Pyrimidine-containing polycyclic derivatives as KRAS G12D regulatory compounds

Abstract

To provide compounds, pharmaceutical compositions, and methods for inhibiting KRAS (e.g., KRAS G12C and / or KRAS G12D) and treating related cancers. [Solution] This specification provides compounds useful as KRAS G12D and / or KRAS G12C inhibitors and pharmaceutically acceptable salts thereof, methods for producing and using them (alone or in combination with additional agents), and pharmaceutical compositions thereof. In another embodiment, the Disclosure provides a method for treating cancer in a subject that needs to be treated for cancer, comprising administering a therapeutically effective amount of a compound of the Disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure to the subject.

Description

[Technical Field]

[0001] Cross-reference of related applications This application asserts the interests under Section 119(e) of U.S. Patent Provisional Application No. 63 / 581,551 filed on 8 September 2023, U.S. Patent Provisional Application No. 63 / 562,155 filed on 6 March 2024, and U.S. Patent Provisional Application No. 63 / 640,100 filed on 29 April 2024, each of which, for all purposes, is incorporated herein by reference in its entirety. [Background technology]

[0002] The KRAS protein, a Kirsten rat sarcoma 2 virus 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, bile duct cancer, small cell lung cancer, and non-small cell lung cancer (NSCLC). Therefore, there is a need for compounds, pharmaceutical compositions, and methods to inhibit KRAS (e.g., KRAS G12C and / or KRAS G12D) and treat related cancers. [Overview of the Initiative]

[0003] In one embodiment, this disclosure relates to formula J: [ka] A compound thereof, or a pharmaceutically acceptable salt thereof, During the ceremony, X is N, CH, or CR x And, R x C 1~3 Alkyl, C 2~4 Alkenil, C 1~3 Alkoxy, C 1~3 Thioalkyl, -CN, (CH2) m CN, Hello, C1~3 haloalkyl, or C 3~6 cycloalkyl, 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, CR 1a R 1b , C(=CR 1c R 1d ), C(=O), or -C(R 1e )=, R 1a and R 1b are each independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -OH, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl, alternatively, R 1a and R 1b in combination with the atoms to which they are attached can form C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl having one heteroatom which is O, and each cycloalkyl and heterocyclyl is substituted with 0, 1, 2, or 3 R 1x , R 1c and R 1d are each independently H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl, alternatively, R 1c and R 1d in combination with the atoms to which they are attached can form C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl having one heteroatom which is O, and each cycloalkyl and heterocyclyl is substituted with 0, 1, 2, or 3 R 1x , R 1eThese are H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Each R 1x These are independently C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -OH. L 2 O, S, CR do not exist. 2a R 2b , C(=CR 2c R 2d ), C(=O), or =C(R 2e )- and therefore, L 2 If O or S, L 1 CR 1a R 1b And, R 2a and R 2b Each of these is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -OH, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 2a and R 2b These can combine with the atoms to which they are bonded to form C3-C6 cycloalkyl groups. Alternatively, R 1b and R 2b These combine with the atoms to which they are bonded to form C3-C6 cycloalkyl, 4-10 member heterocyclyl, and C6-C 10 They can form aryls or 5-14 member heteroaryls, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl has 0, 1, 2, or 3 R 2x It has been replaced with, R 2c and R 2d Each of these is independently H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 2c and R 2dThese can combine with the atoms to which they are bonded to form a C3-C6 cycloalkyl or a 3-6 membered heterocycline having one heteroatom which is O, and each cycloalkyl and heterocycline may have 0, 1, 2, or 3 R 2x It has been replaced with, R 2e These are H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 1e and R 2e These combine with the atoms to which they are bonded to form C5-C6 cycloalkyl, 5-10 member heterocyclyl, and C6-C 10 They can form aryls or 5-14 member heteroaryls, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl has 0, 1, 2, or 3 R 2x It has been replaced with, Each R 2x These are independently C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -OH. Or, L 1 and L 2 They combine, [ka] It can form L 3 It does not exist, CR 3a R 3b , C(=CR 3c R 3d ), C(=O), or =C(R 3e )- and, R 3a and R 3b Each of these is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -OH, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 3a and R 3b, in combination with the atoms to which they are bonded, can form C3~C6 cycloalkyl, alternatively, R 2b and R 3b , in combination with the atoms to which they are bonded, can form C3~C6 cycloalkyl, R 3c and R 3d are each independently H, C1~C3 alkyl, halo, C1~C6 haloalkyl, -CN, C1~C3 cyanoalkyl, or C3~C6 cycloalkyl, alternatively, R 3c and R 3d , in combination with the atoms to which they are bonded, can form C3~C6 cycloalkyl, or 3~6-membered heterocyclyl having one O heteroatom, and each cycloalkyl and heterocyclyl is substituted with 0, 1, 2, or 3 R 3x , each R 3x is independently C1~C3 alkyl, C1~C3 alkoxy, halo, C1~C6 haloalkyl, C1~C6 haloalkoxy, or -OH, R 3e is H, C1~C3 alkyl, halo, C1~C6 haloalkyl, -CN, C1~C3 cyanoalkyl, or C3~C6 cycloalkyl, alternatively, R 2e and R 3e , in combination with the atoms to which they are bonded, can form C5~C6 cycloalkyl, 5~10-membered heterocyclyl, C6~C 10 aryl, or 5~14-membered heteroaryl, L 4 is absent, CR 4a R 4b , C(=CR 4c R 4d ), C(=O), or =C(R 4e )-, R 4a and R 4beach is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -OH, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl, or, R 4a and R 4b combined with the atoms to which they are bonded, can form C3-C6 cycloalkyl, or, R 3b and R 4b combined with the atoms to which they are bonded, can form C3-C6 cycloalkyl, R 4c and R 4d each is independently H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl, or, R 4c and R 4d combined with the atoms to which they are bonded, can form C3-C6 cycloalkyl or 3-6 membered heterocyclyl having one heteroatom which is O, each cycloalkyl and heterocyclyl is substituted with 0, 1, 2, or 3 R 4x , each R 4x is independently C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -OH, R 4e is H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl, or, R 3e and R 4e combined with the atoms to which they are bonded, can form C5-C6 cycloalkyl, whereby, when L 2 is =C(R 2e )-, then L 1 is -C(R 1e )=, or L 3 is =C(R 3e )-, and L3 ga = C(R 3e )- If L 2 is =C(R 2e )- or L 4 is =C(R 4e )- and, R A R is phenyl, naphthyl, or a 5-14 member heteroaryl, A This is 0, 1, 2, 3, 4, or 5 R A2 It has been replaced with, Each R A2 These are independently -OH, C1~C 10 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C 10 Alkoxy, C1-C 10 Hydroxyalkyl, C2-C 10 Alkoxyalkyl, C1-C6 alkyl-N(R A2a )(R A2b ), C1~C 10 Thioalkyl, 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 member heterocyclyl, -(C1-C6 alkyl)-(3-14 member heterocyclyl), C6-C 14Aryl, -(C1~C6 alkyl)-(C6~C 14 The alkyl group is a 5-14 member heteroaryl group, or a -(C1-C6 alkyl)-(5-14 member heteroaryl group), and each alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, and haloalkyl group has 0, 1, 2, or 3 R groups. A3 Each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl has 0, 1, 2, or 3 R A4 It has been replaced with, Each R A2a and R A2b These are H, C1~C independently. 10 It is an alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl, Each R A3 These are independently: Haro, -CN, -OR A3a , -SR A3a , -N(R A3a )(R A3b ), C3-C8 cycloalkyl, or 5-14 member heteroaryl, Each R A3a and R A3b These are H, C1~C independently. 10 It is an alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl, Each R A4 These 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 These are independently H or C1-C6 alkyl groups. Alternatively, two R A2 These combine to form R A On the two adjacent atoms above, C3~C10 Cycloalkyl, C6~C 10 They can form aryls, 3-10 membered heterocyclines, or 5-14 membered heteroaryls, and each cycloalkyl, aryl, heterocycline, and heteroaryl has 0, 1, 2, or 3 R A5 It has been replaced with, Each R A5 These are, independently, C1~C 10 Alkyl, C2~C 10 Alkenyl, C2~C 10 Alkynyl, halo, C1-C6 haloalkyl, -CN, or C3-C8 cycloalkyl, R B is H or R B1 And, R B If H, then at least one R A2 is -OR A2x And, R B1 and R A2x Each of them operates independently. [ka] And, W and V are independent of each other, NR B2 , O, or S, Each R B2 These are, independently, C1~C 12 Alkyl, C1-C6 alkoxy, C2-C6 alkoxyalkyl, C1-C6 alkyl-N(R) B2a )(R B2b ), C1~C 10 Thioalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, C6-C 14 It is an aryl or 5-14 member heteroaryl, C3-C8 cycloalkyl, C6-C 14 Aryls, or 5- to 14-membered heteroaryls, have 0, 1, 2, or 3 R B2c It has been replaced with, Each R B2a and R B2b These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl. Each R B2c These 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 a cycloalkyl, L C is, combined or [ka] 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 C1-C3 alkyl, R Y2 is H or C1-C3 alkyl, Alternatively, R Y1 and R Y2 These combine to form C3~C 10 Forming cycloalkyl or 3-10 membered heterocyclines, R C These are 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 member heterocyclyl, C6-C 14 Aryl or 5-14 member heteroaryl, each consisting of a C3-C8 cycloalkyl, a 3-14 member heterocyclyl, and a C6-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 These are independently selected from C1-C6 alkyl groups. Each R C3These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C8 alkynyl, C1-C6 alkoxyalkyl, C1-C6 hydroxyalkyl, halo, C1-C6 haloalkyl, C1-C6 heteroalkyl, and -(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, =CHF, =CF2, oxo, -OR C3a , -SR C3a , -N(R C3a )(R C3b ), -N3, SF5, C3~C8 cycloalkyl, -(C1~C6 alkyl)-(C3~C8 cycloalkyl), 3~10 member heterocyclyl, -(C1~C6 alkyl)-(3~10 member heterocyclyl), C6~C 10 Aryl, -(C1~C6 alkyl)-(C6~C 10 The alkyl group is a 5-10 member heteroaryl group, or a -(C1-C6(alkyl)-(5-10 member heteroaryl group), where each alkyl group has 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 Substituted with 3-10 membered heterocyclines, each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl having 0, 1, 2, or 3 halos, -CN, or RC3a2 Each alkenyl is substituted with 0, 1, 2, or 3 halos, and each alkoxyalkyl and alkynyl is substituted with 0, 1, 2, or 3 C1-C6 alkyl, C1-C6 haloalkyl, 0 or 1 C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 10 Substituted with aryl or 5-10 membered heteroaryl compounds, Each R C3a and R C3b These are H, C1~C independently. 10 Alkyl, C1-C6 haloalkyl, C6-C 10 The compounds are aryls, C3-C6 cycloalkyls, 3-6 membered heterocyclines, or 5-10 membered heteroaryls, each aryl and heteroaryl having 0, 1, 2, or 3 halos, -CN, or R groups. 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 These are independently C1-C3 alkyl, halo, C1-C6 haloalkyl, C3-C8 cycloalkyl, -(C1-C3 alkyl)-(C3-C8 cycloalkyl), 3-10 member heterocyclyl, -(C1-C3 alkyl)-(3-10 member heterocyclyl), C6-C 10 Aryl, -(C1~C3 alkyl)-(C6~C 10 Aryl), -(C2~C4 alkynyl)-(C6~C 10 The aryl group is a 5-10 member heteroaryl group, a -(C1-C3 alkyl)-(5-10 member heteroaryl group), or SF5 group, and each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, alkynyl-aryl, heteroaryl, and alkyl-heteroaryl group is substituted with 0, 1, 2, or 3 halos, C1-C3 haloalkyl, C1-C3 haloalkoxy, or SF5 group. Alternatively, R C3a1 and R C3a2These, 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 1, 2, 3, or 4 heteroatoms selected from N, O, S, and Si. Each heteroaryl provides a compound of formula J, or a pharmaceutically acceptable salt thereof, having one, two, three, or four heteroatoms selected from N, O, and S.

[0004] In another embodiment, the Disclosure provides a pharmaceutical composition comprising the compounds of the Disclosure and pharmaceutically acceptable excipients.

[0005] In another embodiment, the Disclosure provides a method for inhibiting the KRAS G12D protein in a subject requiring inhibition of the KRAS G12D protein, comprising administering a therapeutically effective amount of the compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to the subject.

[0006] In another embodiment, the Disclosure provides a method for treating cancer in a subject requiring treatment, comprising administering a therapeutically effective amount of a compound of the Disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure to the subject.

[0007] In another embodiment, the Disclosure provides a method for producing a pharmaceutical product for treating cancer in a subject requiring treatment of cancer, characterized by the use of a compound of the Disclosure or a pharmaceutically acceptable salt thereof.

[0008] In another embodiment, the present disclosure provides a method for producing a pharmaceutical product for inhibiting cancer metastasis in a subject where it is necessary to inhibit cancer metastasis, characterized by using the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0009] In another embodiment, the Disclosure provides the use of the compounds of the Disclosure, or pharmaceutically acceptable salts thereof, for the manufacture of a pharmaceutical product for the treatment of cancer in a subject.

[0010] In another embodiment, the disclosure provides the use of the compounds of the disclosure, or pharmaceutically acceptable salts thereof, for the manufacture of pharmaceuticals for inhibiting cancer metastasis in a subject.

[0011] In another embodiment, the Disclosure provides compounds of the Disclosure, or pharmaceutically acceptable salts thereof, for use in the treatment of cancer in subjects requiring cancer treatment.

[0012] In another embodiment, the Disclosure provides compounds of the Disclosure, or pharmaceutically acceptable salts thereof, for use in inhibiting cancer metastasis in subjects requiring inhibition of cancer metastasis.

[0013] In another embodiment, the Disclosure provides compounds of the Disclosure, or pharmaceutically acceptable salts thereof, for use in therapeutics.

[0014] Furthermore, this specification discloses compounds of subformulas of formula J, such as (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), as well as pharmaceutically acceptable salts thereof. [Modes for carrying out the invention]

[0015] I. Overview This disclosure, in general, is KRAS G12D and / or KRAS G12C This invention relates to methods and compounds for inhibiting [a specific condition], and pharmaceutically acceptable salts thereof. The following description specifies exemplary methods, parameters, etc. However, such descriptions should be understood not as limiting the scope of this disclosure, but rather as descriptions of exemplary embodiments.

[0016] II. Definition When 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.

[0017] A dash ("-") without a space between two letters or symbols is used to indicate bonding points for substituents. For example, -CONH2 is bonded via a carbon atom. Dashes before or after chemical groups are for convenience only, and chemical groups may be shown with or without one or more dashes without losing their usual meaning. A wavy line drawn across a line in a structure indicates bonding points of a group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply direction.

[0018] For example, a squiggly line on a chemical group as shown below, for example [ka] This indicates a bond point, that is, it indicates a cleaved bond in which one group is bonded to another described group.

[0019] As used herein, “compounds of the disclosure” may mean any compound of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), and (IIb-2), or any pharmaceutically acceptable salt thereof. Similarly, the phrase “compound of formula (number)” means a compound of the formula and any pharmaceutically acceptable salt thereof.

[0020] "C u~ C v The prefix "C1-C8 alkyl" indicates that the group has u-v carbon atoms. For example, "C1-C8 alkyl" indicates that the alkyl group has 1-8 carbon atoms.

[0021] "Alkyl" refers to a non-branched or branched saturated hydrocarbon chain. For example, an alkyl group consists of 1 to 20 carbon atoms (i.e., C1 to C2). 20The alkyl group may have 1 to 8 carbon atoms (i.e., C1 to C8 alkyl), 1 to 6 carbon atoms (i.e., C1 to C6 alkyl), or 1 to 3 carbon atoms (i.e., C1 to C3 alkyl). Examples of suitable alkyl groups, but not limited to, include 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), and 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(-CH2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 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 Examples of alkyl groups include -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.

[0022] "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 a chain containing 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 It may contain alkenyls. Alkenyls are 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 It may contain any number of carbon atoms, or any intermediate range. The alkenyl group may have any preferred number of double bonds, including, but not limited to, one, two, three, four, five, or more. Examples of alkenyl groups include, but 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-hexadienyl.

[0023] "Alkynyl" refers to an unbranched or branched hydrocarbon chain containing at least one carbon-carbon triple bond. For example, an alkynyl group contains 2 to 20 carbon atoms (i.e., C 2~20 Alkynyl), 2 to 8 carbon atoms (i.e., C 2~8 Alkynyl), 2-6 carbon atoms (i.e., C 2~6 Alkynyl) or 2 to 4 carbon atoms (i.e., C 2~4It may have an alkynyl group. The term "alkynyl" also includes an alkynyl group having one triple bond and one double bond. 2~6 Examples of alkynyls include, but are not limited to, ethinyl, propa-1-inyl, buta-1-inyl, penta-1-inyl, penta-4-inyl, and penta-1,4-diinyl.

[0024] "Alkoxy" refers to a group having the formula -O-alkyl, in which the alkyl group defined above is bonded to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group consists of 1 to 20 carbon atoms (i.e., C1 to C20). 20 Alkyl(alkoxy), 1 to 12 carbon atoms (i.e., C1 to C) 12 The alkoxy group may have alkoxy, 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), etc. Other examples of suitable alkoxy groups include, but are not limited to, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc.

