inhibitors (RIBOF ... trademark), bevacizumab (Avastin®), bevacizumab + carboplatin + nab-paclitaxel, bevacizumab + carboplatin + pemetrexed, bevacizumab + FOLFIRI, bevacizumab + FOLFOX, bevacizumab + FOLFOXIRI, bevacizumab + leucovorin + 5-FU + oxaliplatin (FOLFOX), bevacizumab + XELOX, bevacizumab, BGB324, binimetinib + encorafenib + cetuximab, brigatinib, cabozantinib, canakinumab, capecitabine, ... FOLFIRI, bevacizumab + FOLFOX, bevacizumab + FOLFOXIRI, bevacizumab + leucovorin + 5-FU + oxaliplatin (FOLFOX), bevacizumab + XELOX, bevacizumab, BGB324, binimetinib + encorafenib + cetuximab, brigatinib, cabozantinib, canakinumab, capecitabine, carboplatin + nab-paclitaxel, bevacizumab + FOLFIRI, bevacizumab + FOLFOX, bevaciz b-paclitaxel, carboplatin + pemetrexed, carboplatin, cemiplimab, cetuximab (Erbitux®), cetuximab + FOLFIRI, cisplatin + gemcitabine, cisplatin + pemetrexed, cisplatin, crizotinib (Xalkori®), cytarabine + daunorubicin, cytarabine + idarubicin, cytarabine, dabrafenib (Tafinlar®), dabrafenib + trametinib, datopotamab deruxtecan (DS-1062), datopotamab deruxtecan + dur valmab, datopotamab deruxtecan + pembrolizumab, daunorubicin, decitabine (Dacogen®), docetaxel, domvanalimab, dostarimab (Jemperli®), doxorubicin, DSP-7888, durvalumab + tremelimumab, durvalumab, enazidenib, enfortumumab vedotin (Padcev®), entrectinib (Tarceva®), erlotinib, etoposide, exemestane (Aromasin®), fluorouracil, FOLFIRI,FOLFIRINOX, FOLFOXIRI, gefitinib (Iressa®), gemcitabine + nab-paclitaxel, gemcitabine, guadecitabine, idarubicin, ifosfamide, imetelstat, irinotecan, ivosidenib, LB-100, lenalidomide (Revlimid®), lenalidomide, lenvatinib (Lenvima®), letrozole (Femara®), leucovorin + nanoliposomal irinotecan, leucovorin, Lonsurf (Orcantas®) trademark), luspatercept, nab-paclitaxel (Abraxane®), napabucasin + FOLFIRI + bevacizumab, nivolumab (Opdivo®), nivolumab + docetaxel, nivolumab + ipilimumab, nogapendekin alfa (N-803) + pembrolizumab, nogapendekin alfa, osiperlimab + tislelizumab, osiperlimab, osimertinib (TagrissO®), oxaliplatin (FOLFOX), paclitaxel, panitumumab, pembrolizumab (Keytru da®, pembrolizumab + carboplatin + nab-paclitaxel, pembrolizumab + carboplatin + pemetrexed, pembrolizumab + lenvatinib + pemetrexed, pembrolizumab + olaparib, pembrolizumab + pemetrexed + carboplatin, pemetrexed (Alimta®), pemetrexed + cisplatin + carboplatin, pevonedistat, progesterone, ramucirumab (Cyramza®), ramucirumab + docetaxel, regorafenib (Stivarga®) (Registered Trademark), rigosertib, roxadustat, sabatolimab, selinexor, tiragolumab plus atezolizumab, tiragolumab, trametinib (Mekinist®), trametinib plus dabrafenib plus panitumumab, trastuzumab plus pertuzumab, trastuzumab deruxtecan (Enhertu®), trastuzumab, vandetanib, vemurafenib, venetoclax, vibostolimab plus pembrolizumab, vibostolimab, vinblastine, vinorelbine, XELOX, or ziv-aflibercept.

[0250] In another embodiment, the present disclosure provides a method for manufacturing a medicament for treating cancer in a subject in need thereof, wherein a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is used.

[0251] In another embodiment, the present disclosure provides a method for manufacturing a medicament for inhibiting cancer metastasis in a subject in need thereof, wherein a compound of the present invention, or a pharmaceutically acceptable salt thereof, is used.

[0252] In another embodiment, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cancer in a subject.

[0253] In another embodiment, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting cancer metastasis in a subject.

[0254] 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.

[0255] 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.

[0256] In another embodiment, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0257] VIII. Combination Therapy 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 is one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents is one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents is two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents is three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents is four additional therapeutic agents.

[0258] 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-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 is one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents is one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents is two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents is three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents is four additional therapeutic agents.

[0259] In some embodiments, the additional therapeutic agent is selected from the group consisting of, for example, an inhibitory immune checkpoint blocker or inhibitor, a stimulatory immune checkpoint stimulator, agonist, or activator, a chemotherapeutic agent, an anti-cancer agent, a radiotherapeutic agent, an anti-neoplastic agent, an anti-proliferative agent, an anti-angiogenic agent, an anti-inflammatory agent, an immunotherapeutic agent, a therapeutic antigen-binding molecule (e.g., monospecific and multispecific antibodies in any format, such as DART®, Duobody®, BiTE®, BiKE, TriKE, XmAb®, TandAb®, scFv, Fab, Fab derivatives, and fragments thereof), a bispecific antibody, a non-immunoglobulin antibody mimic (e.g., adnectin, affibody molecule, affilin, affimer, afftin, alphabody, anticalin, peptide aptamer, armadillo repeat protein (ARM), atrimer, avimer, designed ankyrin repeat protein, and the like). protein, DARPin®), finomers, knottins, Kunitz domain peptides, monobodies, and nanoCLAMPs), antibody-drug conjugates (ADCs), antibody-peptide conjugates, oncolytic viruses, gene modifying or editing agents, cells comprising a chimeric antigen receptor (CAR), engineered T cell receptors (TCR-T), including, for example, T cell immunotherapeutics, NK cell immunotherapeutics, or macrophage immunotherapeutics, or any combination thereof.