[0025] "Alkoxyalkyl" refers to an alkoxy group linked to an alkoxy group that is linked to the remainder of the compound. Alkoxyalkyls have 2 to 6 (C) groups. 2~6 Alkoxyalkyl), 2-5 (C 2~5 Alkoxyalkyl), 2-4 (C 2~4 Alkoxyalkyl groups), or 2-3 (C 2~3 It may have any preferred number of carbon atoms, such as alkoxyalkyls. Alkoxy and alkyl are defined above. Examples of "alkoxyalkyls," but are not limited to, methoxymethyl (CH3OCH2-) and methoxyethyl (CH3OCH2CH2).

[0026] "Bridged" refers to a ring system in which non-adjacent atoms on the ring are bonded by divalent substituents such as alkylenyl or heteroalkylenyl groups, or single heteroatoms.

[0027] "Hydroxyalkyl" refers to a hydroxyl group (-OH) attached to an alkyl group that is linked to the remainder of a compound so that the alkyl group is divalent. Hydroxyalkyls consist of 1 to 8 (C) groups. 1~8 Hydroxyalkyl), 1-6 (C 1~6 Hydroxyalkyl), 2-6 (C 2~6 Hydroxyalkyl), 2-4 (C 2~4 Hydroxyalkyl), or 2-3 (C 2~3 It may have any preferred number of carbon atoms, such as hydroxyalkyl groups. The alkyl group is as defined above, and in this case the alkyl group is divalent.

[0028] As used herein, "halo" or "halogen" refers to fluoro(-F), chloro(-Cl), bromo(-Br), and iodine(-I).

[0029] A "haloalkyl" is an alkyl group defined above in which one or more hydrogen atoms of the alkyl group are replaced by halogen atoms. The alkyl portion of a haloalkyl group consists of 1 to 20 carbon atoms (i.e., C1 to C2). 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, but not limited to, include -CF3, -CHF2, -CFH2, -CH2CF3, fluorochloromethyl, difluorochloromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0030] A "haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced by halogen atoms. Regarding alkyl groups, haloalkoxy groups are C 1-6 It may have any suitable number of carbon atoms. The alkoxy group can be substituted with 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 oversubstituted, for example, perfluorinated. Examples of haloalkoxys include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and perfluoroethoxy.

[0031] "Thioalkyl" refers to a thio group (-SH) attached to an alkyl group that is linked to the remainder of a compound so that the alkyl group is divalent. Thioalkyls consist of 1 to 8 (C) groups. 1~8 Thioalkyl), 1-6 pieces (C 1~6 Thioalkyl), 2-6 (C 2~6 Thioalkyl), 2-4 (C 2~4 Thioalkyl), or 2-3 (C 2~3 It may have any preferred number of carbon atoms, such as thioalkyl groups. The alkyl group is as defined above, and in this case, the alkyl group is divalent.

[0032] A "haloalkylthio" is an alkylthio group as defined above, in which one or more hydrogen atoms of an alkyl group are replaced by halogen atoms. The alkyl portion of a haloalkylthio group consists of 1 to 20 carbon atoms (i.e., C1 to C2). 20 Haloalkylthio), 1 to 12 carbon atoms (i.e., C1 to C) 12 The alkylthio group may have a haloalkylthio, 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.

[0033] "Heteroalkyl" refers to a non-branched or branched saturated hydrocarbon chain containing 1 to 4 heteroatoms.

[0034] "Cyanoalkyl" refers to a compound in which a cyano group (-CN) is attached to an alkyl group that is linked to the remainder of the compound so that the alkyl group is divalent. A cyanoalkyl compound can have 1 to 8 (C) groups. 1~8 Cyanoalkyl), 1-6 pieces (C 1~6 Cyanoalkyl), 2-6 pieces (C 2~6 Cyanoalkyl), 2-4 pieces (C 2~4 Cyanoalkyl, or 2-3 (C 2~3 It may have any preferred number of carbon atoms, such as cyanoalkyl groups. The alkyl group is as defined above, and in this case the alkyl group is divalent.

[0035] "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group having a monocycle or a polycycle of 2, 3, 4 or more atoms, where the polycycle may be condensed, crosslinked, spiro, or any combination thereof. As used herein, cycloalkyl refers to a ring of 3 to 20 carbon atoms (i.e., C 3-20 Cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 Cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 Cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 Cycloalkyl, or a ring of 3-6 carbon atoms (i.e., C 3-6 It contains cycloalkyl groups. 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 fused ring systems having one aromatic ring and one non-aromatic ring, but not being entirely aromatic.

[0036] The term "condensation" refers to a ring system in which two or more rings share a pair of adjacent ring atoms.

[0037] "Spiro" refers to a ring substituent where at least two rings are linked together by a common atom. "Spiro" also refers to a ring substituent linked by two bonds at the same carbon atom. Examples of spiro groups include, but are not limited to, 1,1-diethylcyclopentane, dimethyl dioxolane, and 4-benzyl-4-methylpiperidine, where cyclopentane and piperidine are spiro substituents, respectively.

[0038] "Alkyl-cycloalkyl" refers to a radical having an alkyl component and a cycloalkyl component, where the alkyl component is linked to the cycloalkyl component at its bonding site. The alkyl component is as defined above, except that it is at least a divalent alkylene in order to link with the cycloalkyl component and the bonding site. In some cases, the alkyl component may not be present. The alkyl component is 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 It may contain any number of carbon atoms, such as the cycloalkyl components as defined herein. Examples of alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, and methyl-cyclohexyl.

[0039] "Heterocyclic," "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 monocyclic or polycyclic, such as two, three, four or more rings, and the polycyclics may be condensed, cross-linked, spiro, or any combination thereof. As used herein, a heterocyclyl has 3 to 20 ring atoms (i.e., a 3 to 20-membered heterocyclyl), 3 to 12 ring atoms (i.e., a 3 to 12-membered heterocyclyl), 3 to 10 ring atoms (i.e., a 3 to 10-membered heterocyclyl), 3 to 8 ring atoms (i.e., a 3 to 8-membered heterocyclyl), 4 to 12 ring carbon atoms (i.e., a 4 to 12-membered heterocyclyl), 4 to 8 ring atoms (i.e., a 4 to 8-membered heterocyclyl), or 4 to 6 ring atoms (i.e., a 4 to 6-membered heterocyclyl). Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanil, azetidinyl, and morpholinil.

[0040] "Alkyl-heterocycloalkyl" refers to a radical having an alkyl component and a heterocycloalkyl component, where the alkyl component is linked to the heterocycloalkyl component at the bonding site. The alkyl component is as defined above, except that it is at least a divalent alkylene in order to link with the heterocycloalkyl component and the bonding site. The alkyl component is 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 It may contain any number of carbon atoms, such as those listed above. In some cases, alkyl components may be omitted. Heterocycloalkyl components are as defined above.

[0041] The term "aryl" refers to an aromatic hydrocarbon radical derived by the removal of a single hydrogen atom from a single carbon atom in an aromatic ring system. For example, an aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Exemplary aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), naphthalene, anthracene, and biphenyl.

[0042] "Alkyl-aryl" refers to a radical having an alkyl component and an aryl component, where the alkyl component is linked to the aryl component at the bonding site. The alkyl component is as defined above, except that it is at least a divalent alkylene in order for the alkyl component to link to the aryl component and the bonding site. The alkyl component is 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 It may contain any number of carbon atoms, such as those listed above. In some cases, the alkyl component may be omitted. The aryl component is as defined above. Examples of alkyl-aryl groups include, but are not limited to, benzyl and ethylbenzene.

[0043] "Heteroaryl" refers to an aromatic group comprising an aromatic tautomer or resonance structure having a monocyclic, polycyclic, or multiple fused rings having at least one heteroatom in the ring, i.e., one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the nitrogen or sulfur may be oxidized. Therefore, this term includes rings having one or more cyclic O, N, S, S(O), S(O)2, and N-oxide groups. This term also includes rings having one or more cyclic C(O) groups. As used herein, heteroaryl includes 5 to 20 ring atoms (i.e., 5 to 20-membered heteroaryls), 5 to 12 ring atoms (i.e., 5 to 12-membered heteroaryls), or 5 to 10 ring atoms (i.e., 5 to 10-membered heteroaryls), as well as 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and oxidized forms of the heteroatoms. Examples of heteroaryl groups include, but are not limited to, pyridine-2(1H)-one, pyridazine-3(2H)-one, pyrimidine-4(3H)-one, quinoline-2(1H)-one, pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryls do not contain or overlap with aryls as defined above.

[0044] "Alkyl-heteroaryl" refers to a radical having an alkyl component and a heteroaryl component, where the alkyl component is linked to the heteroaryl component at a bonding site. The alkyl component is as defined above, except that it is at least a divalent alkylene in order to link with the heteroaryl component and the bonding site. The alkyl component is 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 5~6It may contain any number of carbon atoms, such as those listed above. In some cases, alkyl components may be omitted. Heteroaryl components are as defined herein.

[0045] "KRAS G12D" refers to the G12D mutation in the KRAS protein, in which aspartic acid replaces glycine at amino acid position 12.

[0046] "KRAS G12D inhibitor" refers to the compounds of this disclosure, including compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), and (IIb-2). These compounds modulate or inhibit some or all of the activity of KRAS G12D.

[0047] "KRAS G12D-related disease or disorder" refers to a disease or disorder that is associated with, mediated by, or has a KRAS G12D mutation. Representative diseases or disorders include, but are not limited to, KRAS G12D-related cancers.

[0048] "Oxo" refers to an (=O) group or an (O) group.

[0049] pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. "pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, formulations, dosage forms, and other substances useful for preparing pharmaceutical compositions suitable for veterinary or human medicinal use.

[0050] The compounds described herein may be prepared and / or formulated as pharmaceutically acceptable salts, or, where appropriate, as free bases. A pharmaceutically acceptable salt is a non-toxic salt of the free base form of a compound having the desired pharmacological activity of the free base. These salts may be derived from inorganic or organic acids or inorganic or organic bases. For example, a compound containing basic nitrogen may be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monophosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, capronates, heptanoates, propioates, oxalates, malons, succinates, suberates, sebacinates, fumarates, maleates, butin-1,4-diates, and hexine. Examples include -1,6-diates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besilates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, and mandelates. A list of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21. st It can be found in Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0051] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and NX4 +Salts derived from appropriate bases such as (X is a C1-C4 alkyl group) are also examples. Base addition salts such as sodium salts or potassium salts are also examples.

[0052] Compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, are also provided, in which 1 to n hydrogen atoms bonded to a carbon atom can 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 may therefore be useful in increasing the half-life of the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to mammals. For example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," T rends P harmacol .S CI. See 5(12):524-527(1984). Such compounds are synthesized by means known in the art, for example, by using starting materials in which one or more hydrogen atoms are replaced by deuterium.

[0053] Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, respectively. 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 1N may be useful in positron emission tomography (PET) studies to investigate substrate receptor occupancy. Isotope-labeled compounds of formulas J, (I), (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), and (IIb-2) can generally be prepared by conventional techniques known to those skilled in the art, using appropriate isotope-labeling reagents instead of previously used unlabeled reagents, or by processes similar to those described in the examples below.

[0054] Compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more chiral centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- with respect to absolute stereochemistry, or as (D)- or (L)- with respect to amino acids. This disclosure includes all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or separated using conventional techniques, e.g., chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or racemic compounds (or salts) using, for example, chiral high-pressure liquid chromatography (HPLC). This includes the decomposition of (racemic compounds of derivatives). When the compounds described herein contain an olefinic double bond or other geometrically asymmetric center, and unless otherwise specified, these compounds are intended to include both E and Z geometric isomers. Similarly, all tautomer forms are also intended to be included. When a compound is represented in its chiral form, it is understood that embodiments include, but are not limited to, specific diastereolytic or enantiomerically enriched forms. When chirality is not specified but present, it is understood that embodiments cover either specific diastereolytic or enantiomerically enriched forms, or racemic or scaremic mixtures of such compounds. As used herein, “scaremic mixture” is a mixture of stereoisomers in a ratio other than 1:1.

[0055] A "racemate" refers to a mixture of enantiomers. The mixture may contain equal or unequal amounts of each enantiomer.

[0056] "Stereoisomers" refer to compounds with one or more stereocenters that differ in chirality. Examples of stereoisomers include enantiomers and diastereomers. Compounds can exist in stereoisomeric form if they have one or more chiral centers or double bonds with asymmetric substitutions, and therefore can be produced as individual stereoisomers or mixtures. Unless otherwise specified, the description is intended to include individual stereoisomers and mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art (e.g., advanced organic See Chapter 4 of CHEMISTRY, 4th ed., J. March, John Wiley & Sons, New York, 1992.

[0057] "Subject" or "Patient" means to describe humans or vertebrates including dogs, cats, pocket pets, marmosets, horses, cattle, pigs, sheep, goats, elephants, giraffes, chickens, lions, monkeys, owls, rats, squirrels, slender lorises, and mice. "Pocket pet" refers to a group of vertebrates that can fit into a loose coat pocket, such as hamsters, chinchillas, ferrets, rats, guinea pigs, gerbils, rabbits, and sugar gliders.

[0058] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. Dashes before or after chemical groups are for convenience only, and chemical groups may be shown with or without one or more dashes without losing their usual meaning. Wavy lines drawn across lines in a structure indicate the bonding points of groups. Dashed lines indicate optional bonding. Unless chemically or structurally required, the order in which chemical groups are written or the points to which they are bonded to the rest of the molecule are neither directional nor implied. For example, the group "-SO2CH2-" is equivalent to "-CH2SO2-", and both can be bonded in either direction. Similarly, for example, an "arylalkyl" group can be bonded to the rest of the molecule at either the aryl or alkyl portion of the group. u ~C v " or "(C u ~C v Prefixes such as ")" indicate that the following group has u to v carbon atoms. For example, "C 1~6 Both "alkyl" and "C1-C6 alkyl" indicate that the alkyl group has 1 to 6 carbon atoms.

[0059] Unless otherwise specified, the carbon atoms in the compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), and (IIb-2) are intended to have a tetravalent state. If, in some chemical structural representations, the carbon atom does not have enough variables to produce a valency of 4, it should be assumed that the remaining carbon substituent necessary to provide a valency of 4 is hydrogen.

[0060] "Treatment" or "treating" is an approach to obtain beneficial or desired outcomes, including clinical outcomes. Beneficial or desired clinical outcomes may 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) delaying or preventing the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (e.g., metastasis)); and / or (c) alleviating the disease, i.e., causing regression of clinical symptoms (e.g., improving the disease condition, 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).

[0061] As used herein, the term “therapeutic dose” means the amount of the compounds disclosed herein present in a formulation described herein that is required to deliver to the secretions and airway and lung tissues of the subject being treated, or alternatively, to deliver the desired level of the drug into the bloodstream, in order to produce an expected physiological response or desired biological effect when such formulation is administered via a selected route of administration. The exact amount can be readily determined by a person skilled in the art based on the information provided herein, depending on a number of factors, such as the specific compounds disclosed herein, the specific activity of the formulation, the delivery device used, the physical properties of the formulation, its intended use, and subject-related considerations, including the severity of the disease state and the subject's cooperation. The terms “therapeutic dose” or “effective dose” also mean the amount that eliminates or reduces the viral load and / or viral reservoir of the subject.

[0062] "Administration" refers to oral administration, suppository administration, topical contact, parenteral administration, intravenous administration, intraperitoneal administration, intramuscular administration, intrafocal administration, intranasal administration, or subcutaneous administration, subarachnoid administration, or implantation of a sustained-release device, such as a mini osmotic pump. Administration may be carried out according to a schedule specifying the frequency of administration, dosage, and other factors.

[0063] As used herein, “concurrent administration” means the administration of a unit dose of the compound disclosed herein before or after the administration of a unit dose of one or more additional therapeutic agents, for example, within a few seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents within a few seconds or minutes. Or, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein within a few seconds or minutes. In some embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents several hours later (e.g., 1 to 12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein several hours later (e.g., 1 to 12 hours). The co-administration of the compounds disclosed herein with one or more additional therapeutic agents generally refers to the co-administration or sequential administration of the compounds 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.

[0064] The term "subject" is not limited to animals, but includes mammals such as primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is humans.

[0065] "Disease" or "condition" means a physical condition or health state of a patient or subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein. A disease may be autoimmune, inflammatory, cancerous, infectious (e.g., viral infection), metabolic, developmental, cardiovascular, hepatic, 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).

[0066] "Cancer" refers to all types of cancer, neoplasms, or malignant tumors found in mammals, including leukemia, lymphoma, melanoma, neuroendocrine tumors, carcinomas, and sarcomas. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include lymphoma, sarcoma, bladder cancer, bone cancer, brain tumor, 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, tubular carcinoma, lobular carcinoma, primary, metastatic), and ovarian cancer. Examples include pancreatic cancer, liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, squamous cell lung cancer, adenocarcinoma, large cell lung cancer, small cell lung cancer, carcinoid, sarcoma), glioblastoma multiforme, glioma, melanoma, prostate cancer, castration-resistant prostate cancer, breast cancer, triple-negative breast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.g., head, neck, or esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma.

[0067] Additional examples include cancers of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, esophagus, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovarian, sarcoma, stomach, and uterus, or medulloblastoma, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulinoma, malignant carcinoid, Examples include bladder cancer, pre-malignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenocortical cancer, neoplasms of the endocrine or exocrine parts of the pancreas, medullary thyroid carcinoma, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, Paget's disease of the breast, phyllodes tumor, lobular carcinoma, tubular carcinoma, stellate cell carcinoma of the pancreas, stellate cell carcinoma of the liver, or prostate cancer.