[0260] Exemplary Targets In some embodiments, the one or more additional therapeutic agents include, for example, an inhibitor, agonist, antagonist, ligand, modulator, stimulator, blocker, activator, or suppressor 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'-nucleotidase ecto (NT5E, CD73; NCBI Gene ID: 4907); ABL gene Oncogene 1, non-receptor tyrosine kinase (ABL1, BCR-ABL, c-ABL, v-ABL; NCBI Gene ID: 25); Absent-in-melanoma 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), ADORA 2B (A2b, A2BR), ADORA3 (A3); NCBI Gene ID: 134, 135, 136, 137); AKT serine / threonine kinase 1 (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); amine oxidase copper-containing (e.g., AOC1 (DAO1), AOC2, AOC 3 (VAP1); NCBI Gene ID: 26, 314, 8639); androgen receptor (AR; NCBI Gene ID: 367); angiopoietin (ANGPT1, ANGPT2; NCBI Gene ID: 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); apoptosis-inducing factor mitochondrial-associated 1 (AIFM1, AIF; NCBI Gene ID: 9131);Arachidonate 5-lipoxygenase (ALOX5; NCBI Gene ID: 240); asparaginase (ASPG; NCBI Gene ID: 374569); asteraid 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 (BTLA, CD272; NCBI Gene ID: 151888); baculovirus IAP repeat-containing proteins (BIRC2 (cIAP1), BIRC3 (cIAP2), XIAP (BIRC4, IAP3), BIRC5 (survivin); NCBI Gene IDs: 329, 330, 331, 332); basigin (Ok blood group) (BSG, CD147; NCBI Gene ID: 68 2); B-cell lymphoma 2 (BCL2; NCBI Gene ID: 596); BCL2-binding protein 3 (BBC3, PUMA; NCBI Gene ID: 27113); BCL2-like (e.g., BCL2L1 (Bcl-x), BCL2L2 (BIM); Bcl-x; NCBI Gene ID: 598, 10018); beta 3-adrenergic receptor (ADRB3; NCBI Gene ID: 155); bone gamma-carboxyglutamic acid 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 ectodomain (BET) bromodomain-containing proteins (e.g., BRD2, BRD3, BRD4, BRDT; NCBI Gene IDs: 6046, 8019, 23476, 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 anhydrases (CA1, CA2, CA3, CA4, CA5A, CA5 B, 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 IDs: 1048, 1084, 4680); casein kinases (e.g., CSNK1A1 (CK1), CSNK2A1 (CK 2); NCBI Gene ID: 1452, 1457); caspases (e.g., CASP3, CASP7, CASP8; NCBI Gene ID: 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: 72923 0); CC motif chemokine receptors (e.g., CCR3 (CD193), CCR4 (CD194), CCR5 (CD195), CCR8 (CDw198); NCBI Gene ID: 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; NCBI 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 somatomammotropic hormone 1 (CSH1; NCBI Gene ID: 1442); claudins (e.g., CLDN6, CLDN18; NCBI Gene IDs: 9074, 51208); markers of cluster of differentiation - (e.g., CD1A, CD1C, CD1D, CD1E, CD2, CD3 alpha (TRA), CD3 beta (TRB), CD3 gamma (TRG), CD3 delta (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(CS F1R), 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), CD194 (CCR4), CD195 (CCR5), CD207, CD221 (IGF1R), CD222 (IGF2) R), CD223(LAG3), CD226(DNAM1), CD244, CD247, CD248, CD276(B7-H3), CD331(FGFR1), CD332(FGFR2), CD333(FGFR3), CD334(FGFR4);NCBI gene IDs: 909, 911, 912, 913, 914, 919, 920, 923, 925, 926, 930, 931, 933, 940, 941, 942, 945, 951, 952, 953, 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); collagen type IV alpha chain (e.g., COL4A1, COL4A2, COL4A3, COL4A4, COL4A5; NCBI Gene IDs: 1282, 1284, 1285, 1286, 1287); collectin subfamily members 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 IDs: 718, 727); COP9 signalosome subunit 5 (COPS5; NCBI Gene ID: 10987); C-type lectin domain family members (e.g., CLEC4C (CD303), CLEC9A (CD370), CLEC12A (CD3 71); CD371; NCBI Gene ID: 160364, 170482, 283420; C-X-C motif chemokine ligand 12 (CXCL12; NCBI Gene ID: 6387); C-X-C motif chemokine receptors (CXCR1 (IL8R1, CD128), CXCR2 (IL8R2, CD182), CXCR3 (CD182, CD183, IP-10R), CXCR4 (CD184); NCBI Gene ID: 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 P450 family members (e.g., CYP2D6, CYP3A4, CYP11A1, CYP11B2, CYP17A1, CYP19A1, CYP51A1; NCBI Gene IDs: 1565, 1576, 1583, 1585, 1586, 1588, 1595); cytochrome P450 oxidations; reductase (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); diablo IAP-binding mitochondria Chondriac 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 tautomer (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 (ENPP3, 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 zeste2 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 variants) III (EGFRvIII), ERBB2 (HER2, NEU, CD340), ERBB3 (HER3), ERBB4 (HER4); NCBI Gene ID: 1956, 2064, 2065, 2066); epithelial cell adhesion molecule (EPCAM; NCBI Gene ID: 4072); epidermal mitogen-activating factor (EPGN; NCBI Gene ID: 255324); eukaryotic translation elongation factors (e.g., EEF1A2, EEF2; NCBI Gene ID: 1917, 1938); eukaryotic translation initiation factors (e.g., EIF4A1, EIF5A; NCBI Gene ID: 197 3, 1984); exopolitin-1 (XPO1; NCBI Gene ID: 7514); farnesoid X receptor (NR1H4, FXR; NCBI Gene ID: 9971); Fa ligand (FASLG, 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 fragment of Ig receptor (e.g., FCER1A, FCGRT, FCGR3A (CD16); NCBI Gene ID: NCBI Gene ID: 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., FGFR1 (CD331), FGFR2 (CD332), FGFR3 (CD333), FGFR4 (CD334); NCBI Gene ID: 2260, 2261, 2263, 2264); fibroblast growth factors (e.g., FGF1 (FGF alpha), FGF2 (FGF beta), FGF4, FGF5;NCBI Gene ID: 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 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 (FO LH1, PSMA; NCBI Gene ID: 2346); folate receptor 1 (FOLR1; NCBI Gene ID: 2348); forkhead box protein M1 (FOXM1; NCBI Gene ID: 2305); flurin (flurin, 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; N NCBI Gene ID: 2908); glucuronidase beta (GUSB; NCBI Gene ID: 2990); glutamate transfer 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 3 beta (GSK3B; NCBI Gene ID: 2932); glypican 3 (GPC3; NCBI Gene ID: 2719); gonadotropin-releasing hormone 1 (GNRH1; NCBI Gene ID: 2719); 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: 2658); growth factor receptor-bound 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); hepatic 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 deacetylases (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-Kappa-B kinase (IKK beta; NCBI Gene IDs: 3551, 3553); IKAROS family zinc finger (IKZF1 (LYF1), IKZF3; NCBI Gene IDs: 10320, 22806); immune Indoleamine 2,3-dioxygenase (e.g., IDO1, IDO2, NCBI Gene IDs: 3620, 169355); inducible T cell costimulatory molecule (ICOS, CD278; NCBI Gene ID: 29851); inducible T cell costimulatory molecule ligand (ICOSLG, B7-H2; NCBI Gene ID: 23308); insulin-like growth factor receptor (e.g., IGF1R, IGF2R; NCBI Gene IDs: 3480, 3482); insulin-like growth factor (e.g., IGF1, IGF2; NCBI Gene IDs: 3479, 3481); insulin receptor (INSR, CD220; NCBI Gene ID: 3643);Integrin subunits (e.g., ITGA5 (CD49e), ITGAV (CD51), ITGB1 (CD29), ITGB2 (CD18, LFA1, MAC1), ITGB7; NCBI Gene ID: 3678, 3685, 3688, 3695, 3698); 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 ID: 3417, 3418); Janus kinase (e.g., JAK1, JAK2, JAK3; NCBI Gene ID: 3716, 3717, 3718); kallikrein-related peptidase 3 (KLK3; NCBI Gene ID: 354); killer cell immunoglobulin-like receptor, Ig domain and long cytoplasmic tails (e.g., KIR2DL1 (CD158A), KIR2DL2 (CD158B1), KIR2DL3 (CD158B), KIR2DL4 (CD158D), KIR2DL5A (CD158F), KIR2DL5B, KIR3DL1 (CD158E1), KIR3DL2 (CD158K), KIR3DP1 (CD158c), KIR2DS2 (CD158J); NCBI Gene IDs: 3802, 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 ID: 3821, 3822, 3823, 3824, 8302, 10219, 22914); kinase insert domain receptor (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: 4 035); leucine-rich repeat-containing 15 (LRRC15; NCBI Gene ID: 131578); leukocyte immunoglobulin-like receptors (e.g., LILRB1 (ILT2, CD85J), LILRB2 (ILT4, CD85D); NCBI Gene ID: 10288, 10859); leukotriene A4 hydrolase (LTA4H; NCBI Gene ID: 4048); linker for activation of T cells (LAT; NCBI Gene ID: 27040); luteinizing hormone / chorionic gonadotropin receptor (LHCGR; NCBI Gene ID: 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 ID: 4063, 17076); LYN proto-oncogene, Src family tyrosine kinase (LYN; NCBI Gene ID: 4067); lymphocyte cytosolic protein 2 (LCP2; NCBI Gene ID: 3937); 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, 313 3, 3134, 3135); major vault protein (MVP, VAULT1; NCBI Gene ID: 9961); MALT1 paracaspase (MALT1; NCBI Gene ID: 10892); MAPK-activated protein kinase 2 (MAPKAPK2; NCBI Gene ID: 9261); MAPK-interacting serine / threonine kinases (e.g., MKNK1, MKNK2; NCBI Gene ID: 2872, 8569); matrix metallopeptidases (e.g., MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP1 1, 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 NCBI Gene ID: 4170); MDM2 oncogene (MDM2; NCBI Gene ID: 4193); MDM4 regulator of p53 (MDM4; BMFS6; NCBI Gene ID: 4194); mechanistic target of rapamycin kinase (MTOR, FRAP1; NCBI Gene ID: 2475); melan-A (MLANA; NCBI Gene ID: 2315); melanocortin receptors (MC1R, MC2R; NCBI Gene ID: 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 sequence (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 (p38 beta), MAPK12; NCBI Gene IDs: 5594, 5595, 5596) 9, 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 1 (MAP4K1, HPK1; NCBI Gene ID: 11184); mitogen-activated protein kinase kinase kinases (e.g., MAP2K1 (MEK1), MAP2K2 (MEK2), MAP2K7 (MEK7); NCBI Gene IDs: 5604, 5605, 5609); MPL proto-oncogene, thrombopoietin receptor (thrombopoietin receptor, MPL; NCBI Gene ID: 4352); mucins (e.g., MUC1 (including its splice variants (e.g., MUC1 / A, C, D, X, Y, Z, and REP)), MUC5AC, MUC16 (CA125); NCBI Gene ID: 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 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 ID: 5819, 81607); neural cell adhesion molecule 1 (NCAM1, CD56; NCBI Gene ID: 4684); neuropilins (e.g., NRP1 (CD304, VEGF165R), NRP2 (VEGF165R2); NCBI Gene ID: 8828, 8829); neurotrophin receptor tyrosine kinases (e.g., NTRK1 (TRKA), NTRK2 (TRKB), NTRK3 (TRKC); NCBI Gene ID: 4914 , 4915, 4916); NFKB-activating protein (NKAP; NCBI Gene ID: 79576); NIMA-related kinase 9 (NEK9; NCBI Gene ID: 91754); NLR family pyrin domain-containing 3 (NLRP3, NALP3; NCBI Gene ID: 114548); Notch receptors (e.g., NOTCH1, NOTCH2, NOTCH3, NOTCH4; NCBI Gene ID: 4851, 4853, 4854, 4855); NRAS proto-oncogene, GTPase (NRAS; NCBI Gene ID: 4893); Nuclear factor kappa B (NFK B1, NFKB2; NCBI Gene ID: 4790, 4791); nuclear factor, erythroid 2-like 2 (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 2 (NOD2; NCBI Gene ID: 64127); nudix hydrolase 1 (NUDT1; NCBI Gene ID: 452 1); 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); oxoglutarate 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 (PPAR alpha), PPARD (PPAR delta), PPARG (PPAR gamma); NCBI Gene ID: 5465, 5467, 5468); phosphatase and tensin homolog (PTEN; NCBI Gene ID: 5728); phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA; PI3K a PIK3CB (PI3K beta), PIK3CD (PI3K delta), PIK3CG (PI3K gamma); NCBI Gene ID: 5290, 5291, 5293, 5294); phospholipases (e.g., PLA2G1B, PLA2G2A, PLA2G2D, PLA2G3, PLA2G4A, PLA2G5, PLA2G7, PLA2G10, PLA2G12A, PLA2G12B, PLA2 G15; NCBI Gene IDs: 5319, 5320, 5321, 5322, 7941, 8399, 50487, 23659, 26279, 81579, 84647); 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 gen 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 ID: 5156, 5159); plexin B1 (PLXNB1; NCBI Gene ID: 5364); poliovirus receptor (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 transcription regulator (PRAME; NCBI Gene ID: 23532); premelanosome protein (PMEL;NCBI Gene ID: 6490); progesterone receptor (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); Prominin1 (PROM1, CD133; NCBI Gene ID: 8842); promyelocytic leukemia (PML; NCBI Gene ID: 5371); 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 ID: 5742, 5743); proteasome 20S subunit beta 9 (PSMB9; NCBI gene ID: 5698); Protein arginine methyltransferases (e.g., PRMT1, PRMT5; NCBI Gene ID: 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 receptor (PTPRB (PTPB), PTPRC (CD45R); NCBI Gene ID: 5787, 5788); prothymosin alpha (PTMA; NCBI Gene ID: 5757); purine nucleoside phosphorylase (PNP; NCBI Gene ID: 4860); purinergic receptor P2X7 (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: 1 D:5894); RAR-related orphan receptor gamma (RORC; NCBI Gene ID:6097); Ras homolog family member C (RHOC; NCBI Gene ID:389); Ras homolog, mTORC1-binding (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 ID: 5914, 5916); retinoid X receptor (e.g., RXRA, RXRB, RXRG; NCBI Gene ID: 6256, 6257, 6258); Rho-associated coiled-coil-containing protein kinase (e.g., ROCK1, ROCK2; NCBI Gene ID: 6093, 9475); ribosomal protein S6 kinase B1 (RPS6KB1, S6K-beta1; NCBI Gene ID: 6198); ring finger protein 128 (RNF128, GRAIL; NCBI Gene ID: 79589); ROS proto-oncogene ROS1, receptor tyrosine kinase (ROS1; NCBI 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 flutrient-related protein 2 (SFRP2; NCBI gene ID: 6423); secreted phosphoprotein 1 (SPP1; NCBI gene ID: 6696); secretoglobin family 1A member 1 (SCGB1A1; NCBI Gene ID: 7356); selectins (e.g., SELE, SELL (CD62L), SELP (CD62); NCBI Gene IDs: 6401, 6402, 6403); semaphorin 4D (semaphorin, 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 (S IRPA, CD172A; NCBI Gene ID: 140885); signal transducers and activators of transcription (e.g., STAT1, STAT3, STAT5A, STAT5B; NCBI Gene ID: 6772, 6774, 6776, 6777); sirtuin-3 (SIRT3; 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); smooth, 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), SLC4 4A4; 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 kinase (e.g., SPHK1, SPHK2; NCBI Gene ID: 8877 , 56848); sphingosine-1-phosphate receptor 1 agonist (S1PR1, CD363; NCBI Gene ID: 1901); spleen-related 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: 2687 2); steroid sulfatase (STS; NCBI Gene ID: 412); stimulator of interferon response cGAMP interactor 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 ID: 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 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); lymphocyte-specific Protein tyrosine kinase (TEC); NCBI Gene ID: 7006); TEK receptor tyrosine kinase (TEK, CD202B, TIE2; NCBI Gene ID: 7010); human telomerase reverse transcriptase (TERT; NCBI Gene ID: 7015); tenascin C (TNC; NCBI Gene ID: 3371); 3 prime repair exonucleases (e.g., TREX1, TREX2; NCBI Gene IDs: 11277, 11219); thrombomodulin ( THBD, CD141; NCBI Gene ID: 7056); thymidine kinase (e.g., TK1, TK2; NCBI Gene ID: 7083, 7084); thymidine phosphorylase (TYMP; NCBI Gene ID: 1890); thymidylate synthase (TYMS; NCBI Gene ID: 7298); thyroid hormone receptor (THRA, THRB; NCBI Gene ID: 7606, 7608); thyrotropin receptor (TSHR; NCBI Gene ID: 7253);TNFSF superfamily members (e.g., TNFSF4 (OX40L, CD252), TNFSF5 (CD40L), TNFSF7 (CD70), TNFSF8 (CD153, CD30L), TNFSF9 (4-1BB-L, CD137L), TNFSF10 (TRAIL, CD253, APO2L), TNFSF11 (CD254, RANKL2, TRANCE), TNFSF13 (APRIL, CD256, TRAIL2), TNFSF13b (BAFF, BLYS, CD257), TNFSF14 (CD258, LIGHT), TNFSF18 ( GITRL); NCBI Gene IDs: 944, 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); Transfection Transferrin (TF; NCBI Gene ID: 7018); Transferrin Receptor (TFRC, CD71; NCBI Gene ID: 7037); Transforming Growth Factor (e.g., TGFA, TGFB1; NCBI Gene ID: 7039, 7040); Transforming Growth Factor Receptors (e.g., TGFBR1, TGFBR2, TGFBR3; NCBI Gene ID: 7046, 7048, 7049); Transforming Protein E7 (E7; NCBI Gene ID: 1489079); Transglutaminase 5 (TGM5; NCBI Gene ID: 9 333); transient receptor potential cation channel subfamily V member 1 (TRPV1, VR1; NCBI Gene ID: 7442); transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H, IGPR1; NCBI Gene ID: 126259); triggering receptors expressed in myeloid cells (e.g., 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 hydroxylase (e.g., TPH1, TPH2; NCBI Gene ID: 7166, 121278); tumor-associated calcium signaling factor 2 (TACSTD2, TROP2, EGP1; NCBI Gene ID: 4070); tumor necrosis factor (TNF; NCBI Gene ID: 7124); tumor necrosis factor (TNF) receptor superfamily members (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, TNFR13C( NCBI gene ID: 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); immunoglobulin-like and EGF-like domain 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 E2I (UBE2I, UBC9; NCBI Gene ID: 7329); ubiquitin C-terminal hydrolase L5 (UCHL5; NCBI Gene ID: 51377); ubiquitin-specific peptidase 7 (US P7; 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 protein (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 T-cell activation inhibitor 1 (VTCN1, B7-H4; NCBI Gene ID: 79679); V-set immunoregulatory receptor (VSIR, VISTA, B7-H5; NCBI Gene ID: 64115); WEE1G2 checkpoint kinase (WEE1; NCBI Gene ID: 7465); WRNRecQ-like helicase (WRN; RECQ3; NCBI Gene ID: 7486); WT1 transcription factor ( WT1; NCBI Gene ID: 7490; WW domain-containing transcription factor 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 transcription factor (YAP1; NCBI Gene ID: 10413); Zeta chain-associated protein kinase 70 (ZAP70; NCBI Gene ID: 7535);

[0261] In some embodiments, the one or more additional therapeutic agents include, for example, 5'-nucleotidase ecto (NT5E or CD73; NCBI gene ID: 4907); adenosine A 2A Adenosine A receptor (ADORA2A; NCBI gene ID: 135) 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 α (DGKA, DAGK, DAGK1, or DGK-α; NCBI Gene ID: 1606); Fms-like tyrosine kinase 3 (FLT3, CD135; NCBI Gene ID: 2322); integrin-associated protein (IAP, CD47; NCBI Gene ID: 961); interleukin-2 (IL2; NCBI Gene ID: 3558); interleukin-2 receptor (IL2RA, IL2RB, IL2RG; NCBI Gene IDs: 3559, 3560, 3561); Kirsten rat sarcoma virus (Kirsten rat sarcoma, KRAS; NCBI Gene ID: 3845; including mutations such as KRAS G12C or G12D; mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1) (also known as hematopoietic progenitor kinase 1 (HPK1), NCBI Gene ID: 11184); myeloid cell leukemia sequence 1 apoptosis regulator (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: 29126) 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, PARP7; 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 signaling factor 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); WRNRecQ-like helicase (WRN; NCBI Gene ID: 7486); zinc finger protein Helios (IKZF2; NCBI Gene ID: 22807);

[0262] Exemplary Mechanisms of Action Immune Checkpoint Modulators In some embodiments, compounds provided herein are administered with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors and / or one or more stimulators, activators, or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blockade or inhibition of inhibitory immune checkpoints can positively regulate T cell or NK cell activation and prevent immune evasion of cancer cells within the tumor environment. Activation or stimulation of stimulatory immune checkpoints can enhance the effectiveness of immune checkpoint inhibitors in cancer treatment. In various embodiments, immune checkpoint proteins or receptors regulate T cell responses (e.g., as reviewed in Xu, J Exp Clin Cancer Res. (2018) 37:110). In some embodiments, immune checkpoint proteins or receptors regulate NK cell responses (e.g., reviewed 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 Treg depletion can relieve 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).

[0263] 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 (NCBI Gene ID: 10226), and the like. 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 T-cell activation inhibitory factor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA; NCBI Gene ID: 64115); immunoglobulin superfamily member 11 (IGSF11, VSIG3; NCBI Gene ID: 152404); natural killer 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; N NCBI Gene ID: 7292); TNFRSF8 (CD30; NCBI Gene ID: 943), TNFSF8 (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: 8 784), 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: 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 cell immunoreceptor with Ig and ITIM domains (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); Signaling 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 translocation 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., lirilumab (IPH-2102, IPH-4102)); killer cell lectin-like receptor C1 ( 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, two Ig domains killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 1 (KIR2DL1; NCBI Gene ID: 3802); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2; NCBI Gene ID: 3803); killer cell immunoglobulin-like receptor, two Ig domains, and 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).

[0264] In some embodiments, 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 immunoregulatory 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 domain-containing (PV RIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG3, CD223); hepatitis A virus cell 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, one Ig domain, and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 2 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1). In some embodiments, 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 costimulatory molecule (ICOS, CD278); inducible T cell costimulatory molecule 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.

[0265] In some embodiments, compounds provided herein are administered with one or more agonists or activators of one or more NK cell stimulatory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include killer cell immunoglobulin-like receptor, three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, one Ig domain and a long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains and a long cytoplasmic tail 2 (KIR2DL3); (KIR2DL3); killer cell 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 with one or more agonists or activators of one or more NK cell-stimulatory 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, e.g., 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.

[0266] In some embodiments, the one or more immune checkpoint inhibitors comprise a proteinaceous (e.g., an antibody or fragment thereof, or an antibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, the one or more immune checkpoint inhibitors comprise a small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, the one or more immune checkpoint inhibitors comprise a proteinaceous inhibitor (e.g., an antibody or fragment thereof, or an antibody mimetic) of LAG3.

[0267] Examples of CTLA4 inhibitors that can be co-administered include ipilimumab, tremelimumab, BMS-986218, AGEN1181, zalifrelimab (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, and KN-04. 4, 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).