[0068] Leukemia is a broad term referring to progressive malignant diseases of the hematopoietic organs, generally characterized by the abnormal proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemia is generally clinically classified based on (1) the duration and characteristics of the disease: acute or chronic; (2) the types of cells involved: bone marrow (myeloid), lymphocytes (lymphoid), or monocytes; and (3) the increase or absence of abnormal cell counts in the blood: leukemic or aleukemic (subleukemic). Exemplary leukemias that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocythemic leukemia, basophilic leukemia, blastocyte leukemia, and bovine leukemia. disease, chronic myelocytic leukemia, cutaneous leukemia, embryonic cell leukemia, eosinophilic leukemia, gross leukemia, hairy cell leukemia, hematoblastic leukemia, hematoblastic leukemia, histiocytic leukemia disease, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphocytic leukemia Leukemia includes lymphoid leukemia, lymphosarcoma, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemia, or anaplastic cell leukemia.

[0069] "Sarcoma" generally refers to a tumor composed of a substance such as embryonic connective tissue, and generally composed of densely packed cells embedded in a fibrous or homogeneous material. Sarcomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, hydatidiform soft tissue sarcoma, supraamelosarcoma, rhabdomyosarcoma, green sarcoma, choriocarcinoma, embryonic sarcoma, Wilms tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fasciosarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, and idiopathic multiple pigmented hemorrhagic sarcoma. Examples include sarcomas, B-cell immunoblastic sarcomas, lymphomas, T-cell immunoblastic sarcomas, Jensen's sarcoma, Kaposi's sarcoma, Kupffer's astrocytic sarcoma, angiosarcoma, leukemosarcoma, malignant mesenchymal sarcoma, paraosteosarcoma, reticulum sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or telangiectatic sarcoma.

[0070] "Melanoma" is understood to mean a tumor arising from the melanocyte system of the skin and other organs. Examples of melanomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include acral lentiginous melanoma, achromatic melanoma, benign juvenile melanoma, Cloudmann melanoma, S91 melanoma, Harding-Passé melanoma, juvenile melanoma, lentigo malignant melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0071] "Carcinoma" refers to a malignant neoplasm composed of epithelial cells that tend to invade surrounding tissues and metastasize. Examples of carcinomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, lobular carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenoid carcinoma, adrenal cortical carcinoma, alveolar carcinoma, alveolar epithelial carcinoma, basal cell carcinoma, basal cell carcinoma, basal cell carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchogenic lung carcinoma, cerebriform carcinoma, cholangiocarcinoma, choriocarcinoma, mucinous carcinoma, comedone carcinoma, uterine carcinoma, cribriform carcinoma, armory carcinoma, skin carcinoma, cylindrical carcinoma, columnar cell carcinoma, adenoid carcinoma, ductal carcinoma, and sclerotic carcinoma. Durum, embryonic carcinoma, medullary carcinoma, epidermoid carcinoma, adenocarcinoma, exotropic carcinoma, ulcerative carcinoma, fibrous carcinoma, colloidal carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, piloma carcinoma, hematological carcinoma, hepatocellular carcinoma, Haasle cell carcinoma, hyaline carcinoma, adrenal carcinoma, pediatric embryonic carcinoma, carcinoma in situ, carcinoma in epidermis, carcinoma in situ, chromopecher carcinoma, kruticky cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, black carcinoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma Examples include humoral carcinoma, mucocellular carcinoma, mucoepidermoid carcinoma, mucinoma mucosum, mucinous carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, ossoidal carcinoma, papillary carcinoma, periportal carcinoma, pre-invasive carcinoma, squamous cell carcinoma, medullary carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, spongy carcinoma, squamous cell carcinoma, squamous cell carcinoma, string-like carcinoma, telangiectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, nodular carcinoma (carcinoma tuberosum), tubular carcinoma, tubeous carcinoma, verrucous carcinoma, or choriocarcinoma.

[0072] The terms "metastasis," "metastatic," and "metastatic cancer" can be used interchangeably and refer to the spread of a proliferative disorder or disorder, such as cancer, from one organ to another non-adjacent organ or part of the body. Cancer originates in a site of origin, for example, the breast, and that site is called the primary tumor, for example, primary breast cancer. The primary tumor or some cancer cells within the site of origin acquire the ability to invade and spread into the surrounding normal tissue in the local area, and / or to invade the walls of the lymphatic or vascular system and spread through that system to other parts 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. Therefore, if lung cancer metastasizes to the breast, the secondary tumor in the breast site consists of abnormal lung cells, not abnormal breast cells. The secondary tumor in the breast is called metastatic lung cancer. Therefore, the term metastatic cancer refers to a disease in which the subject has a primary tumor, or has had one in the past, 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 the 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 a primary lung tumor, or has a history of one, and has one or more secondary tumors in a second or multiple sites, such as the breast.

[0073] 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., head, neck, or esophagus), colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B-cell lymphoma, or multiple myeloma)), “related” or “related” means that the substance or the activity or function of a substance causes (in whole or in part) a 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) symptoms of a disease.

[0074] As used herein, the term “adjacent carbons” refers to a sequence of carbon atoms that are directly bonded to one another. For example, [ka] Then, C1 and C2 are adjacent carbon atoms, C2 and C3 are adjacent carbon atoms, C3 and C4 are adjacent carbon atoms, and C4 and C5 are adjacent carbon atoms. Similarly, [ka] In this case, C1 and C2 are adjacent carbon atoms, C2 and C3 are adjacent carbon atoms, C3 and C4 are adjacent carbon atoms, C4 and C5 are adjacent carbon atoms, C5 and C6 are adjacent carbon atoms, and C6 and C1 are adjacent carbon atoms.

[0075] As used herein, “solvate” refers to the result of the interaction between a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0076] As used herein, "prodrug" refers to a derivative of a drug that, upon administration to the human body, is converted to the parent drug via several chemical or enzymatic pathways.

[0077] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes, but is not limited to, any solvent, dispersion medium, coating, antimicrobial and antifungal agents, isotonic agents, and absorption retardants, as well as combinations thereof. The use of pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for pharmaceutically active substances is well known in the art. Any conventional medium or agent is intended for use in therapeutic formulations, provided that it is not incompatible with the active ingredient. Supplementary active ingredients may also be incorporated into the formulation. A carrier needs to be “acceptable” in the sense that it is compatible with the other components of the formulation and is physiologically harmless to its recipient.

[0078] III.Compound This specification discloses, in particular, compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), and (IIb-2). In some embodiments, compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), and (IIb-2) are prodrugs.

[0079] In some embodiments, this disclosure relates to formula J: [ka] A compound thereof, or a pharmaceutically acceptable salt thereof, During the ceremony, X is N, CH, or CR x And, R x C 1~3 Alkyl, C 2~4 Alkenil, C 1~3 Alkoxy, C 1~3 Thioalkyl, -CN, (CH2) m CN, Hello, C 1~3 Haloalkyl, or C 3~6It is a cycloalkyl, m is 0, 1, 2, or 3. R 1 , R 2 , R 3 , and R 4 Each of these is independently H or a C1-C3 alkyl group. L 1 O, S, CR 1a R 1b , C(=CR 1c R 1d ), C(=O), or -C(R 1e )= and R 1a and R 1b Each of these is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -OH, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 1a and R 1b These can combine with the atoms to which they are bonded to form a C3-C6 cycloalkyl or a 3-6 membered heterocycline having one heteroatom which is O, and each cycloalkyl and heterocycline may have 0, 1, 2, or 3 R 1x It has been replaced with, R 1c and R 1d Each of these is independently H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 1c and R 1d These can combine with the atoms to which they are bonded to form a C3-C6 cycloalkyl or a 3-6 membered heterocycline having one heteroatom which is O, and each cycloalkyl and heterocycline may have 0, 1, 2, or 3 R 1x It has been replaced with, R 1e These are H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Each R 1xThese are independently C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -OH. L 2 O, S, CR do not exist. 2a R 2b , C(=CR 2c R 2d ), C(=O), or =C(R 2e )- and therefore, L 2 If O or S, L 1 CR 1a R 1b And, R 2a and R 2b Each of these is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -OH, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 2a and R 2b These can combine with the atoms to which they are bonded to form C3-C6 cycloalkyl groups. Alternatively, R 1b and R 2b These combine with the atoms to which they are bonded to form C3-C6 cycloalkyl, 4-10 member heterocyclyl, and C6-C 10 They can form aryls or 5-14 member heteroaryls, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl has 0, 1, 2, or 3 R 2x It has been replaced with, R 2c and R 2d Each of these is independently H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 2c and R 2d These can combine with the atoms to which they are bonded to form a C3-C6 cycloalkyl or a 3-6 membered heterocycline having one heteroatom which is O, and each cycloalkyl and heterocycline may have 0, 1, 2, or 3 R2x It has been replaced with, R 2e These are H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 1e and R 2e These combine with the atoms to which they are bonded to form C5-C6 cycloalkyl, 5-10 member heterocyclyl, and C6-C 10 They can form aryls or 5-14 member heteroaryls, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl has 0, 1, 2, or 3 R 2x It has been replaced with, Each R 2x These are independently C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -OH. Or, L 1 and L 2 They combine, [ka] It can form L 3 It does not exist, CR 3a R 3b , C(=CR 3c R 3d ), C(=O), or =C(R 3e )- and, R 3a and R 3b Each of these is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -OH, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 3a and R 3b These can combine with the atoms to which they are bonded to form C3-C6 cycloalkyl groups. Alternatively, R 2b and R 3bThese can combine with the atoms to which they are bonded to form C3-C6 cycloalkyl groups. R 3c and R 3d Each of these is independently H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 3c and R 3d These can combine with the atoms to which they are bonded to form a C3-C6 cycloalkyl or a 3-6 membered heterocycline having one heteroatom which is O, and each cycloalkyl and heterocycline may have 0, 1, 2, or 3 R 3x It has been replaced with, Each R 3x These are independently C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -OH. R 3e These are H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 2e and R 3e These combine with the atoms to which they are bonded to form C5-C6 cycloalkyl, 5-10 member heterocyclyl, and C6-C 10 It can form aryls or 5-14 member heteroaryls. L 4 It does not exist, CR 4a R 4b , C(=CR 4c R 4d ), C(=O), or =C(R 4e )- and, R 4a and R 4b Each of these is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -OH, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 4a and R 4bThese can combine with the atoms to which they are bonded to form C3-C6 cycloalkyl groups. Alternatively, R 3b and R 4b These can combine with the atoms to which they are bonded to form C3-C6 cycloalkyl groups. R 4c and R 4d Each of these is independently H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 4c and R 4d These can combine with the atoms to which they are bonded to form a C3-C6 cycloalkyl or a 3-6 membered heterocycline having one heteroatom which is O, and each cycloalkyl and heterocycline may have 0, 1, 2, or 3 R 4x It has been replaced with, Each R 4x These are independently C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -OH. R 4e These are H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 3e and R 4e These can combine with the atoms to which they are bonded to form C5-C6 cycloalkyl groups. Therefore, L 2 ga = C(R 2e )- If L 1 -C(R 1e )= or L 3 is =C(R 3e )- and L 3 ga = C(R 3e )- If L 2 is =C(R 2e )- or L 4 is =C(R 4e )- and R AR is phenyl, naphthyl, or a 5-14 member heteroaryl, A This is 0, 1, 2, 3, 4, or 5 R A2 It has been replaced with, Each R A2 These are independently -OH, C1~C 10 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C 10 Alkoxy, C1-C 10 Hydroxyalkyl, C2-C 10 Alkoxyalkyl, C1-C6 alkyl-N(R A2a )(R A2b ), C1~C 10 Thioalkyl, 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 member heterocyclyl, -(C1-C6 alkyl)-(3-14 member heterocyclyl), C6-C 14 Aryl, -(C1~C6 alkyl)-(C6~C 14 The alkyl group is a 5-14 member heteroaryl group, or a -(C1-C6 alkyl)-(5-14 member heteroaryl group), and each alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, and haloalkyl group has 0, 1, 2, or 3 R groups. A3Each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl has 0, 1, 2, or 3 R A4 It has been replaced with, Each R A2a and R A2b These are H, C1~C independently. 10 It is an alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl, Each R A3 These are independently: Haro, -CN, -OR A3a , -SR A3a , -N(R A3a )(R A3b ), C3-C8 cycloalkyl, or 5-14 member heteroaryl, Each R A3a and R A3b These are H, C1~C independently. 10 It is an alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl, Each R A4 These 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 These are independently H or C1-C6 alkyl groups. Alternatively, two R A2 These combine to form R A On the two adjacent atoms above, C3~C 10 Cycloalkyl, C6~C 10 They can form aryls, 3-10 membered heterocyclines, or 5-14 membered heteroaryls, and each cycloalkyl, aryl, heterocycline, and heteroaryl has 0, 1, 2, or 3 R A5 It has been replaced with, Each RA5 These are, independently, C1~C 10 Alkyl, C2~C 10 Alkenyl, C2~C 10 Alkynyl, halo, C1-C6 haloalkyl, -CN, or C3-C8 cycloalkyl, R B is H or R B1 And, R B If H, then at least one R A2 is -OR A2x And, R B1 and R A2x Each of them operates independently. [ka] And, W and V are independent of each other, NR B2 , O, or S, Each R B2 These are, independently, C1~C 12 Alkyl, C1-C6 alkoxy, C2-C6 alkoxyalkyl, C1-C6 alkyl-N(R) B2a )(R B2b ), C1~C 10 Thioalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, C6-C 14 It is an aryl or 5-14 member heteroaryl, C3-C8 cycloalkyl, C6-C 14 Aryls, or 5- to 14-membered heteroaryls, have 0, 1, 2, or 3 R B2c It has been replaced with, Each R B2a and R B2b These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl. Each R B2c These 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 a cycloalkyl, L Cis, combined or [ka] 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 C1-C3 alkyl, R Y2 is H or C1-C3 alkyl, Alternatively, R Y1 and R Y2 These combine to form C3~C 10 Forming cycloalkyl or 3-10 membered heterocyclines, R C These are 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 member heterocyclyl, C6-C 14 Aryl or 5-14 member heteroaryl, each consisting of a C3-C8 cycloalkyl, a 3-14 member heterocyclyl, and a C6-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 These are independently selected from C1-C6 alkyl groups. Each R C3 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C8 alkynyl, C1-C6 alkoxyalkyl, C1-C6 hydroxyalkyl, halo, C1-C6 haloalkyl, C1-C6 heteroalkyl, and -(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, =CHF, =CF2, oxo, -OR C3a , -SR C3a , -N(R C3a )(R C3b ), -N3, SF5, C3~C8 cycloalkyl, -(C1~C6 alkyl)-(C3~C8 cycloalkyl), 3~10 member heterocyclyl, -(C1~C6 alkyl)-(3~10 member heterocyclyl), C6~C 10 Aryl, -(C1~C6 alkyl)-(C6~C 10 The alkyl group is a 5-10 member heteroaryl group, or a -(C1-C6(alkyl)-(5-10 member heteroaryl group), where each alkyl group has 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 Substituted with 3-10 membered heterocyclines, each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl having 0, 1, 2, or 3 halos, -CN, or R C3a2 Each alkenyl is substituted with 0, 1, 2, or 3 halos, and each alkoxyalkyl and alkynyl is substituted with 0, 1, 2, or 3 C1-C6 alkyl, C1-C6 haloalkyl, 0 or 1 C1-C6 haloalkyl, C3-C8 cycloalkyl, C6-C 10 Substituted with aryl or 5-10 membered heteroaryl compounds, Each R C3a and R C3b These are H, C1~C independently.10 Alkyl, C1-C6 haloalkyl, C6-C 10 The compounds are aryls, C3-C6 cycloalkyls, 3-6 membered heterocyclines, or 5-10 membered heteroaryls, each aryl and heteroaryl having 0, 1, 2, or 3 halos, -CN, or R groups. 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 These are independently C1-C3 alkyl, halo, C1-C6 haloalkyl, C3-C8 cycloalkyl, -(C1-C3 alkyl)-(C3-C8 cycloalkyl), 3-10 member heterocyclyl, -(C1-C3 alkyl)-(3-10 member heterocyclyl), C6-C 10 Aryl, -(C1~C3 alkyl)-(C6~C 10 Aryl), -(C2~C4 alkynyl)-(C6~C 10 The aryl group is a 5-10 member heteroaryl group, a -(C1-C3 alkyl)-(5-10 member heteroaryl group), or SF5 group, and each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, alkynyl-aryl, heteroaryl, and alkyl-heteroaryl group is substituted with 0, 1, 2, or 3 halos, C1-C3 haloalkyl, C1-C3 haloalkoxy, or SF5 group. 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 1, 2, 3, or 4 heteroatoms selected from N, O, S, and Si. Each heteroaryl provides a compound of formula J, or a pharmaceutically acceptable salt thereof, having one, two, three, or four heteroatoms selected from N, O, and S.

[0080] In one embodiment, this disclosure relates to formula J: [ka] A compound thereof, or a pharmaceutically acceptable salt thereof, During the ceremony, X is N, CH, or CR x And, R x C 1~3 Alkyl, C 2~4 Alkenil, C 1~3 Alkoxy, C 1~3 Thioalkyl, -CN, (CH2) m CN, Hello, C 1~3 Haloalkyl, or C 3~6 It is a cycloalkyl, m is 0, 1, 2, or 3. R 1 , R 2 , R 3 , and R 4 Each of these is independently H or a C1-C3 alkyl group. L 1 O, S, CR 1a R 1b , C(=CR 1c R 1d ), C(=O), or -C(R 1e )= and R 1a and R 1b Each of these is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -OH, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 1a and R 1b These can combine with the atoms to which they are bonded to form a C3-C6 cycloalkyl or a 3-6 membered heterocycline having one heteroatom which is O, and each cycloalkyl and heterocycline may have 0, 1, 2, or 3 R 1x It has been replaced with, R 1c and R 1dEach of these is independently H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 1c and R 1d These can combine with the atoms to which they are bonded to form a C3-C6 cycloalkyl or a 3-6 membered heterocycline having one heteroatom which is O, and each cycloalkyl and heterocycline may have 0, 1, 2, or 3 R 1x It has been replaced with, R 1e These are H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Each R 1x These are independently C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -OH. L 2 O, S, CR do not exist. 2a R 2b , C(=CR 2c R 2d ), C(=O), or =C(R 2e )- and therefore, L 2 If O or S, L 1 CR 1a R 1b And, R 2a and R 2b Each of these is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -OH, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 2a and R 2b These can combine with the atoms to which they are bonded to form C3-C6 cycloalkyl groups. Alternatively, R 1b and R 2b These combine with the atoms to which they are bonded to form C3-C6 cycloalkyl, 4-10 member heterocyclyl, and C6-C 10They can form aryls or 5-14 member heteroaryls, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl has 0, 1, 2, or 3 R 2x It has been replaced with, R 2c and R 2d Each of these is independently H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 2c and R 2d These can combine with the atoms to which they are bonded to form a C3-C6 cycloalkyl or a 3-6 membered heterocycline having one heteroatom which is O, and each cycloalkyl and heterocycline may have 0, 1, 2, or 3 R 2x It has been replaced with, R 2e These are H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 1e and R 2e These combine with the atoms to which they are bonded to form C5-C6 cycloalkyl, 5-10 member heterocyclyl, and C6-C 10 They can form aryls or 5-14 member heteroaryls, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl has 0, 1, 2, or 3 R 2x It has been replaced with, Each R 2x These are independently C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -OH. Or, L 1 and L 2 They combine, [ka] It can form L 3 It does not exist, CR 3a R 3b , C(=CR 3cR 3d ), C(=O), or =C(R 3e )- and, R 3a and R 3b Each of these is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -OH, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 3a and R 3b These can combine with the atoms to which they are bonded to form C3-C6 cycloalkyl groups. Alternatively, R 2b and R 3b These can combine with the atoms to which they are bonded to form C3-C6 cycloalkyl groups. R 3c and R 3d Each of these is independently H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 3c and R 3d These can combine with the atoms to which they are bonded to form a C3-C6 cycloalkyl or a 3-6 membered heterocycline having one heteroatom which is O, and each cycloalkyl and heterocycline may have 0, 1, 2, or 3 R 3x It has been replaced with, Each R 3x These are independently C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -OH. R 3e These are H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 2e and R 3e These combine with the atoms to which they are bonded to form C5-C6 cycloalkyl, 5-10 member heterocyclyl, and C6-C 10 It can form aryls or 5-14 member heteroaryls. L 4 It does not exist, CR 4a R 4b , C(=CR 4c R 4d ), C(=O), or =C(R 4e )- and, R 4a and R 4b Each of these is independently H, C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, -OH, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 4a and R 4b These can combine with the atoms to which they are bonded to form C3-C6 cycloalkyl groups. Alternatively, R 3b and R 4b These can combine with the atoms to which they are bonded to form C3-C6 cycloalkyl groups. R 4c and R 4d Each of these is independently H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 4c and R 4d These can combine with the atoms to which they are bonded to form a C3-C6 cycloalkyl or a 3-6 membered heterocycline having one heteroatom which is O, and each cycloalkyl and heterocycline may have 0, 1, 2, or 3 R 4x It has been replaced with, Each R 4x These are independently C1-C3 alkyl, C1-C3 alkoxy, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, or -OH. R 4e These are H, C1-C3 alkyl, halo, C1-C6 haloalkyl, -CN, C1-C3 cyanoalkyl, or C3-C6 cycloalkyl. Alternatively, R 3e and R 4eThese can combine with the atoms to which they are bonded to form C5-C6 cycloalkyl groups. Therefore, L 2 ga = C(R 2e )- If L 1 -C(R 1e )= or L 3 is =C(R 3e )- and L 3 ga = C(R 3e )- If L 2 is =C(R 2e )- or L 4 is =C(R 4e )- and, R A R is phenyl, naphthyl, or a 5-14 member heteroaryl, A This is 0, 1, 2, 3, 4, or 5 R A2 It has been replaced with, Each R A2 These are independently -OH, C1~C 10 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C 10 Alkoxy, C1-C 10 Hydroxyalkyl, C2-C 10 Alkoxyalkyl, C1-C6 alkyl-N(R A2a )(R A2b ), C1~C 10 Thioalkyl, 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(RA2a )(R A2b ), -(C0~C3 alkyl)-SF5, -OP(O)(OR A2a )(OR A2b ), C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C3-C8 cycloalkyl), 3-14 member heterocyclyl, -(C1-C6 alkyl)-(3-14 member heterocyclyl), C6-C 14 Aryl, -(C1~C6 alkyl)-(C6~C 14 The alkyl group is a 5-14 member heteroaryl group, or a -(C1-C6 alkyl)-(5-14 member heteroaryl group), and each alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, and haloalkyl group has 0, 1, 2, or 3 R groups. A3 Each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl has 0, 1, 2, or 3 R A4 It has been replaced with, Each R A2a and R A2b These are H, C1~C independently. 10 It is an alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl, Each R A3 These are independently: Haro, -CN, -OR A3a , -SR A3a , -N(R A3a )(R A3b ), C3-C8 cycloalkyl, or 5-14 member heteroaryl, Each R A3a and R A3b These are H, C1~C independently. 10 It is an alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl, Each R A4 These 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 10aryl), halo, -CN, -OH, or -N(R A4a )(R A4b ) and Each R A4a and R A4b These are independently H or C1-C6 alkyl groups. Alternatively, two R A2 These combine to form R A On the two adjacent atoms above, C3~C 10 Cycloalkyl, C6~C 10 They can form aryls, 3-10 membered heterocyclines, or 5-14 membered heteroaryls, and each cycloalkyl, aryl, heterocycline, and heteroaryl has 0, 1, 2, or 3 R A5 It has been replaced with, Each R A5 These are, independently, C1~C 10 Alkyl, C2~C 10 Alkenyl, C2~C 10 Alkynyl, halo, C1-C6 haloalkyl, -CN, or C3-C8 cycloalkyl, R B is H or R B1 And, R B If H, then at least one R A2 is -OR A2x And, R B1 and R A2x Each of them operates independently. [ka] And, W and V are independent of each other, NR B2 , O, or S, Each R B2 These are, independently, C1~C 12 Alkyl, C1-C6 alkoxy, C2-C6 alkoxyalkyl, C1-C6 alkyl-N(R) B2a )(R B2b ), C1~C 10 Thioalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, C6-C 14It is an aryl or 5-14 member heteroaryl, C3-C8 cycloalkyl, C6-C 14 Aryls, or 5- to 14-membered heteroaryls, have 0, 1, 2, or 3 R B2c It has been replaced with, Each R B2a and R B2b These are independently H, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl. Each R B2c These 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 a cycloalkyl, L C is, combined or [ka] 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 C1-C3 alkyl, R Y2 is H or C1-C3 alkyl, Alternatively, R Y1 and R Y2 These combine to form C3~C 10 Forming cycloalkyl or 3-10 membered heterocyclines, R C These are 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 member heterocyclyl, C6-C 14 Aryl or 5-14 member heteroaryl, each consisting of a C3-C8 cycloalkyl, a 3-14 member heterocyclyl, and a C6-C 14Aryl and 3- to 14-membered heteroaryl are 0, 1, 2, 3, or 4 R C3 substituted with, each R C1 is independently selected from C1-C6 alkyl, each R C3 is independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C8 alkynyl, C1-C6 alkoxyalkyl, C1-C6 hydroxyalkyl, halo, C1-C6 haloalkyl, C1-C6 heteroalkyl, -(C1-C6 alkyl)-N(R C3a )(R C3b ), -CN, -C(O)R C3a , -C(O)OR C3a , -C(O)N(R C3a )(R C3b ), -N(R C3a )C(O)(R C3b ), -OC(O)N(R C3a )(R C3b ), -N(R C3a )C(O)(OR C3b ), =CH2, =CF2, oxo, -OR C3a , -SR C3a , -N(R C3a )(R C3b ), -N3, SF5, C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C3-C8 cycloalkyl), 3- to 10-membered heterocyclyl, -(C1-C6 alkyl)-(3- to 10-membered heterocyclyl), C6-C 10 aryl, -(C1-C6 alkyl)-(C6-C 10 aryl), 5- to 10-membered heteroaryl, or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), and each alkyl is substituted with 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 C3a2is substituted with 3- to 10-membered heterocyclyl substituted with, 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 and each alkenyl is substituted with 0, 1, 2, or 3 halo, and 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 aryl, or 5- to 10-membered heteroaryl, each R C3a and R C3b are independently H, C1~C 10 alkyl, C1~C6 haloalkyl, C6~C 10 aryl, C3~C6 cycloalkyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, and each aryl and heteroaryl is substituted with 0, 1, 2, or 3 halo, -CN, or R C3a2 , alternatively, R C3a and R C3b together with the N to which they are bonded form a 3- to 8-membered heterocyclic ring, each R C3a1 and R C3a2 are independently C1~C3 alkyl, halo, C1~C6 haloalkyl, C3~C8 cycloalkyl, -(C1~C3 alkyl)-(C3~C8 cycloalkyl), 3- to 10-membered heterocyclyl, -(C1~C3 alkyl)-(3- to 10-membered heterocyclyl), C6~C 10 aryl, -(C1~C3 alkyl)-(C6~C 10 aryl), -(C2~C4 alkynyl)-(C6~C 10The aryl group is a 5-10 member heteroaryl group, a -(C1-C3 alkyl)-(5-10 member heteroaryl group), or SF5 group, and each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, alkynyl-aryl, heteroaryl, and alkyl-heteroaryl group is substituted with 0, 1, 2, or 3 halos, C1-C3 haloalkyl, C1-C3 haloalkoxy, or SF5 group. 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 1, 2, 3, or 4 heteroatoms selected from N, O, S, and Si. Each heteroaryl provides a compound of formula J, or a pharmaceutically acceptable salt thereof, having one, two, three, or four heteroatoms selected from N, O, and S.

[0081] In some embodiments, this disclosure is R 1 , R 2 , R 3 , and R 4 However, the present disclosure provides a compound of formula J, each independently being H or methyl. In some embodiments, the present disclosure is R 1 , R 2 , R 3 , and R 4 The present disclosure provides a compound of formula J, wherein one or two of the elements are methyl. In some embodiments, the present disclosure is R 1 and R 2 The present disclosure provides a compound of formula J, which is methyl. In some embodiments, the present disclosure provides R 1 , R 2 , R 3 , and R 4 This provides a compound of formula J, where each of the elements is H.

[0082] In some embodiments, the disclosure provides compounds of formula J having the structure of formula (I-1), or pharmaceutically acceptable salts thereof. [ka]

[0083] In some embodiments, the disclosure provides compounds of formula J or I-1 having the structure of formula (I-2), or pharmaceutically acceptable salts thereof. [ka]

[0084] In some embodiments, the disclosure provides compounds of formula J or I-1 having the structure of formula (I-3), or pharmaceutically acceptable salts thereof. [ka]

[0085] In some embodiments, the disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where X is N. In some embodiments, the disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where X is CH. In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where X is CR x And R x (CH2) mCN is 0, 1, 2, or 3. In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where X is CR x And R x is (CH2)CN. In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where X is CR x And R x is a halo. In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where X is CF. In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where X is C-Cl.

[0086] In some embodiments, the present disclosure provides compounds of formula J, I-1, I-2, or I-3, or pharmaceutically acceptable salts thereof, where L 1 CHR 1b In some embodiments, the present disclosure provides compounds of formula J, I-1, I-2, or I-3, or pharmaceutically acceptable salts thereof, where L 1 is CH2. In some embodiments, the present disclosure provides compounds of formula J, I-1, I-2, or I-3, or pharmaceutically acceptable salts thereof, where L 1is CH(CH3). In some embodiments, the present disclosure provides compounds of formula J, I-1, I-2, or I-3, or pharmaceutically acceptable salts thereof, where R 1a and R 1b Each is independently H, C1-C3 alkyl, or halo. In some embodiments, the present disclosure provides compounds of formula J, I-1, I-2, or I-3, or pharmaceutically acceptable salts thereof, where R 1b is a C1-C3 alkyl or halo. In some embodiments, the present disclosure provides compounds of formula J, I-1, I-2, or I-3, or pharmaceutically acceptable salts thereof, where R 1b is H or methyl. In some embodiments, the present disclosure provides compounds of formula J, I-1, I-2, or I-3, or pharmaceutically acceptable salts thereof, where R 1b is H. In some embodiments, the present disclosure provides compounds of formula J, I-1, I-2, or I-3, or pharmaceutically acceptable salts thereof, where R 1b It is methyl.

[0087] In some embodiments, the disclosure provides compounds of formula J, I-1, I-2, or I-3 having the structure of formula (Ib), or pharmaceutically acceptable salts thereof. [ka]

[0088] In some embodiments, the present disclosure provides compounds of formula J, I-1, I-2, I-3, or (Ib), or pharmaceutically acceptable salts thereof, where R 2a and R 2b Each is independently H, C1-C3 alkyl, halo, or C1-C6 haloalkyl. In some embodiments, the present disclosure provides compounds of formula J, I-1, I-2, I-3, or (Ib), or pharmaceutically acceptable salts thereof, where L 2 CHR 2bIn some embodiments, the present disclosure provides compounds of formula J, I-1, I-2, I-3, or (Ib), or pharmaceutically acceptable salts thereof, where R 2b is H or C1-C3 alkyl. In some embodiments, the present disclosure provides compounds of formula J, I-1, I-2, I-3, or (Ib), or pharmaceutically acceptable salts thereof, where R 2b is H. In some embodiments, the present disclosure provides compounds of formula J, I-1, I-2, I-3, or (Ib), or pharmaceutically acceptable salts thereof, where R 2b is a C1-C3 alkyl group. In some embodiments, the present disclosure provides compounds of formula J, I-1, I-2, I-3, or (Ib), or pharmaceutically acceptable salts thereof, where R 2b It is methyl.

[0089] In some embodiments, the present disclosure provides compounds of formula J, I-1, I-2, I-3, or (Ib), or pharmaceutically acceptable salts thereof, where L 3 It is a combination.

[0090] In some embodiments, the disclosure provides compounds of formula J, I-1, I-2, I-3, or (Ib) having the structure of formula (IIb), or pharmaceutically acceptable salts thereof. [ka]

[0091] In some embodiments, the present disclosure provides compounds of formula J, I-1, I-2, I-3, (Ib), or (IIb) having the structure of formula (IIb-1), or pharmaceutically acceptable salts thereof. [ka]

[0092] In some embodiments, the present disclosure provides compounds of formula J, I-1, I-2, I-3, (Ib), or (IIb) having the structure of formula (IIb-2), or pharmaceutically acceptable salts thereof. [ka]

[0093] In some embodiments, the present disclosure provides compounds of formula J, I-1, I-2, I-3, or (Ib), or pharmaceutically acceptable salts thereof, where L 3 CR 3a R 3b In some embodiments, the present disclosure provides compounds of formula J, I-1, I-2, I-3, or (Ib), or pharmaceutically acceptable salts thereof, where R 3a and R 3b H is H.

[0094] In some embodiments, the present disclosure provides compounds of formula J, I-1, I-2, I-3, or (Ib) having the structure of formula (Ib-1), or pharmaceutically acceptable salts thereof. [ka]

[0095] In some embodiments, the disclosure provides compounds of formula J, I-1, I-2, I-3, Ib, or Ib-1 having the structure of formula (Ib-2), or pharmaceutically acceptable salts thereof. [ka]

[0096] In some embodiments, the disclosure provides compounds of formula J, I-1, I-2, I-3, Ib, or Ib-1 having the structure of formula (Ib-3), or pharmaceutically acceptable salts thereof. [ka]

[0097] In some embodiments, the present disclosure provides a compound of formula J, I-1, I-2, I-3, Ib, or Ib-1, which has the structure of formula (Ib-4), or a pharmaceutically acceptable salt thereof.

Chemical Formula

[0098] In some embodiments, the present disclosure provides a compound of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), and / or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein R A is phenyl substituted with 0, 1, 2, 3, 4, or 5 R A2 groups. In some embodiments, the present disclosure provides a compound of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), and / or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein R A is phenyl substituted with 0, 1, or 2 R A2 groups. In some embodiments, the present disclosure provides a compound of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), and / or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein R A is phenyl substituted with 0, 1, 2, 3, 4, or 5 R A2 groups. In some embodiments, the present disclosure provides a compound of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), and / or (IIb-2), or a pharmaceutically acceptable salt thereof, wherein R A is phenyl substituted with 2 or 3 R A2It is a naphthyl substituted with. In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), and / or (IIb-2), or pharmaceutically acceptable salts thereof, where R A These are pyridyl, benzothienyl, benzothiazolyl, or isoquinolinyl, each containing 0, 1, 2, 3, 4, or 5 R atoms. A2 It has been replaced with.