[0268] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be co-administered include pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, cosibelimab (CK-301), sasanlimab (PF-06801591), tislelizumab (BGB-A317), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, Retifanlimab (MGA-012), BI-754091, balstilimab (AGEN-2034), AMG-404, toripalimab (JS-001), cetrelimab (JNJ-63723283), genolimuzumab (CBT-501), LZM-009, prorugolimab (BCD-100), lodapolimab (LY-3300054), SHR-1201, camrelizumab (SHR-1210), Sym-021, budigalimab (ABBV-181), PD1-PIK, BAT-1306, avelumab (MSB0010718C), CX-072, CBT -502, dostallimab (TSR-042), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155), embafolimab (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, zimbelelimab (AB122), spartalizumab (P DR-001), and compounds disclosed in WO 2018195321, WO 2020014643, WO 2019160882, or WO 2018195321, and 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), 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), vintrafusp alfa (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, PD-L1 inhibitors include CA-170, GS-4224, GS-4416, and lazertinib (GNS-1480; PD-L1 / EGFR).

[0269] Examples of inhibitors of TIGIT that can be co-administered include tiragolumab (RG-6058), vibostolimab, donvanalimab, donvanalimab (AB154), AB308, BMS-986207, AGEN-1307, COM-902, or etigilimab.

[0270] An example of an inhibitor of LAG3 that can be co-administered is leramirimab (LAG525).

[0271] Inhibition of regulatory T cell (Treg) activity or Treg depletion can alleviate the suppression of anti-tumor immune responses and may 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 with one or more inhibitors of Treg activity or Treg depletion agents. Treg inhibition or depletion can enhance the effectiveness of immune checkpoint inhibitors in cancer treatment.

[0272] In some embodiments, compounds provided herein are administered with one or more Treg inhibitors. In some embodiments, the Treg inhibitor can suppress migration of Tregs into the tumor microenvironment. In some embodiments, the Treg inhibitor can reduce the immunosuppressive function of Tregs. In some embodiments, the Treg inhibitor can modulate 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 proteins (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).

[0273] Examples of Helios degraders that may be co-administered include, but are not limited to, I-57 (Novartis) and compounds disclosed in WO 2019 / 038717, WO 2020 / 012334, WO 2020 / 0117759, and WO 2021 / 101919.

[0274] In some embodiments, compounds provided herein are administered with one or more Treg-depleting agents. In some embodiments, the Treg-depleting agent is an antibody. In some embodiments, the Treg-depleting antibody has antibody-dependent cellular cytotoxicity (ADCC) activity. In some embodiments, the Treg-depleting antibody is Fc-modified to have enhanced ADCC activity. In some embodiments, the Treg-depleting 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).

[0275] In some embodiments, Treg inhibitors or Treg depletors that may be co-administered include C-C motif chemokine receptor 4 (CCR4), C-C motif chemokine receptor 7 (CCR7), C-C motif chemokine receptor 8 (CCR8), C-X-C motif chemokine receptor 4 (CXCR4; CD184), TNFRSF4 (OX40), TNFRSF18 (GITR, CD357), TNFRSF9 (4-1BB, CD137), cytotoxic Treg receptor 4 (CCR4; CD184), TNFRSF18 (GITR, CD357), TNFRSF18 ... Cytotoxic T-lymphocyte-associated protein 4 (CTLA4, CD152), programmed cell death 1 (PDCD1, PD-1), sialyl Lewis x (CD15s), CD27, ectonucleoside 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 and combinations thereof.

[0276] Examples of Treg-depleting anti-CCR8 antibodies that may 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.

[0277] An example of a Treg-depleting anti-CCR4 antibody that can be administered is mogamulizumab.

[0278] Inhibition, depletion, or reprogramming of unstimulated 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; WO 2016049641). Exemplary targets for depleting or reprogramming unstimulated 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 with one or more myeloid cell depleting or reprogramming agents, such as an anti-TREM-1 antibody (e.g., PY159; an antibody disclosed in WO 2019032624) or an anti-TREM-2 antibody (e.g., PY314; an antibody disclosed in WO 2019118513).

[0279] Cluster of differentiation agonists or activators In some embodiments, the compounds provided herein are administered with an agent that targets a cluster of differentiation (CD) marker. Exemplary agents that target CD markers that can be co-administered include the following: A6, AD-IL24, neratinib, tucatinib (ONT 380), mobocertinib (TAK-788), tesevatinib, trastuzumab (HERCEPTIN®), 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, and dasatinib. imatinib, nilotinib, sorafenib, lenvatinib mesylate, ofranelgene obadenovec, cabozantinib malate, AL-8326, ZLJ-33, KBP-7018, sunitinib malate, pazopanib derivatives, AGX-73, revastinib, NMS-088, lucitanib hydrochloride, midostaurin, cediranib, dovitinib, sitravatinib, tivozanib, masitinib, regorafenib, olverenvatinib dimesylate (HQP-1351), cabozantinib, ponatinib and famitinib L-malate, CX-2029 (ABBV-2029), SCB-313, CA-170, COM-701, CDX-301, GS-3583, asnercept (APG-101), APO-010, and International Publication Nos. 2016196388, 2016033570, 2015157386, 199203459, 199221766, 2004080462, 2005020921, and International Publication No. 2006009755, International Publication No. 2007078034, International Publication No. 2007092403, International Publication No. 2007127317, International Publication No. 2008005877, International Publication No. 2012154480, International Publication No. 2014100620, International Publication No. 2014039714, International Publication No. 2015134536, International Publication No. 2017167182, International Publication No. 2018112136, International Publication No. 2018112140, International Publication No. 2019155067,International Publication No. 2020076105, International Application PCT No. US2019063091, International Publication No. 19173692, International Publication No. 2016179517, International Publication No. 2017096179, International Publication No. 2017096182, International Publication No. 2017096281, International Publication No. 2018089628, International Publication No. 2017096179 , International Publication No. 2018089628, International Publication No. 2018195321, International Publication No. 2020014643, International Publication No. 2019160882, International Publication No. 2018195321, International Publication No. 200140307, ​​International Publication No. 2002092784, International Publication No. 2007133811, International Publication No. 2009046541, International Publication No. 2010083253, International Publication No. 2011076781, International Publication No. 2013056352, International Publication No. 2015138600, International Publication No. 2016179399, International Publication No. 2016205042, International Publication No. 2017178653, International Publication No. 2018026600, International Publication No. 2018057669, International Publication Examples of agents that target CD markers include, but are not limited to, agents disclosed in International Publication No. 2018107058, International Publication No. 2018190719, International Publication No. 2018210793, International Publication No. 2019023347, International Publication No. 2019042470, International Publication No. 2019175218, International Publication No. 2019183266, International Publication No. 2020013170, International Publication No. 2020068752, 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).

[0280] In some embodiments, agents targeting CD markers that may be co-administered include the following: PBF-1662, BLZ-945, pemigatinib (INCB-054828), rogaratinib (BAY-1163877), AZD4547, lobritinib (FGF-401), quizartinib dihydrochloride, SX-682, AZD-5069, PLX-9486, avapritinib (BLU-285), ripretinib (DCC-2618), imatinib mesylate, JSP-191, BLU-263, CD117 - small molecule inhibitors such as ADC, AZD3229, telatinib, borolanib, GO-203-2C, AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708, HM-30181A, motixafortide (BL-8040), LY2510924, blixafor (TG-0054), X4P-002, mavorixafor (X4P-001-IO), Plerixafor, CTX-5861, or REGN-5678 (PSMA / CD28).

[0281] In some embodiments, agents targeting CD markers that may be co-administered include the following: interleukin-2 receptor subunit gamma, eltrombopag, lintatolimod, poly ICLC (NSC-301463), reboxone, apoxim, RIBOXXIM®, MCT-465, MCT-475, G100, PEPA-10, eftozanermin alfa (ABBV-621), E-6887, motolimod, levothyroxine ... Small molecule agonists such as siquimod, sergantolimod (GS-9688), VTX-1463, NKTR-262, AST-008, CMP-001, cobitolimod, tilsotolimod, ritenimod, MGN-1601, BB-006, IMO-8400, IMO-9200, agatolimod, DIMS-9054, DV-1079, lefitolimod (MGN-1703), CYT-003, and PUL-042.

[0282] In some embodiments, agents targeting CD markers that may be co-administered include the following: 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, felzalutamab (MOR-202), TAK-079, TAK573, daratumumab (DARZALEX®), TTX-030, cericlerumab ( RG7876), APX-005M, ABBV-428, ABBV-927, mitazarimab (JNJ-64457107), lenzilumab, alemtuzumab, emactuzumab, AMG-820, FPA-008 (caviralizumab), PRS-343 (CD-137 / Her2), AFM-13 (CD16 / CD30), belantamab mafodotin (GSK-2857916), AFM26 (BCMA / CD16A), simulukafusp 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, leratolimab (ONO-4482), LAG-525, MK-4280, fianlimab (REGN-3767), INCAGN2385, enselimab (TSR-033), atipotuzumab, BrevaRex (MAB-AR-20).5), MEDI-9447 (oleculab), CPX-006, IPH-53, BMS-986179, NZV-930, CPI-006, PAT-SC1, rituximab (IPH-2102), lactamab (IPH-4102), monalizumab, BAY-1834942, NEO-201 (CEACAM 5 / 6), iodine (131I) apamistamab (131I-BC8 (lomab-B)), MEDI0562 (tavorixizumab), GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, denosumab, BION-1301, MK-4166, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, CTB-006 , INBRX-109, GEN-1029, pepinemab (VX-15), vopratelimab (JTX-2011), GSK3359609, covolimab (TSR-022), MBG-453, INCAGN-2390, and antibodies such as the compounds disclosed in WO 2017096179, WO 2017096276, WO 2017096189, and WO 2018 / 089628.