[0099] In some embodiments, the Disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where each R A2 These 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 has 0, 1, 2, or 3 R A3 It is replaced by each R A2a Each R is independently a C1-C6 haloalkyl or a C3-C8 cycloalkyl, and each R A3 In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where each R A2 These are independently Me, -OH, -C(Cl)=CH2, -CH=CHF2, [ka] F, Cl, -CH2CF3, -OCF3, -O-cyclopropyl, -SCF3, or -CH2-cyclopropyl. In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R A2 These are independently -OH, NH2, [ka] It is F, or -CH2CH3.

[0100] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R A teeth, [ka] [ka] [ka] That is the case.

[0101] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R A teeth, [ka] [ka] That is the case.

[0102] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R A teeth, [ka] [ka] That is the case.

[0103] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R A teeth, [ka] That is the case.

[0104] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R A teeth, [ka] That is the case.

[0105] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R A teeth, [ka] That is the case.

[0106] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R A teeth, [ka] That is the case.

[0107] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R A teeth, [ka]

[0108] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R A teeth, [ka] That is the case.

[0109] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R B R B1 That is the case.

[0110] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R B is H and at least one R A2 is -OR A2x That is the case.

[0111] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R B R B1 And at least one R A2 is -OR A2x That is the case.

[0112] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, wherein, R B1 and R A2x Each of them operates independently. [ka] And, V is independent of NR B2 Or it is O.

[0113] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, wherein, R B1 and R A2x Each of them operates independently. [ka] That is the case.

[0114] In some embodiments, the Disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where each R B2 These are independently C1-C6 alkyl, C3-C8 cycloalkyl, and C6-C 14 It is an aryl or 5-14 member heteroaryl, C3-C8 cycloalkyl, C6-C 14 Aryls, or 5- to 14-membered heteroaryls, have 0, 1, or 2 R B2c It is replaced by each R B2c These are independently C1-C6 alkyl, halo, C1-C6 haloalkyl, -CN, or C3-C 10 It is a cycloalkyl compound. In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where each R B2 These are independently C1-C4 alkyl or C6-C 10 It is an aryl compound. In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where each R B2 R is independently methyl, ethyl, n-propyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, n-octyl, cyclohexyl, or Ph. In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R B2R is independently methyl, ethyl, n-propyl, isopropyl, tert-butyl, or Ph. In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R B2 These are independently methyl or ethyl.

[0115] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R B1 teeth, [ka]

[0116] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R B1 teeth, [ka] That is the case.

[0117] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R B1 teeth, [ka] That is the case.

[0118] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R B1 and R A2x Each [ka] That is the case.

[0119] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R B1 and R A2x Each [ka] That is the case.

[0120] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R B1 teeth, [ka] And R B2 These are C1-C3 alkyl groups, and each R A2 R is independently -OH, F, C1-C3 alkyl, NH2, C2-C3 alkynyl, or C1-C3 haloalkyl. In some embodiments, each R A2 These are independently -OH, F, NH2, or ethynyl.

[0121] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where L C teeth, [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, and R Y2 is H or C1-C3 alkyl, or R Y1 and R Y2 These combine to form C3-C6 cycloalkyl groups.

[0122] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where L C teeth, [ka] And, Y is C or Si, n is 0 or 1, q is 0 or 1, R Y1 is H or Me, and R Y2 is H or Me, or R Y1 and R Y2 These combine to form cyclopropyl.

[0123] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, wherein, R C This is 0, 1, 2, or 3 RC3 It is a 3-14 member heterocycline that is substituted with Each R C3 These are independently C1-C6 alkyl, halo, C1-C6 haloalkyl, =CH2, -OR C3a , or -(C1~C6 alkyl)-(5~10 member heteroaryl), where each alkyl is 1-OC(O)N(R C3a1 )(R C3a2 ), -OR C3a1 , or replaced with N3, Each R C3a These are independently C1-C6 haloalkyl groups, Each R C3a1 and R C3a2 These are independently C1-C3 alkyl, C1-C6 haloalkyl, and C6-C 10 The aryl or 5-10 membered heteroaryl is substituted with 0, 1, 2, 3, or 4 halos, C1-C3 haloalkyls, C1-C3 haloalkoxys, or SF5. Alternatively, R C3a1 and R C3a2 These atoms, together with the N atoms they are bonded to, form a 3- to 8-membered heterocycle.

[0124] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, wherein, R C This is 0, 1, 2, or 3 R C3 It is a 3-14 member heterocycline that is substituted with Each R C3 These are independently C1-C6 alkyl, halo, C1-C6 haloalkyl, =CH2, -OR C3a , or -(C1~C6 alkyl)-(5~10 member heteroaryl), where each alkyl is 1-OC(O)N(R C3a1 )(R C3a2 ), -OR C3a1 , or replaced with N3, Each RC3a These are independently C1-C6 haloalkyl groups, Each R C3a1 and R C3a2 These are independently C1-C3 alkyl, C1-C6 haloalkyl, or C6-C 10 It is an aryl, and each aryl is replaced by one SF5. Alternatively, R C3a1 and R C3a2 These atoms, together with the N atoms they are bonded to, form a 3- to 8-membered heterocycle.

[0125] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where L C teeth, [ka] And, Y is C, n is 0, q is 0, R Y1 H is R Y2 is H. In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where L C It is -CH2-.

[0126] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, wherein, R C It is an 8-14 member heterocycline with 0, 1, 2, or 3 R C3 It has been replaced with, Each R C3These are independently C1-C6 alkyl, halo, =CH2, -OR C3a , or -(C1~C6 alkyl)-(5~10 member heteroaryl), Each alkyl group contains one -OC(O)N(R) C3a1 )(R C3a2 ), -OR C3a1 , or replaced with N3, Each R C3a These are independently C1-C6 haloalkyl groups, Each R C3a1 and R C3a2 These are independently C1-C3 alkyl, C1-C6 haloalkyl, or C6-C 10 It is an aryl, and each aryl is replaced by one SF5. Alternatively, R C3a1 and R C3a2 These atoms, together with the N atoms they are bonded to, form a 3- to 8-membered heterocycle.

[0127] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where L C teeth, [ka] And, Y is C or Si, n is 1, q is 1, R Y1 is Me, and R Y2 is Me, or R Y1 and R Y2 These combine to form a cyclopropyl. In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R C is 0, 1, or 2 R C3 It is a 3-7 member heterocycline that is substituted with each RC3 These are independently halo or C1-C6 haloalkyl.

[0128] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R 1b is H or methyl, and R C3 is -CH2OR C3a1 Or F, R C3a1 is a 5-6 member heteroaryl substituted with one halo or C1-C2 haloalkyl. In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R 1b is H or methyl, and R C3 is F. In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R 1b is H or methyl, and R C3 is -CH2OR C3a1 And R C3a1 is a six-membered heteroaryl substituted with one C1 haloalkyl. In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R 1b R is either H or methyl. C3 is -CH2OR C3a1 And R C3a1 This is pyridazine, pyrimidine, or pyrazine, and the pyridazine, pyrimidine, or pyrazine is substituted with one CF3 molecule.

[0129] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where L C It is -CH2- and R C This is one R C3 It is a 3-14 member heterocycline that is substituted with R C3 is one -OR C3a1 , or -SR C3a1 These are C1-C6 alkyl groups that are substituted with R C3a1 is a 5-10 member heteroaryl substituted with 0, 1, or 2 C1-C3 haloalkyl or C1-C3 haloalkoxy. In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where L C It is -CH2- and R C This is one R C3 It is a 4-8 member heterocycline that is substituted with R C3 is -CH2OR C3a1 And R C3a1 It is a pyrimidine, and the pyrimidine is substituted with one trifluoromethyl group.

[0130] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where -OL C -R C The part is, [ka] [ka] [ka] That is the case.

[0131] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where -OL C -R C The part is, [ka] [ka] [ka] That is the case.

[0132] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where -OL C -R C The part is, [ka] [ka] [ka] That is the case.

[0133] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where -OLC -R C The part is, [ka] [ka] That is the case.

[0134] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where -OL C -R C The part is, [ka] That is the case.

[0135] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where -OL C -R C The part is, [ka] [ka] [ka] That is the case.

[0136] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where -OL C -R CThe part is, [ka] That is the case.

[0137] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where -OL C -R C The part is, [ka] That is the case.

[0138] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where -OL C -R C The part is, [ka] That is the case.

[0139] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R D is F or Cl. In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, where R D It is F.

[0140] In some embodiments, the present disclosure provides compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, the compounds having the following structures. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9] [Table 4-10] [Table 4-11] [Table 4-12] [Table 4-13] [Table 4-14]

[0141] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof, the compound having the following structure: [ka]

[0142] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof, the compound having the following structure: [ka]

[0143] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof, the compound having the following structure: [ka]

[0144] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof, the compound having the following structure: [ka]

[0145] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof, the compound having the following structure: [ka]

[0146] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof, the compound having the following structure: [ka]

[0147] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof, the compound having the following structure: [ka]

[0148] In some embodiments, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof, the compound having the following structure: [ka]

[0149] Furthermore, in vivo metabolites of the compounds described herein are also included within the scope of this specification. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, mainly by enzymatic processes. Thus, this includes novel and non-trivial compounds produced by processes that involve contacting the compound with a mammal for a sufficient time to obtain the metabolite. Such products are typically radiolabeled (e.g., 14 C or 3 H) The compound is prepared and administered to animals, such as rats, mice, guinea pigs, monkeys, or humans, at a detectable dose (e.g., above approximately 0.5 mg / kg), allowing sufficient time for metabolism (typically about 30 seconds to 30 hours), and the conversion product is identified by isolating it from urine, blood, or other biological samples. These products are labeled and therefore easily isolated (others are isolated by using antibodies that can bind to epitopes remaining in the metabolites). The metabolite structure is determined in a conventional manner, for example, by MS analysis or NMR analysis. Generally, the analysis of metabolites is performed in the same manner as in conventional drug metabolism studies. The conversion product is useful in diagnostic assays for therapeutic administration of the compound, even if it does not possess its own HSV antiviral activity unless otherwise found in vivo.

[0150] Recipes and methods for determining the stability of compounds in surrogate gastrointestinal secretion are known. A compound is defined herein as stable in the gastrointestinal tract if, upon incubation at 37°C for 1 hour, less than approximately 50 mole percent of protecting groups are deprotected in surrogate intestinal fluid or gastric fluid. Stability in the gastrointestinal tract does not mean that a compound cannot be hydrolyzed in vivo. Prodrugs are typically stable in the digestive system but can be substantially hydrolyzed to the parent drug in the gastrointestinal lumen, liver, lungs, or other metabolic organs, or generally intracellularly. As used herein, a prodrug is understood to be a compound chemically designed to efficiently release the parent drug after overcoming biological barriers to oral delivery.

[0151] In some embodiments, compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or pharmaceutically acceptable salts thereof, are prodrugs. In some embodiments, the prodrugs described herein exhibit improved biological properties after in vivo administration in a subject, including enhanced pharmacokinetics such as higher exposure, higher oral bioavailability, and / or higher maximal blood concentrations, as well as enhanced tissue distribution, compared to in vivo administration of an equivalent volume of the parent drug in the subject.

[0152] IV. Pharmaceutical Compositions Furthermore, this specification discloses pharmaceutical compositions comprising a pharmaceutically effective amount of the compound of this disclosure (e.g., formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2)), or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier or excipient. Furthermore, this specification provides pharmaceutical compositions comprising a pharmaceutically effective amount of the compound of this disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. For example, this specification provides pharmaceutical compositions comprising a pharmaceutically effective amount of the compound of this disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0153] The compounds disclosed herein can be formulated with conventional carriers and excipients. Tablets may include, for example, excipients, flow enhancers, fillers, binders, or combinations thereof. Aqueous formulations are prepared in sterile form and are generally isotonic when intended for delivery by means other than oral administration. Exemplary excipients include, but are not limited to, those described in the "HANDBOOK OF PHARMACEUTICAL EXCIPIENTS" (1986). Excipients may 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, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 4-11, 5-6, 5-7, 5-8, 5-9, 5-10, 5-11, 6-7, 6-8, 6-9, 6-10, 6-11, 7-8, 7-9, 7-10, 7-11, 8-9, 8-10, 8-11, 9-10, or 9-11).

[0154] In some embodiments, the compounds disclosed herein have pharmacokinetic properties (e.g., oral bioavailability) suitable for oral administration. Formulations suitable for oral administration may be presented, for example, as separate units such as capsules, cachetes, or tablets, each containing a predetermined amount of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil liquid emulsions. The active ingredient may also be administered, for example, as a bolus, lick, or paste.

[0155] Tablets may optionally be prepared by compression or molding with at least minor components. Compressed tablets may optionally be prepared by compressing the active ingredient in a free-flowing form such as powder or granules, mixed with a binder, lubricant, inert diluent, preservative, surfactant, dispersant, or a combination thereof, using a suitable machine. Molded tablets may optionally be prepared by molding a mixture of powdered active ingredients moistened with an inert liquid diluent using a suitable machine. Tablets may optionally be coated or scored and optionally formulated to provide sustained or controlled release of the active ingredient therefrom.

[0156] In the case of infections of the eyes or other external tissues (e.g., mouth and skin), the formulation may be applied as a topical ointment or cream containing the active ingredient in amounts such as 0.075–20% w / w (e.g., 0.6% w / w, 0.7% w / w, etc., containing the active ingredient in increments of 0.1% w / w, ranging from 0.1% to 20%), 0.2–15% w / w, or 0.5–10% w / w. When formulated as an ointment, the active ingredient may, in some embodiments, be used with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream having an oil-in-water cream base.

[0157] In some embodiments, the aqueous phase of the cream base may include, for example, 30% to 90% (e.g., 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%) w / w polyhydric alcohols, i.e., alcohols 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, compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include, but are not limited to, dimethyl sulfoxide and related analogues. In some embodiments, the cream or emulsion does not contain water.

[0158] The oily phase of an emulsion may consist of known components in known forms. In some embodiments, the phase comprises only an emulsifier (also known as an emulsion). In some embodiments, the phase comprises a mixture of at least one emulsifier and a fat, oil, or a combination thereof. In some embodiments, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. In summary, emulsifiers with or without stabilizers constitute a so-called emulsifying wax, and the wax, together with oils and fats, constitutes a so-called emulsifying ointment base that can form the oily dispersion phase of a cream formulation.

[0159] Suitable emulsions and emulsion stabilizers for use in formulations include, 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.

[0160] The selection of suitable oils or fats for the formulation may be based on achieving desired aesthetic properties. In some embodiments, the cream may be a non-oily, non-stainable, and washable product having a moderate consistency to avoid leakage from tubes or other containers. In some embodiments, the ester may be a blend of branched esters known as linear or branched, one or two basic alkyl esters, such as diisoadipates, isocetyl stearate, propylene glycol diesters of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, CRODAMOL® CAP, or combinations thereof. In some embodiments, high-melting-point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be included.

[0161] In some embodiments, the compounds disclosed herein are administered alone. In some embodiments, the compounds disclosed herein are 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, the pharmaceutical composition comprises at least one additional therapeutic agent. In some embodiments, the pharmaceutical composition disclosed herein comprises one or more additional therapeutic agents. In some embodiments, one or more additional therapeutic agents are independently chemotherapeutic agents, immunotherapeutic agents, hormonal agents, antihormonal agents, targeted therapeutic agents, or anti-angiogenic agents.

[0162] 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 forms and may be prepared by any of the methods well known in the field of pharmacy. Exemplary techniques and formulations can be found, for example, in REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Publishing Co., Easton, PA). Such methods may include the step of associating the compounds disclosed herein with a carrier constituting at least one of the minor components. Generally, formulations may be prepared by homogeneously and closely associating the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product.

[0163] When used for oral use, for example, tablets, lozenges, licks, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, solutions, syrups, or elixirs may be prepared. Formulations intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such formulations may contain at least one agent, including sweeteners, flavoring agents, coloring agents, and preservatives, in order to provide a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may include, 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 coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained effect over a long period. For example, time-delaying agents such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with wax.

[0164] Formulations for oral use may also be presented as rigid gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as 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.

[0165] Aqueous suspensions contain the active substance in a mixture with excipients suitable for the preparation of aqueous suspensions. Such excipients may include, for example, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum, as well as dispersants or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxides and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxides and partial esters derived from fatty acids, and hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain, for example, at least a preservative such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, one or more sweeteners (such as sucrose or saccharin), or a mixture thereof. Further non-limiting examples of suspensions include cyclodextrins. In some embodiments, the suspension is sulfobutyl ether beta-cyclodextrin (SEB-beta-CD), for example, CAPTISOL®.

[0166] Oil suspensions can be formulated by suspending the active ingredient in vegetable oil (e.g., peanut oil, olive oil, sesame oil, coconut oil, or a combination thereof), or in mineral oil such as liquid paraffin, or a combination thereof. Oral suspensions may contain thickeners such as beeswax, solid paraffin, cetyl alcohol, or a combination thereof. In some embodiments, sweeteners and / or flavoring agents as described above may be added to provide an oral preparation with a pleasant mouthfeel. In some embodiments, the formulations disclosed herein are preserved by the addition of antioxidants such as ascorbic acid.

[0167] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water can provide active ingredients in mixtures with dispersants or wetting agents, suspending agents, preservatives, and combinations thereof. Suitable dispersants or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, such as sweeteners, flavoring agents, and colorants, may also be present.

[0168] 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 acacia gum and tragacanth gum, naturally occurring phosphatides such as soy lecithin, esters or partial esters derived from fatty acids, and hexitol anhydrides such as sorbitan monooleate, as well as condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavorings. The syrup and elixir may be formulated with sweeteners such as glycerol, sorbitol, or sucrose. Such formulations may also contain, for example, lubricants, preservatives, flavorings, colorings, or combinations thereof.

[0169] The pharmaceutical composition may be in the form of a sterile injection or intravenous preparation, for example, a sterile aqueous or oily suspension for injection. This suspension may be formulated according to known techniques using the preferred dispersants or wetting agents and suspending agents described above. The sterile injection or intravenous preparation may also be a sterile injection solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol, or it may be prepared as a lyophilized powder. Acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile solid oils may be used as solvents or suspension media. For this purpose, any solvent-free solid oil containing synthetic monoglycerides or diglycerides may be used. In addition, fatty acids such as oleic acid may also be used in the preparation of injections. 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.

[0170] The amount of active ingredient that can be combined with a carrier to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. For example, a sustained-release formulation intended for oral administration to humans may contain approximately 1 mg to 2000 mg of active ingredient, formulated with an appropriate and convenient amount of carrier material that can 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 approximately 1 mg to 1000 mg of active ingredient, formulated with an appropriate and convenient amount of carrier material that can vary from 5% to 95% (weight:weight) of the total formulation. Pharmaceutical compositions can be prepared to provide an amount that is easily measurable for administration. For example, an aqueous solution intended for intravenous infusion may contain 3 μg to 500 μg of active ingredient per milliliter of solution to allow for the injection of a suitable volume at a rate of approximately 30 mL / hour.

[0171] Formulations suitable for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent of the active ingredient. In some embodiments, the compounds disclosed herein are included in the pharmaceutical compositions disclosed herein at concentrations of 0.5% to 20% (e.g., 0.5% to 10%, 1.5% w / w).

[0172] Suitable formulations for topical oral administration include flavored lozenges, gelatin and glycerin, or pastels containing the active ingredient in an inert base material such as sucrose and acacia or tragacanth (i.e., the compounds and / or additional therapeutic agents disclosed herein); and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0173] Formulations for rectal administration can be provided as suppositories containing, for example, a suitable base including cocoa butter or salicylate.

[0174] Formulations suitable for intravaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations, each containing an active ingredient and a carrier known to be suitable in the art.

[0175] Suitable formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostads, and solutes to make the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners.

[0176] The formulations may be presented in unit dose or multi-dose containers, such as sealed ampoules and vials, and can be stored in a freeze-dried state requiring only the addition of a sterile liquid carrier, such as sterile water for injection, immediately before use. Immediate injection solutions and suspensions are prepared from the aforementioned types of sterile powders, granules, and tablets. Preferred unit dose formulations contain the daily dose or unit daily subdose of the active ingredient as listed above herein, or appropriate fractions thereof.

[0177] In particular, it should be understood that, in addition to the aforementioned components, the formulation may contain other standard agents in the relevant art with respect to the type of formulation in question, and for example, those suitable for oral administration may contain flavoring agents.

[0178] Furthermore, veterinary formulations are provided that include the compounds disclosed herein together with a carrier for veterinary use.

[0179] Veterinary carriers are substances useful for administering formulations, and may be solid, liquid, or gaseous substances that are inert or acceptable in veterinary technology and compatible with the active ingredient. These veterinary formulations can be administered orally, parenterally, or by any other desired route.

[0180] The compounds described herein are used to provide controlled-release pharmaceutical compositions ("controlled-release formulations") comprising one or more compounds as active ingredients, wherein the release of the active ingredients can be controlled and regulated to enable lower dosing frequency or to improve the pharmacokinetic or toxicity profile of a given active ingredient.

[0181] The effective dose of the active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is used prophylactically (low dose) or for active viral infections, the delivery method, and the pharmaceutical composition, and is 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., 10 to 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 candidate daily dose for an adult weighing approximately 70 kg may 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 may take the form of a single dose or multiple doses. For example, the candidate daily dose for an adult weighing approximately 70 kg may range from 1 mg to 1000 mg (e.g., 5 mg to 500 mg), and may take the form of a single dose or multiple doses.

[0182] V. Kit This specification also provides kits comprising the compounds disclosed herein, or pharmaceutically acceptable salts thereof. In some embodiments, the kits described herein may include labels and / or instructions for use for the treatment of a disease or condition in a subject (e.g., a human) requiring treatment of a disease or condition. In some embodiments, the disease or condition is a viral infection.

[0183] In some embodiments, the kit may also include one or more additional therapeutic agents and / or instructions for use of 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) requiring treatment of the disease or condition.

[0184] In some embodiments, the kits provided herein include individual dose units of the compound described herein, or pharmaceutically acceptable salts, racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, amorphous forms, hydrates, or solvates thereof. Examples of individual dose units include pills, tablets, capsules, pre-filled syringes, or syringe cartridges, IV bags, inhalers, nebulizers, etc., each of which may contain a therapeutically effective dose of the compound in question, or pharmaceutically acceptable salts, racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs, amorphous forms, hydrates, or solvates thereof. In some embodiments, the kit may have a single dose unit and several other dose units, such as a number of dose units required for a particular regimen or period.

[0185] Products comprising the compounds disclosed herein, or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or tautomers thereof, and containers are also provided. In some embodiments, the container for the product is a vial, bottle, ampoule, pre-filled syringe, blister package, tin, can, bottle, box, intravenous bag, inhaler, or sprayer.

[0186] VI. Administration One or more compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (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. Preferred routes include oral, rectal, nasal, pulmonary, topical (including oral and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, subarachnoid, and epidural). It will be understood that the route may vary, for example, depending on the recipient's condition. An advantage of the compounds herein is that they are orally bioavailable and can be administered orally.

[0187] The compounds disclosed herein (also referred to herein as active ingredients) can be administered by any route appropriate to the condition being treated.

[0188] Preferred routes of administration include oral, rectal, nasal, topical (including buccal and sublingual), percutaneous, 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 recipient's condition. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0189] The compounds of this disclosure may be administered to an individual according to an effective administration plan for a desired period or duration, such as at least about one month, at least about two months, at least about three months, at least about six months, or at least about twelve months or more. In some embodiments, the compounds are administered daily or on an intermittent schedule over the lifespan of the individual.

[0190] The dosage or frequency of administration of the compounds disclosed herein may be adjusted throughout the course of treatment at the discretion of the administering physician.

[0191] The compound can be administered to an individual (e.g., a human) in an effective dose. In some embodiments, the compound is administered once daily.

[0192] The compound may be administered by any convenient route and means, such as oral or parenteral (e.g., intravenous) administration. Possible therapeutic doses of the compound include approximately 0.00001 mg / kg body weight to approximately 10 mg / kg body weight per day, for example, approximately 0.0001 mg / kg body weight to approximately 10 mg / kg body weight per day, or for example, approximately 0.001 mg / kg body weight to approximately 1 mg / kg body weight per day, or for example, approximately 0.01 mg / kg body weight to approximately 1 mg / kg body weight per day, or for example, approximately 0.05 mg / kg body weight to approximately 0.5 mg / kg body weight per day, or for example, approximately 0.3 mg to approximately 30 mg per day, or for example, approximately 30 mg to approximately 300 mg per day.

[0193] The compounds of this disclosure may be combined with one or more additional therapeutic agents at any dose of the compounds of this disclosure (e.g., about 1 mg to about 1000 mg of the compounds). Effective therapeutic doses may range from about 1 mg to about 1000 mg per dose, for example, about 50 mg to about 500 mg per dose, or for example, about 100 mg to about 400 mg per dose, or for example, about 150 mg to about 350 mg per dose, or for example, about 200 mg to about 300 mg per dose. Other therapeutically effective doses of the compounds disclosed herein are approximately 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or 500 mg per dose. Other therapeutically effective doses of the compounds disclosed herein are approximately 100 mg per dose, or approximately 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, or 500 mg per dose. A single dose may be administered hourly, daily, or weekly. For example, a single dose may be administered approximately every 1, 2, 3, 4, 6, 8, 12, or 16 hours, or every 24 hours. Alternatively, a single dose may be administered approximately every 1, 2, 3, 4, 5, or 6 days, or every 7 days. Furthermore, a single dose may be administered approximately every 1, 2, or 3 weeks, or every 4 weeks. In some embodiments, a single dose may be administered approximately once a week. Alternatively, a single dose may be administered approximately once a month.

[0194] Other therapeutically effective doses of the compounds disclosed herein are approximately 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg per dose.

[0195] The frequency of administration of the compounds disclosed herein may be determined by the individual patient’s needs, and may be, for example, once a day, twice a day, or more times. Administration of the compounds will continue for as long as necessary to treat the disease or condition. For example, the compounds may be administered to a person with cancer for a period of about 20 to 180 days, or for example, about 20 to 90 days, or for example, about 30 to 60 days.

[0196] Administration may be intermittent, involving periods of several days or more during which the patient receives a daily dose of the compound, followed by periods of several days or more during which the patient does not receive a daily dose of the compound. For example, a patient may receive a certain dose of the compound every other day or three times per week. As a further example, a patient may receive a certain 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 certain 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 administration and subsequent non-administration of the compound may be repeated as clinically necessary to treat the patient.

[0197] In some embodiments, a pharmaceutical composition is provided comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents (e.g., 1, 2, 3, 4, 1 or 2, 1-3, or 1-4), and a pharmaceutically acceptable excipient.

[0198] In some embodiments, kits are provided that include a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

[0199] In some embodiments, the compounds of the Disclosure, or pharmaceutically acceptable salts thereof, are combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, the compounds of the Disclosure, or pharmaceutically acceptable salts thereof, are combined with two additional therapeutic agents. In some embodiments, the compounds of the Disclosure, or pharmaceutically acceptable salts thereof, are combined with three additional therapeutic agents. In some embodiments, the compounds of the Disclosure, or pharmaceutically acceptable salts thereof, are 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 and / or selected from different classes.

[0200] In some embodiments, when the compounds of this disclosure are 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.

[0201] In some embodiments, the compounds of the present disclosure are combined with one or more additional therapeutic agents in a unit dosage form for co-administration to a patient, for example, as a solid dosage form for oral administration.

[0202] In some embodiments, the compounds of this disclosure are administered concurrently with one or more additional therapeutic agents.

[0203] To extend the effects of the compounds of this disclosure, it is often desirable to delay the absorption of the compounds by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous substance with poor water solubility. In this case, the absorption rate of the compound depends on its dissolution rate, which may then depend on the crystal size and crystalline form. Alternatively, delaying the absorption of parenterally administered compound forms is achieved by dissolving or suspending the compound in an oily medium. Injectable depot formulations are prepared by forming a microencapsulation matrix of the compound in a biodegradable polymer such as polylactic acid-polyglycolide. The compound release rate can be controlled depending on the ratio of the compound to the polymer and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Injectable depot formulations can also be prepared by encapsulating the compound in liposomes or microemulsions compatible with body tissues.

[0204] VII.How to use This disclosure further relates to the use of the compounds disclosed herein for the treatment and / or prevention of diseases and / or conditions caused by inhibition of KRAS G12D and / or G12C. Furthermore, this disclosure relates to the use of said compounds for the preparation of pharmaceuticals for the treatment and / or prevention of cancer.

[0205] The pharmaceuticals referred to herein may be prepared by conventional processes, which involve combinations of the compounds described herein with pharmaceutically acceptable carriers.

[0206] In some embodiments, the Specified provides a method for inhibiting the KRAS G12D protein in a subject requiring inhibition of the KRAS G12D protein, comprising administering to the subject a therapeutically effective amount of a compound of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2).

[0207] In some embodiments, the Specified provides a method for treating cancer in a subject requiring treatment, comprising administering to the subject a therapeutically effective amount of a compound of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2).

[0208] In some embodiments, methods for treating and / or preventing cancer are provided herein.

[0209] In some embodiments, methods for treating and / or preventing KRAS G12D-related cancers are provided herein.

[0210] In some embodiments, the Specified Information Provides a method for reducing cell proliferation, comprising contacting cells with a compound of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2).

[0211] In some embodiments, KRAS G12D-related diseases or conditions include cancer. In some embodiments, cancer is a hematological cancer. In some embodiments, cancer is a solid tumor. In some embodiments, cancer is a malignant tumor. In some embodiments, cancer includes metastatic cancer. In some embodiments, cancer is resistant or refractory to one or more anticancer therapies. In some embodiments, more than 50% of cancer cells have one or more cell surface immune checkpoint receptors (e.g., so-called "hot" inflammatory checkpoint receptors). In some embodiments, more than 1% and less than 50% of cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., so-called "warm" cancer or tumor). In some embodiments, less than 1% of cancer cells detectably express one or more cell surface immune checkpoint receptors (e.g., so-called "cold" cancer or tumor).

[0212] In some embodiments, KRAS G12D-related diseases or conditions include blood cancers, e.g., 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) Lymphoma (FL), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL), primary macroglobulinemia (Waldestrom's macroglobulinemia, WM), and / or myeloma (e.g., multiple myeloma, MM) )) is.

[0213] In some embodiments, KRAS G12D-related diseases or conditions include epithelial tumors (e.g., carcinoma, squamous cell carcinoma, basal cell carcinoma, squamous intraepithelial neoplasm), tubular tumors (e.g., adenocarcinoma, adenoma, adenomyoma), mesenchymal tumors or soft tissue tumors (e.g., sarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, dermatofibrosarcoma, neurofibrosarcoma, fibrous histiocytoma, angiosarcoma, angiomyxoma, leiomyoma, chondroma, chondrosarcoma, hydatidiform soft tissue sarcoma, epithelioid hemangioendothelioma, Spitz tumor, synovial sarcoma), and lymphoma.