[0283] In some embodiments, agents targeting CD markers that may be co-administered include the following: CD19-ARTEMIS, TBI-1501, CTL-119 huCART-19 T cells, iso-cel, lysocabtagene maraleucel (JCAR-017), axicabtagene ciloleucel (KTE-C19, Yescarta®), axicabtagene ciloleucel (KTE-X19), US7741465, US6319494, UCART-19, tabelecleucel (EBV-CTL), Ttisagenlecleucel-T (CTL019), CD19CAR-CD28-CD3zeta-EGFRt-expressing T cells, CD19 / 4-1BBL-armored CAR T cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-zeta T 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), Anti-CD19 CAR T-cell therapy (Silent IL-6 expression, Cancer, Shanghai Unicar Therapeutic Biopharmaceutical Therapeutic 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-CD20CAR T cells (chronic lymphocytic leukemia / B-cell lymphoma), HY-001, ET-019002, YTB-323, GC-012 (CD19 / APRIL), GC-022 (CD19 / CD22), CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn / mem, UCAR-011, ICTCAR-014, GC-007F, PTG-01, CC-97540, GC-007G, TC-310, GC-197, tisagenlecleucel-T, CART-19, tisagenlecleucel (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-1 CAR-T, ICTCAR-053, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), AUTO-2, anti-BCMA CAR 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, or cell therapies such as those disclosed in WO 2012079000 or WO 2017049166.

[0284] Cluster of differentiation 47 (CD47) inhibitors In some embodiments, compounds provided herein are administered with an inhibitor of CD47 (IAP, MER6, OA3; NCBI Gene ID: 961). Examples of CD47 inhibitors include anti-CD47 mAbs (Vx-1004), anti-human CD47 mAbs (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 the following: CC-90002, magrolimab (Hu5F9-G4), AO-176 (Vx-1004), retaplimab (IBI-188), lemzoparimab (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 International Publication No. 199727873, International Publication No. 199940940, International Publication No. 2002092784, International Publication No. 2005044857, International Publication No. 2009046541, International Publication No. 2010070047, International Publication No. 2011143624, International Publication No. 2012170250, International Publication No. 201310975 2, International Publication No. 2013119714, International Publication No. 2014087248, International Publication No. 2015191861, International Publication No. 2016022971, International Publication No. 2016023040, International Publication No. 2016024021, International Publication No. 2016081423, International Publication No. 2016109415, International Publication No. 2016141328, International Publication No. 2016188449, International Publication No. 2017027422 No., International Publication No. 2017049251, International Publication No. 2017053423, International Publication No. 2017121771, International Publication No. 2017194634, International Publication No. 2017196793, International Publication No. 2017215585, International Publication No. 2018075857, International Publication No. 2018075960, International Publication No. 2018089508, International Publication No. 2018095428, International Publication No. 2018137705,International Publication No. 2018233575, International Publication No. 2019027903, International Publication No. 2019034895, International Publication No. 2019042119, International Publication No. 2019042285, International Publication No. 2019042470, International Publication No. 2019086573, International Publication No. 2019108733, International Publication No. 2019138367, International Publication No. 2019144895, International Publication No. 2019157843, Examples of suitable CD47 inhibitors include compounds disclosed in International Publication Nos. WO 2019179366, WO 2019184912, WO 2019185717, WO 2019201236, WO 2019238012, WO 2019241732, WO 2020019135, WO 2020036977, WO 2020043188, and WO 2020009725. 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 magrolimab.

[0285] In some embodiments, the CD47 inhibitor is 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), IMM-0207 (CD47 / VEGF), or any combination thereof. GF), 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.

[0286] Drugs targeting SIRPa In some embodiments, a compound provided herein is administered with an agent that targets SIRPa (NCBI Gene ID: 140885; UniProt P78324). Examples of agents that target SIRPa include SIRPa inhibitors (such as AL-008, RRx-001, and CTX-5861), and anti-SIRPa antibodies (FSI-189 (GS-0189), ES-004, BI-765063, ADU1805, CC-95251, Q-1801 (SIRPa / PD-L1). Additional SIRPα targeting agents of use are described, for example, in WO 200140307, ​​WO 2002092784, WO 2007133811, WO 2009046541, WO 2010083253, WO 2011076781, WO 20120133811, WO 20110133812, WO 20110133813, WO 20110133814, WO 20110133815, WO 20110133816, WO 20110133817, WO 20110133818, WO 20110133819 ... 2013056352, WO 2015138600, WO 2016179399, WO 2016205042, WO 2017178653, WO 2018026600, WO 2018057669, WO 2018107058, WO 2018190719, WO 2018210793, WO 2019023347, WO 2019042470, WO 2019175218, WO 2019183266, WO 2020013170 and WO 2020068752.

[0287] FLT3R agonists In some embodiments, a compound provided herein is administered with an FLT3R agonist. In some embodiments, a compound provided herein is administered with an FLT3 ligand. In some embodiments, a compound provided herein is administered with an FLT3L-Fc fusion protein, for example, as described in WO 2020 / 263830. In some embodiments, a compound provided herein is administered with GS-3583 or CDX-301. In some embodiments, a compound provided herein is administered with GS-3583.

[0288] Agonists or activators of members of the TNF Receptor Superfamily (TNFRSF) In some embodiments, the compounds provided herein are agonists of one or more TNF receptor superfamily (TNFRSF) members, such as 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; 355), 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; 8796), 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; 11565) 0), 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).

[0289] Exemplary anti-TNFRSF4 (OX40) antibodies that may be co-administered include MEDI6469, MEDI6383, tabolixizumab (MEDI0562), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and the antibodies described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628.

[0290] Exemplary anti-TNFRSF5 (CD40) antibodies that may be co-administered include RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0291] In some embodiments, the anti-TNFRSF7 (CD27) antibody varlilumab (CDX-1127) is co-administered.

[0292] Exemplary anti-TNFRSF9 (4-1BB, CD137) antibodies that may be co-administered include urelumab, utomilumab (PF-05082566), AGEN-2373, and ADG-106.

[0293] In some embodiments, the anti-TNFRSF17 (BCMA) antibody GSK-2857916 is co-administered.

[0294] Exemplary anti-TNFRSF18 (GITR) antibodies that may be co-administered include MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and the antibodies described in International Publication Nos. WO 2017096179, WO 2017096276, WO 2017096189, and WO 2018089628. In some embodiments, an antibody or fragment thereof that simultaneously targets TNFRSF4 (OX40) and TNFRSF18 (GITR) is co-administered. Such antibodies are described, for example, in WO 2017096179 and WO 2018089628.

[0295] Bispecific antibodies targeting TNFRSF family members that can be co-administered include PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), AFM-13 (CD16 / CD30), odronectumab (REGN-1979; CD20 / CD3), AMG-420 (BCMA / CD3), INHIBRX-105 (4-1BB / PDL1), FAP-4-IBBL (4-1BB / FAP), pramotamab (XmAb-13676; CD3 / CD20), RG-7828 (CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), and IMM-0306 (CD47 / CD20).

[0296] Bispecific T cell engager In some embodiments, the compounds provided herein are administered 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), odronextamab (REGN-1979; CD20 / CD3), MCLA-117 (CD3 / CLEC12A), JNJ-0819 (heme / CD3), JNJ-7564 (CD3 / heme), AMG-757 (DLL3-CD3), AMG-330 (CD33 / CD3), AMG-420 (BCMA / CD3), AMG-427 (FLT3 / CD3), AMG-562 (CD19 / CD3), AMG-596 (EGFRvIII / CD3), AMG-673 (CD33 / 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 / CDw123), JNJ-9383 (MGD-015), AMG-424 (CD38 / CD3), tidutamab (XmAb-18087 (SSTR2 / CD3)), JNJ-63709178 (CD123 / CD3), mgD-007 (CD3 / gpA33), mgD-009 (CD3 / B7H3), IMCgp100 (CD3 / gp100),XmAb-14045 (CD123 / CD3),XmAb-13676 (CD3 / CD20),tidutamab (XmAb-18087;Examples of suitable anti-CD3 binding bispecific molecules include SSTR2 / CD3, catumaxomab (CD3 / EpCAM), REGN-4018 (MUC16 / CD3), mosunetuzumab (RG-7828; CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), GRB-1302 (CD3 / Erbb2), GRB-1342 (CD38 / CD3), and GEM-333 (CD3 / CD33). Optionally, the anti-CD3 binding bispecific molecule may or may not have an Fc domain. Exemplary bispecific T cell engagers that can be co-administered target CD3 and tumor-associated antigens 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).

[0297] Bispecific and trispecific natural killer (NK) cell engagers In some embodiments, the compounds provided herein are administered with a bispecific NK cell engager (BiKE) or tri-specific NK-cell engager (TriKE) (e.g., without an Fc domain), or a bispecific antibody (e.g., with an Fc domain) against an NK cell activating receptor, 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, BiKE, or TriKE that can be co-administered include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). Optionally, the anti-CD16 binding bispecific molecule may or may not have an Fc domain. Exemplary bispecific NK cell engagers that can be co-administered target CD16 and one or more tumor-associated antigens described herein (e.g., 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.

[0298] MCL1 apoptosis regulator, BCL2 family member (MCL1) inhibitor In some embodiments, compounds provided herein are administered with an inhibitor of the MCL1 apoptosis regulator, a 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.

[0299] SHP2 inhibitors In some embodiments, 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.

[0300] Hematopoietic progenitor kinase 1 (HPK1) inhibitors and degraders In some embodiments, the compounds provided herein are administered with an inhibitor of mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1, HPK1; NCBI gene ID: 11184).

[0013] Examples of inhibitors of hematopoietic progenitor kinase 1 (HPK1) include, but are not limited to, those described in WO2020092621, WO2018183956, WO2018183964, WO2018167147, WO2018049152, WO2020092528, WO2016205942, WO2016090300, WO2018049214, WO2018049200, WO2018049191, WO2018102366, WO2018049152, and WO2016090300.

[0301] Apoptosis signal-regulating kinase (ASK) inhibitors In some embodiments, compounds provided herein are administered with an ASK inhibitor, such as 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 WO2013112741 (Gilead Sciences).