[0214] In some embodiments, KRAS G12D-related diseases or conditions include solid tumors in tissues or organs, or solid tumors arising from tissues or organs, 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, tendonoid, 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 sialadenoma, adenoid cystic carcinoma of the salivary gland, mucoepidermoid carcinoma of the salivary gland, Warthin's tumor of the salivary gland); • Esophagus (e.g., Barrett's esophagus, dysplasia, and adenocarcinoma); • The gastrointestinal tract (including the stomach (e.g., gastric adenoma, primary gastric lymphoma, gastrointestinal stromal tumor (GIST), metastatic deposition, 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-Landau (VHL)-associated serous cystic neoplasm, serous cystadenocara); mucinous cystic neoplasm (MCN), intraductal papillary mucinous neoplasm (IPMN), intraductal oncocytic papillary neoplasm) IOPN), intraductal tubular tumors of the pancreas, cystic acinar neoplasms (including acinar cell cystadenoma, acinar cell cystadenocarcinoma, and pancreatic adenocarcinoma), invasive ductal adenocarcinoma (including tubular adenocarcinoma and adenosquamous cell carcinoma), mucinous carcinoma, medullary carcinoma, hepatoid carcinoma, signet ring cell carcinoma, anaplastic carcinoma, anaplastic carcinoma with osteoclast-like giant cells, acinar cell carcinoma, neuroendocrine tumors, neuroendocrine microadenomas, neuroendocrine tumors (NETs), neuroendocrine carcinomas (NECs) (including small cell or large cell NECs), islet cell adenomas, gastrin-producing tumors, glucagon-producing tumors, serotonin-producing NETs, ​​somatostatin-producing tumors, VIP-producing tumors, solid pseudopapillary neoplasms (SPNs), pancreatic blastomas); • Gallbladder (e.g., carcinoma of the gallbladder and extrahepatic bile ducts, intrahepatic bile duct cancer); • Neuroendocrine conditions (e.g., adrenocortical carcinoma, carcinoid tumor, pheochromocytoma, pituitary adenoma); • Thyroid gland (e.g., poorly differentiated (undifferentiated) carcinoma, medullary carcinoma, oncocytic tumor, papillary carcinoma, adenocarcinoma); • Liver (e.g., adenoma, mixed type of hepatocellular carcinoma and cholangiocarcinoma, lamellar carcinoma, hepatoblastoma, hepatocellular carcinoma, mesenchymal tumor, nested stromal epithelial tumor, undifferentiated carcinoma; hepatocellular carcinoma, intrahepatic cholangiocarcinoma, cystic 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, chromophobic renal cell carcinoma, clear cell carcinoma, clear cell sarcoma, metanephrotic adenoma, metanephrotic adenofibrilloma, renal mucinous tubular spindle cell carcinoma, renal tumor, nephroblastoma (Wilms' tumor), papillary adenoma, papillary renal cell carcinoma, renal oncocytoma, renal cell carcinoma, succinate dehydrogenase-deficient renal cell carcinoma, collecting duct carcinoma); • Breast (for example, invasive ductal carcinoma (including, but not limited to, acinar cell carcinoma, adenoid cystic carcinoma, apocrine carcinoma, cribriform carcinoma, glycogen-rich / clear cell carcinoma, inflammatory carcinoma, lipid-rich carcinoma, medullary carcinoma, metaplastic carcinoma, micropapillary carcinoma, mucinous carcinoma, neuroendocrine carcinoma, malignant splenocyte carcinoma, papillary carcinoma, sebaceous carcinoma, secretory breast carcinoma, tubular carcinoma); lobular carcinoma (including, but not limited to, pleomorphic cell carcinoma, signet ring cell carcinoma); • Peritoneal tissue (e.g., mesothelioma; primary peritoneal cancer); • Ovaries (e.g., choriocarcinoma, epithelial tumors, germ cell tumors, sex cord-stromal tumors), Fallopian tubes (e.g., serous adenocarcinoma, mucinous carcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma, undifferentiated carcinoma, Müller's tumor, adenosarcoma, leiomyosarcoma, teratoma, germ cell tumors, choriocarcinoma, trophoblastic tumors), uterus (e.g., cervical cancer, endometrial polyps, endometrial hyperplasia, carcinoma in situ (EIC)), endometrial cancer (e.g., endometrioid carcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, squamous cell carcinoma) Female reproductive tissue, including epithelial carcinoma, transitional 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., adenofibrilloma, carcinofibrilloma, adenosarcoma, carcinosarcoma (malignant mixed mesodermal sarcoma MMMT)), endometrial stromal tumor, malignant Müllerian ductal mixed tumor of the endometrium, choriocarcinoma of pregnancy (partial hydatidiform mole, complete hydatidiform mole, invasive hydatidiform mole, placental attachment tumor)), vulva, vagina; • Male reproductive organs, including the prostate, testes (e.g., germ cell tumors, spermatocyte seminomas), and penis; • Bladder (e.g., squamous cell carcinoma, urothelial carcinoma, bladder urothelial carcinoma); • Brain (e.g., gliomas (e.g., astrocytoma (non-invasive, low-grade, poorly differentiated, glioblastoma; oligodendroglioma, ependymoma), meningioma, ganglioglioma, schwannoma, craniopharyngioma, chordoma, non-Hodgkin lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL) HL, pituitary tumor; • Eyes (e.g., retinocytoma, retinoblastoma, intraocular melanoma, posterior uveal melanoma, iris hamartoma); • Head and neck (e.g., nasopharyngeal cancer, endolymphatic sac tumor, E) LST), epidermal carcinoma, laryngeal carcinoma (squamous cell carcinoma, SCC) (e.g., glottic carcinoma, supraglottic carcinoma, subglottic carcinoma, combined laryngeal carcinoma), in situ carcinomas, wart-like, spindle cell carcinomas, and basal SCCs, undifferentiated carcinomas, laryngeal adenocarcinoma, adenoid cystic carcinoma, neuroendocrine carcinoma, laryngeal sarcomas), paragangliomas of the head and neck (e.g., carotid body, paraganglioma, vagus nerve); • Thymus (e.g., thymoma); • The heart (for example, 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, and pleuropulmonary blastoma); • Lymphomas (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), painless non-Hodgkin lymphoma (iNHL), refractory iNHL), Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (B-cell lymphoma and T This includes cellular lymphomas (e.g., Burkitt lymphoma); large B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, slow B-cell lymphoma, low-grade B-cell lymphoma, fibrin-associated diffuse large B-cell lymphoma; primary humoral lymphoma; plasmablastic lymphoma; extranodal NK / T-cell lymphoma (nasal type); peripheral T-cell lymphoma, cutaneous T-cell lymphoma, angioimmunoblastic T-cell lymphoma; follicular T-cell lymphoma; systemic T-cell lymphoma); lymphangioleiomyomatosis; · central nervous system system, CNS) (e.g., gliomas, including 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) cell tumors, 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. Subependymal tumors, myxopapillary ependymomas, ependymomas (e.g., cell, papillary, clear cell, elongated ependymal cell), poorly differentiated ependymomas), optic gliomas, and non-gliomas (e.g., choroid plexus tumors, neuronal and mixed neuronal / glial cell tumors, pineal tumors, germ cell tumors, medulloblastomas, meningeal tumors, primary CNS lymphomas, germ cell tumors, pituitary adenomas, cranial and paravertebral nerve tumors, stellate region tumors); neurofibromas, meningiomas, peripheral nerve sheath tumors, neuroblastoma group tumors (neuroblastoma, ganglioblastoma, gangliomas), trisomia 19 ependymomas, but not limited to these); • Neuroendocrine tissue (e.g., preganglionic system including adrenal medulla (pheochromocytoma) and extraadrenal paraganglioma); • Skin (including, for example, clear cell hidradenoma, benign cutaneous fibrous histiocytoma, cystoma, hidradenoma, melanoma (cutaneous melanoma, mucosal melanoma), pilomatoma, and Spitz tumor); • Soft tissue (e.g., invasive angiomyxoma, alveolar rhabdomyosarcoma, hydatidiform soft tissue sarcoma, angiofibroma, hemangiomatous fibrous histiocytoma, synovial sarcoma, biphasic synovial sarcoma, clear cell sarcoma, dermatofibrosarcoma protuberans, desmoid fibromatosis, small round cell tumor, fibroplastic small round cell tumor, elastic fibroma, embryonal rhabdomyosarcoma, Ewing's sarcoma / primitive neuroectodermal tumor) Examples include tumor (PNET), extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, paravertebral sarcoma, inflammatory myofibroblastoma, lipoblastoma, lipoma, chondroid lipoma, liposarcoma / malignant lipomatous tumor, liposarcoma, myxoid liposarcoma, fibromyxoid sarcoma, lymphangioleiomyoma, malignant myoepithelioma, malignant soft tissue melanoma, myoepithelial carcinoma, myoepithelioma, myxoinflammatory fibroblast sarcoma, undifferentiated sarcoma, perivascular cell tumor, rhabdomyosarcoma, non-rhabdomyosarcoma, soft tissue sarcoma (NRSTS), soft tissue leiomyosarcoma, undifferentiated sarcoma, and well-differentiated liposarcoma.

[0215] In some embodiments, the KRAS G12D-related 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.

[0216] In some embodiments, KRAS G12D-related diseases or conditions include non-small cell lung cancer (NSCLC), melanoma, triple-negative breast cancer (TNBC), nasopharyngeal cancer (NPC), and microsatellite-stable colorectal cancer (MSS). The cancer is selected from CRC, thymoma, and gastrointestinal stromal tumor (GIST). In some embodiments, the cancer is metastatic.

[0217] In some embodiments, the KRAS G12D-related disease or condition is a cancer of the pancreas, bladder, colorectal, breast, prostate, kidney, hepatocellular carcinoma, lung, ovarian, cervical, uterine, stomach, bile duct, testicular, esophageal, head and neck, 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 colorectal cancer.

[0218] In some embodiments, KRAS G12D-related diseases or conditions include pancreatic cancer, colorectal cancer, non-small cell lung cancer, endometrial cancer, uterine endometrical carcinoma, cholangiocarcinoma, testicular germ cell cancer, cervical squamous cell carcinoma, Alternatively, it could be cancer associated with myelodysplastic syndrome.

[0219] In some embodiments, cancer is myelodysplastic syndrome. In some embodiments, cancer is high-risk myelodysplastic syndrome or low-risk myelodysplastic syndrome. In some embodiments, cancer is high-risk myelodysplastic syndrome. In some embodiments, cancer is high-risk myelodysplastic syndrome.

[0220] 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 uterine cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is testicular germ cell cancer. In some embodiments, the cancer is cervical squamous cell carcinoma. In some embodiments, the cancer is bile duct cancer.

[0221] The effective dose of the active ingredient used may vary depending on the specific compound used, the mode of administration, the condition being treated, and the severity of the condition being treated. Such doses can be easily determined by those skilled in the art.

[0222] When treating or preventing KRAS G12D-related diseases or conditions requiring the compounds of this disclosure, generally satisfactory results are obtained when the compounds are administered at a daily dose of approximately 0.1 milligrams to approximately 300 milligrams per kilogram of animal body weight. In some embodiments, the compounds of this disclosure are administered as a single daily dose, in 2 to 6 divided doses per day, or in a sustained-release form. For most large mammals, the total daily dose is approximately 1 milligram to approximately 1000 milligrams, or approximately 1 milligram to approximately 50 milligrams. For a 70 kg adult human, the total daily dose is generally approximately 0.1 milligrams to approximately 200 milligrams. This dosage regimen can be adjusted to provide an optimal therapeutic response. In some embodiments, the total daily dose is approximately 1 milligram to 900 milligrams, approximately 1 milligram to 800 milligrams, approximately 1 milligram to 700 milligrams, approximately 1 milligram to 600 milligrams, approximately 1 milligram to 400 milligrams, approximately 1 milligram to 300 milligrams, approximately 1 milligram to 200 milligrams, approximately 1 milligram to 100 milligrams, approximately 1 milligram to 50 milligrams, approximately 1 milligram to 20 milligrams, or approximately 1 milligram to 10 milligrams.

[0223] The compounds or compositions thereof of this application may be administered once, twice, three times, or four times daily using any preferred form described above. Administration or treatment with the compounds may be continued for several days; for example, treatment will typically last for at least 7, 14, or 28 days for one treatment cycle. Treatment cycles alternate periodically with rest periods of approximately 1 to 28 days, usually about 7 or 14 days, between cycles. Treatment cycles may also be continuous in other embodiments.

[0224] In some embodiments, the methods described herein include administering an initial daily dose of about 1 to 800 mg of the compound described herein, and increasing the dose incrementally until clinical efficacy is achieved. The dose may be increased using increments of about 5, 10, 25, 50, or 100 mg. The dose may be increased daily, every other day, twice a week, or once a week.

[0225] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, are administered in combination with one or more additional therapeutic agents or modes of treatment.

[0226] In some embodiments, the Disclosure provides a pharmaceutical composition or method in which one or more further additional therapeutic agents or additional therapeutic modes comprise one, two, three, or four additional therapeutic agents and / or therapeutic modes.

[0227] In some embodiments, the Disclosure provides pharmaceutical compositions or methods in which an additional therapeutic agent or mode of treatment is selected from immune checkpoint modulators, antibody-drug conjugates (ADCs), anti-apoptotic agents, targeted anticancer agents, chemotherapeutic agents, surgery, or radiotherapy.

[0228] In some embodiments, the present disclosure provides pharmaceutical compositions or methods in which the immune checkpoint modulator is selected from anti-PD-(L)1 antibodies, anti-TIGIT antibodies, anti-CTLA4 antibodies, anti-CCR8 antibodies, anti-TREM1 antibodies, anti-TREM2 antibodies, CD47 inhibitors, DGKα inhibitors, HPK1 inhibitors, FLT3 agonists, adenosine receptor antagonists, CD39 inhibitors, CD73 inhibitors, IL-2 variants (IL-2v), and CAR-T cell therapy.

[0229] In some embodiments, the Disclosure provides a pharmaceutical composition or method in which the anti-PD-(L)1 antibody is selected from pembrolizumab, nivolumab, semiprimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosiberimab, sasamlimab, tislerizumab, retifanlimab, valstilimab, tripalimab, cetrelimab, genolimuzumab, prorugolimab, rhodapolimab, camrelizumab, buzigalimab, avelumab, dostalimab, emvafolimab, cintilimab, and zimbererimab.

[0230] In some embodiments, the present disclosure provides a pharmaceutical composition or method in which the anti-TIGIT antibody is selected from tilagolmab, vivostrimab, domvanarimab, AB308, AK127, BMS-986207, and etigirimab.

[0231] In some embodiments, the disclosure provides a pharmaceutical composition or method in which the anti-CTLA4 agent is selected from ipilimumab, tremelimumab, and zarifremab.

[0232] In some embodiments, the present disclosure provides a pharmaceutical composition or method in which the CD47 inhibitor is selected from maglorimab, letaprimab, remzopalimab, AL-008, RRx-001, CTX-5861, FSI-189 (GS-0189), ES-004, BI-765063, ADU1805, CC-95251, and Q-1801.

[0233] In some embodiments, the present disclosure provides pharmaceutical compositions or methods in which the adenosine receptor antagonist is etramandent (AB928), taminadenant, TT-10, TT-4, or M1069.

[0234] In some embodiments, the present disclosure provides a pharmaceutical composition or method in which the CD39 inhibitor is TTX-030.

[0235] In some embodiments, the present disclosure provides a pharmaceutical composition or method in which the CD73 inhibitor is quemliculstat (AB680), uriredlimab, mupadlimab, ORIC-533, ATG-037, PT-199, AK131, NZV930, BMS-986179, or oleculumab.

[0236] In some embodiments, the present disclosure provides a pharmaceutical composition or method in which IL-2v is aldesleukin (Proleukin), bempegaldesleukin (NKTR-214), nembaleukin 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.

[0237] In some embodiments, the disclosure provides a pharmaceutical composition or method in which the ADC is selected from sacituzumab govitecan, datopotamab deruxtecan, enfortumab vedotin, and trastuzumab deruxtecan.

[0238] In some embodiments, the present disclosure provides a pharmaceutical composition or method in which an additional therapeutic agent is selected from idelalisib, sacituzumab govitecan, maglorimab, GS-0189, GS-3583, zimbererimab, GS-4224, GS-9716, GS-6451, GS-1811 (JTX-1811), quemliculstat (AB680), eturmadenant (AB928), dombanalimab, AB308, PY159, PY314, AGEN-1223, AGEN-2373, axicapbutazine siloleucel, and brexcabutazine autoleucel.

[0239] 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 therapeutic agents as described below. In some embodiments, the one or more additional therapeutic agents are independently chemotherapeutic agents, immunotherapeutic agents, hormonal agents, antihormone agents, targeted therapeutic agents, or anti-angiogenic agents.

[0240] In some embodiments, one or more additional therapeutic agents include therapeutic agents 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, one or more additional therapeutic agents include high-risk myelodysplastic syndrome (HR MDS). The present invention includes therapeutic agents used to treat MDS. In some embodiments, one or more additional therapeutic agents include azacitidine (Vidaza®), decitabine (Dacogen®), lenalidomide (Revlimid®), cytarabine, idarubicin, daunorubicin, cytarabine + daunorubicin, cytarabine + idarubicin, pevonedistat, venetoclax, sabatrimab, guadecitabine, rigosatib, ivosidenib, enazidenib, selinexol, BGB324, DSP-7888, or SNS-301.

[0241] In some embodiments, one or more additional therapeutic agents include therapeutic agents used to treat low-risk myelodysplastic syndrome (LR MDS). In some embodiments, one or more additional therapeutic agents include lenalidomide, azacitidine, roxadustat, raspatercept, imeterstat, LB-100, or ligosatib.

[0242] In some embodiments, one or more additional therapeutic agents include therapeutic agents used to treat colorectal cancer. In some embodiments, one or more additional therapeutic agents include 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 (Orcantas®), XELOX, FOLFOXIRI, bevacizumab + leucovorin + 5-FU + oxaliplatin (FOLFOX), bevacizumab + FOLFIRI, bevacizumab + FOLFOX, aflibercept + FOLFIRI, cetuximab + FOLFIRI, bevacizumab + XELOX, bevacizumab + FOLFOXIRI, binimetinib + encorafenib + cetuximab, trametinib + dabrafenib + panitumumab, trastuzumab + pertuzumab, napabucasin + FOLFIRI + bevacizumab, or nivolumab + ipilimumab.

[0243] In some embodiments, one or more additional therapeutic agents include therapeutic agents used to treat non-small cell lung cancer (NSCLC). In some embodiments, one or more additional therapeutic agents include afatinib, albumin-bound paclitaxel, alectinib, atezolizumab, bevacizumab, bevacizumab, cabozantinib, carboplatin, cisplatin, crizotinib, dabrafenib, docetaxel, erlotinib, etoposide, gemcitabine, nivolumab, paclitaxel, pembrolizumab, pemetrexed, ramucirumab, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine, vinorelbine, alectinib (Ale Censa (registered trademark), dabrafenib (Tafinlar (registered trademark)), trametinib (Mekinist (registered trademark)), osimertinib (Tagrisso (registered trademark)), entrectinib (Tarceva (registered trademark)), crizotinib (Xalkori (registered trademark)), pembrolizumab (Keytruda (registered trademark)), carboplatin, pemetrexed (Alimta (registered trademark)), nab-paclitaxel (Abraxane (registered trademark)), ramucirumab (Cyramza (registered trademark)), 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 Pemetrexed + Carboplatin, Cisplatin + Pemetrexed, Bevacizumab + Carboplatin + Nab-Paclitaxel, Cisplatin + Gemcitabine, Nivolumab + Docetaxel, Carboplatin + Pemetrexed, Carboplatin + Nab-Paclitaxel, or Pemetrexed + Cisplatin + Carboplatin, Datopotamab Deruxtecan (DS-1062), Trastuzumab Deruxtecan (Enhertu®), Enfortumab Vedotin (Padcev®), Durvalumab, Canakinumab,Includes semiprimab, nogapendkin alfa, avelumab, tilagolmab, dombanarimab, vivostrimab, osiperlimab, datopotamab deruxtecan + pembrolizumab, datopotamab deruxtecan + durvalumab, durvalumab + tremelimumab, pembrolizumab + lenvatinib + pemetrexed, pembrolizumab + olaparib, nogapendkin alfa (N-803) + pembrolizumab, tilagolmab + atezolizumab, vivostrimab + pembrolizumab, or osiperlimab + tislerizumab.

[0244] In some embodiments, one or more additional therapeutic agents include therapeutic agents used to treat pancreatic cancer. In some embodiments, one or more additional therapeutic agents include 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.