[0302] Bruton's tyrosine kinase (BTK) inhibitors 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-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, HM71224, ibrutinib, M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, PCI-32765, and TAS-5315.

[0303] Cyclin-dependent kinase (CDK) inhibitors In some embodiments, the compounds provided herein are selected from the group consisting 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: 1019); :1019); cyclin-dependent kinase 6 (CDK6, MCPH12; PLSTIRE; NCBI Gene ID:1021); cyclin-dependent kinase 7 (CDK7, CAK; CAK1; HCAK; MO15; STK1; CDKN7; p39MO15; NCBI Gene ID:1022), or cyclin-dependent kinase 9 (CDK9, TAK; C-2k; CTK1; CDC2L4; PITALRE; NCBI Gene ID:1025). Inhibitors of CDK1, 2, 3, 4, 6, 7, and / or 9 include abemaciclib, alvocidib (HMR-1275, flavopiridol), AT-7519, dinaciclib, Ibrance, FLX-925, LEE001, palbociclib, samuracilib, ribociclib, rigosertib, selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, mirciclib, trilaciclib, simulosertib hydrate (TAK931), and TG-02.

[0304] Discoidin domain receptor (DDR) inhibitors In some embodiments, compounds provided herein are combined with inhibitors 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 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), U.S. Patent Application Publication Nos. 2009-0142345 (Takeda Pharmaceutical), 2011-0287011 (Oncomed Pharmaceuticals), WO 2013 / 027802 (Chugai Pharmaceutical), and WO 2013 / 034933 (Imperial Innovations).

[0305] Targeted E3 ligase ligand conjugates In some embodiments, compounds provided herein are administered with a targeted E3 ligase ligand conjugate. Such conjugates have a target protein binding moiety and an E3 ligase binding moiety (e.g., an inhibitor of apoptosis protein (IAP) (e.g., XIAP, c-IAP1, c-IAP2, NIL-IAP, Bruce, and Survival) E3 ubiquitin ligase binding moiety, a Von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety, a cereblon E3 ubiquitin ligase binding moiety, or a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety) and can be used to promote or increase degradation of the targeted protein, e.g., via the ubiquitin pathway. In some embodiments, the targeted E3 ligase ligand conjugate comprises a targeting moiety or binding moiety that targets or binds a protein described herein and an E3 ligase ligand or binding moiety. In some embodiments, the targeted E3 ligase ligand conjugate comprises Cbl proto-oncogene B (CBLB; Cbl-b, Nbla00127, RNF56; NCBI Gene ID: 868) and 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 of, e.g., BTK and an E3 ligase ligand or binding moiety). See, e.g., WO2018098280. In some embodiments, the targeted E3 ligase ligand conjugate comprises a binding moiety that targets or binds to interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK-4); a 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 moiety.See, e.g., WO 2019099926, WO 2018226542, WO 2018119448, WO 2018223909, WO 2019079701. Additional targeted E3 ligase ligand conjugates that can be co-administered are described, e.g., in WO 2018237026, WO 2019084026, WO 2019084030, WO 2019067733, WO 2019043217, WO 2019043208, and WO 2018144649.

[0306] Histone deacetylase (HDAC) inhibitors In some embodiments, the compounds provided herein are administered with an inhibitor of histone deacetylase, for example, 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, mocetinostat, panobinostat, pracinostat, xinostat (JNJ-26481585), resminostat, licorinostat, romidepsin, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustin, remetinostat, and entinostat.

[0307] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors In some embodiments, 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.

[0308] Janus kinase (JAK) inhibitors In some embodiments, 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), restortinib, momelotinib (CYT0387), irginatinib maleate (NS-018), pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019.

[0309] Lysyl oxidase-like protein (LOXL) inhibitors In some embodiments, compounds provided herein are administered in combination with an inhibitor of a LOXL protein, e.g., 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 WO2009017833 (Arresto Biosciences), WO2009035791 (Arresto Biosciences), and WO2011097513 (Gilead Biologics).

[0310] Matrix metalloproteinase (MMP) inhibitors In some embodiments, the compounds provided herein are inhibitors of matrix metallopeptidases (MMPs), such as 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), MMP29 (NCBI Gene ID: 4340), MMP29 (NCBI Gene ID: 4341), MMP20 (NCBI Gene ID: 4342), MMP21 (NCBI Gene ID: 4343), MMP22 (NCBI Gene ID: 4344), MMP23 (NCBI Gene ID: 4 and / or MMP28 (NCBI Gene ID: 79148). Examples of MMP9 inhibitors include marimastat (BB-2516), sipemastat (Ro 32-3555), GS-5745 (andecaliximab), and those described in WO2012027721 (Gilead Biologics).

[0311] RAS and RAS pathway inhibitors In some embodiments, the compounds provided herein are directed to KRAS proto-oncogene, GTPase (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, GTPase (NRAS; also known as NS6; CMNS; The treatment is administered in conjunction with an inhibitor of the HRAS proto-oncogene (NRAS; ALPS4; N-ras; NRAS1; NCBI Gene ID: 4893) or HRAS proto-oncogene, a 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). The Ras inhibitor can inhibit Ras at either the polynucleotide level (e.g., transcription inhibitors) or the polypeptide level (e.g., GTPase enzyme inhibitors). 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 may 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 adaptor-, AZD-4785, siG12D-LODER™, and 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, rabocertinib, and ulixertinib. Exemplary Ras GTPase inhibitors that can be co-administered include lidigosertib. Exemplary PI3K inhibitors that may be co-administered include idelalisib (Zydelig®), alpelisib, buparlisib, pitilisib, inavolisib (RG6114), and ASN-003. Exemplary AKT inhibitors that may be co-administered include capivasertib and GSK2141795. Exemplary PI3K / mTOR inhibitors that may be co-administered include daptolisib, omipalisib, voxalisib, gedatolisib, GSK2141795, GSK-2126458, inavolisib (RG6114), sapanisertib, ME-344, sirolimus (oral nano-amorphous formulation, cancer), racemetyrosine (TYME-88 (mTOR / cytochrome P450 3A4)), temsirolimus (TORISEL®, 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-administration of the MEK inhibitor selumetinib and the CDK4 / 6 inhibitor palbociclib. See, e.g., Zhou, et al., Cancer Lett. 2017 Nov 1;408:130-137. Also, K-RAS and mutant N-RAS can be reduced by neratinib, an irreversible inhibitor of ERBB1 / 2 / 4. See, e.g., Booth, et al., Cancer Biol Ther. 2018 Feb 1;19(2):132-137.

[0312] Mitogen-activated protein kinase (MEK) inhibitors In some embodiments, a compound provided herein is administered with an inhibitor of mitogen-activated protein kinase kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI Gene ID: 5609). Examples of MEK inhibitors include antroquinol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosetib plus trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, and refametinib.

[0313] Phosphatidylinositol 3-kinase (PI3K) inhibitors In some embodiments, the compounds provided herein are directed to phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits, e.g., 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, P110BET A, 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, P110δ, 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, BAY10824391, BEZ235, bupallisib (BKM120), BYL719 (alpelisib), CH5132799, and copanlisib (BAY 80-6946), duvelisib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771, GSK2269557, idelalisib (Zydelig®), INCB50465, IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG 7604, rigosertib, RP5090, RP6530, SRX3177, taselisib, TG100115, TGR-1202 (umbralisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, wortmannin, ZSTK474, and the compounds disclosed in International Publication No. 2005113556 (ICOS), International Publication No. 2013052699 (Gilead Calistoga), WO 2013116562 (Gilead Calistoga), WO 2014100765 (Gilead Calistoga), WO 2014100767 (Gilead Calistoga), and WO 2014201409 (Gilead Sciences).

[0314] Spleen Tyrosine Kinase (SYK) inhibitor In some embodiments, 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, celdulatinib (PRT-062607), enstopretinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), gusacitinib (ASN-002), and those described in U.S. Pat. No. 8,450,321 (Gilead Connecticut), and U.S. Patent Application Publication No. 20150175616.

[0315] Toll-like receptor (TLR) agonists In some embodiments, the compounds provided herein are administered with an agonist of a toll-like receptor (TLR), e.g., 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).Examples of TLR7 agonists that may be co-administered include DS-0509, GS-9620 (vesatolimod), vesatolimod 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 those disclosed in U.S. Patent Application Publication No. 20100143301 (Gilead Sciences), U.S. Patent Application Publication No. 20110098248 (Gilead Sciences), and U.S. Patent Application Publication No. 20110098248 (Gilead Sciences). Sciences), and U.S. Patent Application Publication No. 20090047249 (Gilead Sciences), U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 20140073642 (Janssen), WO 2014056953 (Janssen), WO 2014076221 (Janssen), WO 2014128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Therapeutics), and U.S. Patent Application Publication No. 20130251673 (Novira Examples include compounds disclosed in Therapeutics.An example of a TLR7 / TLR8 agonist that can be co-administered is NKTR-262. Examples of 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 U.S. Patent Application Publication No. 20140045849 (Janssen), U.S. Patent Application Publication No. 201400736 42 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Examples of compounds disclosed in US Patent Application Publication No. 20130251673 (Novira Therapeutics) include compounds disclosed in US Pat.Exemplary TLR9 agonists that may be co-administered include AST-008, CMP-001, IMO-2055, IMO-2125, ritenimod, 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 lintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.

[0316] Tyrosine kinase inhibitors (TKIs) In some embodiments, the compounds provided herein are administered with a tyrosine kinase inhibitor (TKI). The TKI may target the epidermal growth factor receptor (EGFR), as well as receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bustinib, brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391 (Src ), lapatinib, lestaurtinib, lenvatinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rociletinib, surufatinib (HMPL-012), sunitinib, famitinib, L-malic acid, (MAC-4), tivoanib, TH-4000, and MEDI-575 (anti-PDGFR antibody). Exemplary EGFR-targeted agents include neratinib, tucatinib (ONT-380), tecevatinib, mobocertinib (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 (LECLAZA®, and Booth, et al., Cancer Biol Ther. 2018 Feb. 1;19(2):132-137. Antibodies targeting EGFR include, but are not limited to, modotuximab, cetuximab sarotarocan (RM-1929), seribantumab, necitumumab, depatuxizumab mafodotin (ABT-414), tomzotuximab, depatuxizumab (ABT-806), and cetuximab.

[0317] chemotherapy drugs In some embodiments, the compounds provided herein are administered in combination with a chemotherapeutic or anti-neoplastic agent.

[0318] As used herein, the terms "chemotherapeutic agent" or "chemotherapeutic agent" (or "chemotherapy" in the case of treatment with a chemotherapy agent) are meant to encompass any non-proteinaceous (e.g., non-peptidic) compound useful in the treatment of cancer. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodepa, carboquone, meturedepa, and uredepa; ethylenimines and methylameramines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimerolomelamine; acetogenins such as bullatacin and bullatacinone; camptothecins, including the synthetic analog topotecan; bryostatin, kallistatin; CC-1065, including the synthetic analogs adozelesin, carzelesin, and bizelesin; cryptoxanthin; ficins, especially cryptophycin 1 and cryptophycin 8; dolastatins; duocarmycins, including synthetic analogs KW-2189 and CBI-TMI; eleutherobin; 5-azacytidine; pancratistatin; sarcodictyin; spongistatins; nitrogen mustards, such as chlorambucil, chlornaphazine, cyclophosphamide, glufosfamide, evofosfamide, bendamustine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine, fenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, foremustine, lomustine, nimustine, and ranimustine;Antibiotics, such as enediyne antibiotics (e.g., calicheamicins, particularly calicheamicin gamma II and calicheamicin phi II), dynemycins, including dynemycin A, bisphosphonates such as clodronate, esperamicin, neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin leucine, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, chelamycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenime antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as demopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as cladribine, pentostatin, fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as furoic acid; radiotherapeutic agents such as radium-223; trichothecenes, particularly T-2 toxin, veracrine A, roridin A, and anguidine; taxoids such as paclitaxel (TAXOL®), Abraxane, docetaxel (TAXOTERE®), cabazitaxel, BIND-014, and tesetaxel;Sabizablin (Veru-111); platinum analogues such as cisplatin and carboplatin, NC-6004 nanoplatin; aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; hestravcil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; elformutine; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; fluoropyrimidines; folinic acid; podophyllic acid, 2-ethylhydrazide; procarbazine; polysaccharide K (PSK); Razoxane; Rhizoxin; Sizofiran; Spirogermanium; Tenuazonic acid; Trabectedin, Triaziquone; 2,2',2''-Trichlorotriemylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Chlorambucil; Gemcitabine (GEMZA R®); 6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vancristine; vinorelbine (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin, aminopterin, xeloda; ibandronate; CPT-11; topoisomerase inhibitors RFS 2000; difluoromethylornithine (DFMO); retinoids, e.g., retinoic acid; capecitabine; NUC-1031; FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin); FOLFIRI (folinic acid, 5-fluorouracil, irinotecan);Examples include 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. Such agents can be conjugated to antibodies or any of the targeting agents described herein to create antibody drug conjugates (ADCs) or targeted drug conjugates.

[0319] Antihormonal drugs Also included within the definition of "chemotherapeutic agent" are antihormonal agents such as antiestrogens and selective estrogen receptor modulators (SERMs), inhibitors of the enzyme aromatase, antiandrogens, and pharmaceutically acceptable salts, acids, or derivatives of any of the above that act to regulate or inhibit hormone action on tumors.

[0320] Examples of antiestrogens and SERMs include, for example, tamoxifen (including NOLVADEX™), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and toremifene (FARESTON®).

[0321] Inhibitors of the enzyme aromatase regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazole, aminoglutethimide, megestrol acetate (MEGACE®), exemestane, formestane, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®).

[0322] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, ODM-204, enobosarm (GTX-024), darolutamide, and IONIS-AR-2.5Rx (apatorsen).

[0323] Examples of progesterone receptor antagonists include onapristone. Additional progesterone targeting agents include TRI-CYCLEN LO (norethindrone + ethinyl estradiol), norgestimate + ethinyl estradiol (Tri-Cyclen), and levonorgestrel.

[0324] Antiangiogenic agents In some embodiments, the compounds provided herein are administered with an anti-angiogenic agent. Anti-angiogenic agents that may be co-administered include retinoid acid and its derivatives, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®, regorafenib, necuranib, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulfate (clupeine), sulfated chitin derivatives (prepared from snow crab shell), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, modulators of matrix metabolism including proline analogs such as l-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, d,l-3,4-dehydroproline, thiaproline, and the like. benzodiazepine, α,α'-dipyridyl, β-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2 macroglobulin-2 serum, chicken inhibitor of metalloproteinases-3 (Ch...

Claims

1. Equation IIb: 【Chemical 865】 A compound of or a pharmaceutically acceptable salt thereof During the ceremony, X is N, CH, or CR ｘ And, R ｘ is, (CH ２ ) ｍ CN, or halo, m is 0, 1, 2, or 3. L ２ CR ２ａ R ２ｂ And, Or, L ２ is either O or S, R ２ａ and R ２ｂ are each independently H, C １ ~C ３ alkyl, C １ ~C ３ alkoxy, halo, C １ ~C ６ haloalkyl, C １ ~C ６ haloalkoxy, -CN, C １ ~C ３ cyanoalkyl, or C ３ ~C ６ cycloalkyl, Alternatively, R ２ａ and R ２ｂ These combine with the atoms to which they are bonded, C ３ ~C ６ It can form cycloalkyl groups, R Ａ is phenyl or naphthyl, and R Ａ This is 0, 1, 2, 3, 4, or 5 R Ａ２ It has been replaced with, Each R Ａ２ These are independently -OH, C １ ~C １０ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C １０ Alkoxy, C １ ~C １０ Hydroxyalkyl, C ２ ~C １０ Alkoxyalkyl, C １ ~C ６ Alkyl-N(R) Ａ２ａ ) (Caution Ａ２ｂ ), C １ ~C １０ Thioalkyl, halo, C １ ~C ６ Haloalkyl, -CN, -C(O)R Ａ２ａ , -C(O)OR Ａ２ａ , -OC(O)R Ａ２ａ , -OC(O)OR Ａ２ａ , -C(O)N(R Ａ２ａ ) (Caution Ａ２ｂ ), -N(R Ａ２ａ )C(O)(R Ａ２ｂ ), -OC(O)N(R Ａ２ａ ) (Caution Ａ２ｂ ), -N(R Ａ２ａ )C(O)(OR Ａ２ｂ ), oxo, -OR Ａ２ａ ,-SR Ａ２ａ , -S(O) ２ R Ａ２ａ , -S(O) ２ OR Ａ２ａ , -N(R Ａ２ａ ) (Caution Ａ２ｂ ), - (C ０ ~C ３ Alkyl)-SF ５ , -OP(O)(OR Ａ２ａ ) ( OR Ａ２ｂ ), C ３ ~C ８ Cycloalkyl, -(C １ ~C ６ (Alkyl)-(C ３ ~C ８ Cycloalkyl), 3-14 member heterocyclyl, -(C １ -C ６ -(alkyl)-(3- to 14-membered heterocyclyl), C ６ -C １４ -aryl, -(C １ -C ６ -(alkyl)-(C ６ -C １４ -aryl), 5- to 14-membered heteroaryl, or -(C １ -C ６ -(alkyl)-(5- to 14-membered heteroaryl), wherein each alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, and haloalkyl is substituted with 0, 1, 2, or 3 R Ａ３ groups, and each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl is substituted with 0, 1, 2, or 3 R Ａ４ groups, Each R Ａ２ａ and R Ａ２ｂ is, independently, H, C １ ~C １０ alkyl, C １ ~C ６ haloalkyl, or C ３ ~C ８ cycloalkyl, and Each R Ａ３ These are independently: Halo, -CN, -OR Ａ３ａ ,-SR Ａ３ａ , -N(R Ａ３ａ ) (Caution Ａ３ｂ ), C ３ ~C ８ It is a cycloalkyl or a 5-14 member heteroaryl, Each R Ａ３ａ and R Ａ３ｂ H and C are independent of each other. １ ~C １０ Alkyl, C １ ~C ６ Haloalkyl, or C ３ ~C ８ It is a cycloalkyl, Each R Ａ４ Independently, C １ ~C ６ Alkoxy, C １ ~C ６ Hydroxyalkyl, C ２ ~C ６ Alkoxyalkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, C １ ~C ６ Haloalkylthio, C ３ ~C ８ Cycloalkyl, -(C １ ~C ６ (Alkyl)-(C ６ ~C １０ aryl), halo, -CN, -OH, or -N(R Ａ４ａ ) (Caution Ａ４ｂ ) and Each R Ａ４ａ and R Ａ４ｂ H or C １ ~C ６ It is alkyl, Alternatively, two R's Ａ２ They combine to form R Ａ On the two adjacent atoms above, C ３ ~C １０ Cycloalkyl, C ６ ~C １０ It can form aryls, 3-10 membered heterocyclines, or 5-14 membered heteroaryls. R Ｂ H is, L Ｃ is, combined or 【Chemical 867】 And, Y is either C or Si. n is 0, 1, 2, or 3. q is 0, 1, 2, or 3. R Ｙ１ is H or C １ ~C ３ It is alkyl, R Ｙ２ is H or C １ ~C ３ It is alkyl, Alternatively, R Ｙ１ and R Ｙ２ They combine to form C ３ ~C １０ Forming a cycloalkyl or 3-10 membered heterocycline, R Ｃ H, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Hydroxyalkyl, C ２ ~C ６ Alkoxyalkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, -NH ２ , - NHR Ｃ１ , -N(R Ｃ１ ) ２ , C ３ ~C ８ Cycloalkyl, 3-14 member heterocyclyl, C ６ ~C １４ It is an aryl or a 5- to 14-membered heteroaryl, and each C ３ ~C ８ Cycloalkyl, 3-14 member heterocyclyl, C ６ ~C １４ Aryls and 3- to 14-membered heteroaryls have 0, 1, 2, 3, or 4 R Ｃ３ It has been replaced with, Each R Ｃ１ Independently, C １ ~C ６ Selected from alkyl groups, Each R Ｃ３ Independently, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ８ Alkinyl, C １ ~C ６ Alkoxyalkyl, C １ ~C ６ Hydroxyalkyl, halo, C １ ~C ６ Haloalkyl, C １ ~C ６ Heteroalkyl, -(C １ ~C ６ Alkyl)-N(R Ｃ３ａ ) (Caution Ｃ３ｂ ), -CN, -C(O)R Ｃ３ａ , -C(O)OR Ｃ３ａ , -C(O)N(R Ｃ３ａ ) (Caution Ｃ３ｂ ), -N(R Ｃ３ａ )C(O)(R Ｃ３ｂ ), -OC(O)N(R Ｃ３ａ ) (Caution Ｃ３ｂ ), -N(R Ｃ３ａ )C(O)(OR Ｃ３ｂ ), = CH ２ , = CF ２ , oxo, -OR Ｃ３ａ ,-SR Ｃ３ａ , -N(R Ｃ３ａ ) (Caution Ｃ３ｂ ), -N ３ SF ５ , C ３ ~C ８ Cycloalkyl, -(C １ ~C ６ (Alkyl)-(C ３ ~C ８ Cycloalkyl), 3-10 membered heterocyclyl, -(C １ ~C ６ Alkyl)-(3-10 membered heterocyclyl), C ６ ~C １０ Ariel, - (C １ ~C ６ (Alkyl)-(C ６ ~C １０ aryl), 5-10 member heteroaryl, or -(C １ ~C ６ It is (alkyl)-(5-10 member heteroaryl), Each alkyl group has 0, 1, 2, or 3 -CN, -C(O)OR Ｃ３ａ１ , -C(O)N(R Ｃ３ａ１ ) (Caution Ｃ３ａ２ ), -N(R Ｃ３ａ１ )C(O)(R Ｃ３ａ２ ), -OC(O)N(R Ｃ３ａ１ ) (Caution Ｃ３ａ２ ), - OR Ｃ３ａ１ ,-SR Ｃ３ａ１ , N ３ SF ５ , or 0, 1, 2 or 3 R Ｃ３ａ２ Substituted with 3- to 10-membered heterocyclines, each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl having 0, 1, 2, or 3 halos, -CNs, or Rs Ｃ３ａ２ Each alkenyl is substituted with 0, 1, 2, or 3 halos, and each alkoxyalkyl and alkynyl has 0, 1, 2, or 3 C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, 0 or 1 C １ ~C ６ C substituted with haloalkyl ３ ~C ８ Cycloalkyl, C ６ ~C １０ Substituted with aryl or 5-10 membered heteroaryl compounds, Each R Ｃ３ａ and R Ｃ３ｂ H and C are independent of each other. １ ~C １０ Alkyl, C １ ~C ６ Haloalkyl, C ６ ~C １０ Ariel, C ３ ~C ６ The compounds are cycloalkyl, 3-6 membered heterocyclyl, or 5-10 membered heteroaryl, where each aryl and heteroaryl has 0, 1, 2, or 3 halos, -CNs, or Rs. Ｃ３ａ２ It has been replaced with, Alternatively, R Ｃ３ａ and R Ｃ３ｂ These, together with the N atoms to which they are bonded, form a 3- to 8-membered heterocycle. Each R Ｃ３ａ１ and R Ｃ３ａ２ Independently, C １ ~C ３ Alkyl, Halo, C １ ~C ６ Haloalkyl, C ３ ~C ８ Cycloalkyl, -(C １ ~C ３ (Alkyl)-(C ３ ~C ８ Cycloalkyl), 3-10 membered heterocyclyl, -(C １ ~C ３ Alkyl)-(3-10 membered heterocyclyl), C ６ ~C １０ Ariel, - (C １ ~C ３ (Alkyl)-(C ６ ~C １０ Aryl), - (C ２ ~C ４ Alkinyl)-(C) ６ ~C １０ aryl), 5-10 member heteroaryl, -(C １ ~C ３ Alkyl)-(5-10 member heteroaryl), or SF ５ Each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, alkynyl-aryl, heteroaryl, and alkyl-heteroaryl contains 0, 1, 2, or 3 halos, C １ ~C ３ Haloalkyl, C １ ~C ３ Haloalkoxy, or SF ５ It has been replaced with, Alternatively, R Ｃ３ａ１ and R Ｃ３ａ２ These, together with the N atoms to which they are bonded, form a 3- to 8-membered heterocycle. R Ｄ It is a halo, Each heterocyclyl has one, two, three, or four heteroatoms selected from N, O, S, and Si. Each heteroaryl is a compound or a pharmaceutically acceptable salt thereof having one, two, three, or four heteroatoms selected from N, O, and S.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is N.

3. R ２ａ and R ２ｂ These are H and C, which are independent of each other. １ ~C ３ Alkyl, halo, or C １ ~C ６ A compound according to claim 1, which is a haloalkyl compound, or a pharmaceutically acceptable salt thereof.

4. L ２ CHR ２ｂ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R2b is H or C1-C3 alkyl.

5. Structure of equation (IIb-2): 【Chemical 876】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the above.

6. R Ａ This is 0, 1, 2, 3, 4 or 5 R Ａ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein naphthyl is substituted with .

7. Each R Ａ２ Independently, C １ ~C ６ Alkyl, -OH, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinil, Halo, C １ ~C ６ Haloalkyl, -OR Ａ２ａ ,-SR Ａ２ａ , or -(C １ ~C ６ (Alkyl)-(C ３ ~C ８ ) and each alkenyl has 0, 1, 2, or 3 R Ａ３ It has been replaced with, Each R Ａ２ａ Independently, C １ ~C ６ Haloalkyl, or C ３ ~C ８ It is a cycloalkyl, Each R Ａ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, is independently a halo.

8. L Ｃ teeth, 【Chemical 885】 And, Y is either C or Si. n is either 0 or 1, q is either 0 or 1, R Ｙ１ is H or Me, R Ｙ２ is H or Me, Alternatively, R Ｙ１ and R Ｙ２ The compounds according to claim 1, or pharmaceutically acceptable salts thereof, which combine to form a cyclopropyl group.

9. R Ｃ This is 0, 1, 2, or 3 R Ｃ３ It is a 3- to 14-membered heterocycline that is substituted with Each R Ｃ３ Independently, C １ ~C ６ Alkyl, Halo, C １ ~C ６ Haloalkyl, =CH ２ , -OR Ｃ３ａ , or -(C １ ~C ６ Alkyl)-(5-10 member heteroaryl), where each alkyl is 1-OC(O)N(R Ｃ３ａ１ ) (Caution Ｃ３ａ２ ), - OR Ｃ３ａ１ , or N ３ It has been replaced with, Each R Ｃ３ａ Independently, C １ ~C ６ It is a haloalkyl, Each R Ｃ３ａ１ and R Ｃ３ａ２ Independently, C １ ~C ３ Alkyl, C １ ~C ６ Haloalkyl, C ６ ~C １０ The aryl or 5- to 10-membered heteroaryl is a compound containing 0, 1, 2, 3, or 4 halos, C １ ~C ３ Haloalkyl, C １ ~C ３ Haloalkoxy, or SF ５ It has been replaced with, Alternatively, R Ｃ３ａ１ and R Ｃ３ａ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the nitrogen atoms to which they are bonded together form a 3- to 8-membered heterocycle.

10. L Ｃ is, -CH ２ - The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. R Ｃ is 0, 1, or 2 R Ｃ３ It is a 3- to 7-membered heterocycline that is substituted with Each R Ｃ３ These are independently, halo, or C １ ~C ６ A compound according to claim 1, which is a haloalkyl compound, or a pharmaceutically acceptable salt thereof.

12. R Ｄ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein F is F.

13. X is N, CH, or C-Cl, L ２ is CH ２ , CHCH ３ , CHCH ２ CH ３ , CHCHF ２ or 【Chemical Formula 896】 And, R Ａ teeth, 【Chemical 897】 And, The aforementioned -OL-L Ｃ -R Ｃ The part is, 【Chemical 898】 【Chemical 899】 【Chemical 900】 And, R Ｄ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein F is F.

14. R Ａ teeth, 【Chemical 901】 The compound according to claim 13, or a pharmaceutically acceptable salt thereof.

15. Structure: 【Chemical 907】 【Chemical 908】 【Chem.909】 【Chemical 910】 【Chemical 911】 【Chemical 912】 【Chemical 913】 【Chemical 914】 【Chemical Formula 915】 【Chemical Formula 916】 【Chemical 917】 【Chemical Formula 918】 【Chemical Formula 919】 【Chemical Formula 920】 【Chemical 921】 【Chemical 922】 【Chemical 923】 【Chemical 924】 【Chemical 925】 【Chemical 926】 【Chemical Formula 927】 【Chemical Formula 928】 【Chemical 929】 【Chemical 930】 【Chemical 931】 【Chemical 932】 【Chemical 933】 【Chemical 934】 【Chemical 935】 【Chemical 936】 【Chemical 937】 【Chemical Formula 938】 【Chemical 939】 【Chemical 940】 【Chemical 941】 【Chemical 942】 【Chemical 943】 【Chemistry 944】 【Chemical 945】 【Chemical 946】 【Chemical 947】 【Chemical Formula 948】 【Chemical 949】 【Chemical 950】 【Chemical 951】 【Chemical 952】 【Chemical 953】 【Chemical 954】 【Chemical 955】 A compound having, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 and a pharmaceutically acceptable excipient.

17. A composition for treating cancer in a subject requiring treatment, comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

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