[0245] In some embodiments, one or more additional therapeutic agents include therapeutic agents used to treat endometrial cancer. In some embodiments, one or more additional therapeutic agents include carboplatin, paclitaxel, cisplatin, doxorubicin, ifosfamide, progesterone, anastrozole (Arimidex®), letrozole (Femara®), exemestane (Aromasin®), pembrolizumab (Keytruda®), lenvatinib (Lenvima®), or dostarimab (Jemperli®).

[0246] In some embodiments, one or more additional therapeutic agents are independently SNS-301, 5-FU + leucovorin + oxaliplatin + irinotecan, 5-FU + nanoliposomal irinotecan, 5-FU, afatinib (Gilotrif®), aflibercept (Zaltrap®), aflibercept + FOLFIRI, albumin-conjugated paclitaxel, alectinib (Alecensa®), anastrozole (Arimidex®), atezolizumab, avelumab, azacitidine (Vidaza®) (Trademark), Bevacizumab (Avastin (Registered Trademark)), 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, Carboplatin + Na β-paclitaxel, carboplatin + pemetrexed, carboplatin, semiprimab, 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, dombanarimab, 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, Ibosidenib, LB-100, Lenalidomide (Revlimid®), Lenalidomide, Lenvatinib (Lenvima®), Letrozole (Femara®), Leucovorin + Nanoliposomal Irinotecan, Leucovorin, Lonsurf (Orcantas®) (Trademark), Raspatercept, nab-paclitaxel (Abraxane®), napabucasin + FOLFIRI + bevacizumab, nivolumab (Opdivo®), nivolumab + docetaxel, nivolumab + ipilimumab, nogapendkin alfa (N-803) + pembrolizumab, nogapendkin alfa, osiperlimab + tislerizumab, osiperlimab, osimertinib (Tagrisso®), oxaliplatin (FOLFOX), paclitaxel, panitumumab, pembrolizumab (Keytru da(registered trademark), pembrolizumab + carboplatin + nab-paclitaxel, pembrolizumab + carboplatin + pemetrexed, pembrolizumab + lenvatinib + pemetrexed, pembrolizumab + olaparib, pembrolizumab + pemetrexed + carboplatin, pemetrexed (Alimta(registered trademark)), pemetrexed + cisplatin + carboplatin, pevonedistat, progesterone, ramucirumab (Cyramza(registered trademark)), ramucirumab + docetaxel, regorafenib (Stivarga(registered trademark) These are registered trademarks: rigosatib, roxadustat, sabatrimab, selinexol, tiragolumab + atezolizumab, tiragolumab, trametinib (Mekinist®), trametinib + dabrafenib + panitumumab, trastuzumab + pertuzumab, trastuzumab deruxtecan (Enhertu®), trastuzumab, vandetanib, vemurafenib, venetoclax, vivostrimab + pembrolizumab, vivostrimab, vinblastine, vinorelbine, XELOX, or ziv-aflibercept.

[0247] In another embodiment, the Disclosure provides a method for producing a pharmaceutical product for treating cancer in a subject requiring treatment of cancer, characterized by the use of a compound of the Disclosure or a pharmaceutically acceptable salt thereof.

[0248] In another embodiment, the present disclosure provides a method for producing a pharmaceutical product for inhibiting cancer metastasis in a subject where it is necessary to inhibit cancer metastasis, characterized by using the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0249] In another embodiment, the Disclosure provides the use of the compounds of the Disclosure, or pharmaceutically acceptable salts thereof, for the manufacture of a pharmaceutical product for the treatment of cancer in a subject.

[0250] In another embodiment, the disclosure provides the use of the compounds of the disclosure, or pharmaceutically acceptable salts thereof, for the manufacture of pharmaceuticals for inhibiting cancer metastasis in a subject.

[0251] In another embodiment, the Disclosure provides compounds of the Disclosure, or pharmaceutically acceptable salts thereof, for use in the treatment of cancer in subjects requiring cancer treatment.

[0252] In another embodiment, the Disclosure provides compounds of the Disclosure, or pharmaceutically acceptable salts thereof, for use in inhibiting cancer metastasis in subjects requiring inhibition of cancer metastasis.

[0253] In another embodiment, the Disclosure provides compounds of the Disclosure, or pharmaceutically acceptable salts thereof, for use in therapeutics.

[0254] VIII. Combination Therapy In some embodiments, compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2) provided herein, or pharmaceutically acceptable salts thereof, are administered in combination with one or more additional therapeutic agents to treat or prevent a disease or condition disclosed herein. In some embodiments, the one or more additional therapeutic agents are one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are four additional therapeutic agents.

[0255] In some embodiments, the pharmaceutical compositions provided herein comprise compounds of formula J, (I-1), (I-2), (I-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (IIb), (IIb-1), or (IIb-2) provided herein, or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one, two, three, or four additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are one additional therapeutic agent. In some embodiments, the one or more additional therapeutic agents are two additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are three additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are four additional therapeutic agents.

[0256] In some embodiments, additional therapeutic agents include, for example, inhibitory immune checkpoint blockers or inhibitors, stimulant immune checkpoint stimulants, agonists or activators, chemotherapeutic agents, anticancer agents, radiotherapy agents, antineoplastic agents, antiproliferative agents, anti-angiogenic agents, anti-inflammatory agents, immunotherapy agents, therapeutic antigen-binding molecules (e.g., monospecific and multispecific antibodies of any form, such as DART®, Duobody®, BiTE®, BiKE, TriKE, XmAb®, TandAb®, scFv, Fab, Fab derivatives, and their fragments), bispecific antibodies, non-immunoglobulin antibody mimics (e.g., adonectin, afibody, affin, affimer, afitin, alphabody, antikalin, peptide aptamers, armadillo repeat proteins). Cells containing proteins (including ARM), atrimers, avimers, designed ankyrin repeat proteins (DARPin®), finomers, Nottin, Knitz domain peptides, monobodies, and nanoCLAMPs), antibody-drug conjugates (ADCs), antibody-peptide conjugates), oncolytic viruses, gene modifiers or editing agents, and chimeric antigen receptors (CARs) (e.g., Examples include T cell immunotherapy agents, NK cell immunotherapy agents, or macrophage immunotherapy agents, cells containing genetically modified T cell receptors (TCR-T), or any combination thereof.

[0257] Exemplary target In some embodiments, one or more additional therapeutic agents include inhibitors, agonists, antagonists, ligands, modulators, stimulants, blockers, activators, or inhibitors of a target (e.g., polypeptides or polynucleotides), such as those listed below. 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 proto-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 (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 receptor (e.g., ADORA1 (A1), ADORA2A (A2a, A2AR), ADORA2B (A2b, A2BR), ADORA3 (A3), NCBI gene IDs: 134, 135, 136, 13 7) AKT serine / threonine kinase 1 (AKT1, AKT, PKB, NCBI gene ID: 207), alanylaminopeptidase, membrane (ANPEP, CD13, NCBI gene ID: 290), ALK receptor tyrosine kinase (ALK, CD242, NCBI gene ID: 238), α-fetoprotein (AFP, NCBI gene ID: 174), copper-containing amine oxidase (e.g., AOC (amine oxidase copper) 1 (DAO1), AOC2, AOC3 (VAP1), NCBI gene IDs: 26, 314, 8639), androgen receptor (androgenreceptor (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-related 1 (AIFM1, AIF, NCBI gene ID: 9131), arachidonic acid 5-lipoxygenase (ALOX5, NCBI gene ID: 240), asparaginase (ASPG, NCBI gene ID: 374569), asteroid homolog 1 (ASTE1, NCBI gene ID: 28990), ATM serine / threonine kinase (ATM, NCBI gene ID: 472), AT P-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-related (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), basidine (Ok blood group) (BSG, CD147, NCBI gene ID: 682), B-cell lymphoma 2 (B-cell lymphoma 2, BCL2, NCBI gene ID:596), BCL2 binding component 3 (BCL2 binding component 3, BBC3, PUMA, NCBI gene ID: 271) 13) BCL2-like (e.g., BCL2L1 (Bcl-x), BCL2L2 (BIM), Bcl-x, NCBI gene ID: 598, 10018), β3-adrenergic receptor (ADRB3, NCBI gene ID: 155), bone gamma-carboxyglutamate protein (BGLAP, NCBI gene ID: 632), bone morphogenetic protein-10 ligand (BMP10, NCBI gene ID: 27302), bradykinin receptor (e.g., BDKRB1, BDKRB2, NCBI gene ID: 623, 624), B-RAF (BRAF, NCBI gene ID: 273), breakpoint cluster region (BCR, NCBI gene ID: 613), bromodomain and extradomain (BET ) Bromodomain-containing proteins (e.g., BRD2, BRD3, BRD4, BRDT, NCBI gene IDs: 6046, 8019, 23476, 676), Bruton's tyrosine kinase kinases (BTK, NCBI gene ID: 695), cadherins (e.g., CDH3 (p-cadherin), CDH6 (k-cadherin), NCBI gene IDs: 1001, 1004), cancer / testicular antigens (e.g., CTAG1A, CTAG1B, CTAG2, NCBI gene IDs: 1485, 30848, 246100), cannabinoid receptors (e.g., CNR1 (CB1), CNR2 (CB2), NCBI gene IDs: 1268, 1269), carbohydrate sulfotransferase 15 (CHST15, NCBI gene ID: 51363), carbonic anhydrase (e.g., CA (carbonic anhydrase)) 1, CA2, CA3, CA4, CA5A, CA5B, CA6, CA7, CA8, CA9, CA10, CA11, CA12, CA13, CA14, NCBI gene IDs: 759, 760, 761, 762, 763, 765, 766, 767, 768, 770, 771, 11238, 23632, 56934, 377677), carcinoembryonic antigen-associated cell adhesion molecules ( For example, CEACAM3 (CD66d), CEACAM5 (CD66e), CEACAM6 (CD66c), NCBI gene IDs: 1048, 1084, 4680), casein kinases (for example, CSNK1A1 (CK1), CSNK2A1 (CK2), NCBI gene IDs: 1452, 1457), caspases (for example, CASP3, CASP7, CASP8) (NCBI gene IDs: 836, 840, 841, 864), Cathenin β1 (CTNNB1, NCBI gene ID: 1499), Cathepsin G (CTSG, NCBI gene ID: 1511), Cbl proto-oncogene B (CBLB, Cbl-b, NCBI gene ID: 868), CC motif chemokine ligand 21 (CCL21, NCBI gene ID: 6366), CC motif chemokine receptor 2 (CCR2, NCBI gene ID: 729230), CC motif chemokine receptor (e.g., CCR3 (CD193), CCR4 (CD194), CCR5 (CD195), CCR8 (CDw198), NCBI gene IDs: 1232, 1233, 1234, 1237), CCAAT enhancer-binding protein α (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 kinase (e.g., CHEK1 (CHK1), CHEK2 (CHK2), NCBI gene IDs: 1111, 11200), cholecystokinin B receptor (CCKBR, NCBI gene ID: 887), chorionic somatomammotropin hormone 1Hormone 1, CSH1, NCBI gene ID: 1442), claudins (e.g., CLDN6, CLDN18, NCBI gene IDs: 9074, 51208), differentiation cluster markers (e.g., CD1A, CD1C, CD1D, CD1E, CD2, CD3 alpha (TRA), CD beta (TRB), CD gamma (TRG), CD delta (TRD), CD4, CD8A, CD8B, CD19, CD20 (MS4A1)) , CD22, CD24, CD25 (IL2RA, TCGFR), CD28, CD33 (SIGLEC3), CD37, CD38, CD39 (ENTPD1), CD40 (TNFRSF5), CD44 (MIC 4, PGP1), CD47(IAP), CD48(BLAST1), CD52, CD55(DAF), CD58(LFA3), CD74, CD79a, CD79b, CD80(B7-1), CD84, CD86 (B7-2), CD96(TACTILE), CD99(MIC2), CD115(CSF1R), CD116(GMCSFR, CSF2RA), CD122(IL2RB), CD123(IL3RA), C D128(IL8R1), CD132(IL2RG), CD135(FLT3), CD137(TNFRSF9, 4-1BB), CD142(TF, TFA), CD152(CTLA4), CD160, CD 182(IL8R2), CD193(CCR3), CD194(CCR4), CD195(CCR5), CD207, CD221(IGF1R), CD222(IGF2R), CD223(LAG3), CD 226(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, 696 5, 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 IVα chains (e.g., COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, NCBI gene IDs: 1282, 1284, 1285, 1286, 1287), collectin subfamily member 10 (COLEC10, NCBI gene ID: 10584), colony-stimulating factors (e.g., CSF (colony stimulating factor) 1 (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 (CD371), CD371, NCBI gene IDs: 160364, 170482, 283420), CXC motif chemo Cain ligand 12 (CXCL12, NCBI gene ID: 6387), CXC motif chemokine receptors (CXCR1 (IL8R1, CD128), CXCR2 (IL8R2, CD182), CXCR3 (CD182, CD183, IP-10R), CXCR4 (CD184), NCBI gene IDs: 2833, 3577, 3579, 7852), cyclin D1 (CCND1, BCL1, NCBI gene ID: 595), cyclin-dependent kinases (e.g., CDK (cyclin dependent kinase) 1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, C DK8, 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 ID: 1565, 1576, 1583, 1585, 1586, 1588, 1595), Cytochrome P450 oxidoreductase (POR, NCBI gene ID: 5447), Cytokine-inducible SH2-containing protein (CISH, NCBI gene ID: 1154), Cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152, NCBI gene ID: 1493), DEAD-box helicases (e.g., DDX5, DDX6, DDX58, NCBI gene IDs: 1655, 1656, 23586), delta-like canonical Notch ligands (e.g., DLL3, DLL4, NCBI gene IDs: 10683, 54567), Diablo IAP-binding mitochondrial protein (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), discoidine domain receptor tyrosine kinases (e.g., DDR1 (CD167), DDR2, CD167, NCBI gene ID: 780) ,4921), DNA-dependent protein kinase (PRKDC, NCBI gene ID: 5591), DNA topoisomerase (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 (endoglin, ENG, NCBI gene ID: 2022), endoplasmic reticulum aminopeptidases (e.g., ERAP1, ERAP2, NCBI gene IDs: 51752, 64167), zeste2 polycomb repression Enhancers of 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), ephrin (e.g., EFNA1, EFNA4, EFNB2, NCBI gene IDs: 1942, 1945, 1948), epidermal growth factor receptor (e.g., ERBB) 1 (HER1, EGFR), ERBB1 variant III (EGFRvIII), ERBB2 (HER2, NEU, CD340), ERBB3 (HER3), ERBB4 (HER4), NCBI gene IDs: 1956, 2064, 2065, 2066), epithelial cell adhesion molecules (EPCAM, NCBI gene ID: 4072), epithelial mitogenic factors (EPGN, NCBI gene ID: 255324), eukaryotic translation elongation factors (e.g., EEF1A2, EEF2, NCB) I gene ID: 1917, 1938), eukaryotic translation initiation factors (e.g., EIF4A1, EIF5A, NCBI gene ID: 1973, 1984), exportin-1 (XPO1, NCBI gene ID: 7514), farnesoid X receptor (NR1H4, FXR, NCBI gene ID: 9971), Fas ligand (FASLG, FASL, CD95L, CD178, TNFSF6, NCBI gene ID: 356), fatty acid amide hydrolase (fatty acid amide hydrolase (FAAH, NCBI gene ID: 2166), fatty acid synthase (FASN, FAS, NCBI gene ID: 2194), Ig receptor Fc fragments (e.g., FCER1A, FCGRT, FCGR3A (CD16), NCBI gene IDs: 2205, 2214, 2217), Fc receptor-like 5 (FCRL5, CD307,NCBI gene ID: 83416), fibroblast-activating protein α (FAP, NCBI gene ID: 2191), fibroblast growth factor receptor (e.g., FGFR (fibroblast growth factor receptor) 1 (CD331), FGFR2 (CD332), FGFR3 (CD333), FGFR4 (CD334), NCBI gene IDs: 2260, 2261, 2263, 2264), fibroblast growth factor (e.g., FGF (fibroblast growth FGF-1 (FGFα), FGF-2 (FGFβ), FGF-4, FGF-5 (NCBI gene IDs: 2246, 2247, 2249, 2250), Fibronectin 1 (FN1, MSF, NCBI gene ID: 2335), FMS-related receptor tyrosine kinases (e.g., FLT1 (VEGFR1), FLT3 (STK1, CD135), FLT4 (VEGFR2), NCBI gene IDs: 2321, 2322, 2324), FMS-related receptor tyrosine kinase 3 ligand (FLT3LG, NCBI gene ID: 2323), Adhesion plaque kinase 2 (PTK2, FAK1, NCBI gene ID: 5747), Folate hydrolase 1 (FOLH1, PSMA, NCBI gene ID: 2346), Folate receptor 1 (FOLR1, NCBI gene ID: 2348), Forkhead box protein M1 (FOXM1, NCBI gene ID: 2305), FURIN (FURIN, PACE, NCBI gene ID: 5045), FYN tyrosine kinase (FYN, SYN, NCBI gene ID: 2534), galectin (e.g., LGALS3, LGALS8 (PCTA1), LGALS9, NCBI gene IDs: 3958, 3964, 3965), glucocorticoid receptor (NR3C1, GR, NCBI gene ID: 2908), glucuronidase β (GUSB, NCBI gene ID: 2990), glutamate metabolite receptor 1 (GRM1, NCBI gene ID: 2911), glutaminase (GLS, NCBI gene ID: 2744), glutathione S-transferase Pi (GSTP1, NCBI gene ID: 2950), glycogen synthase kinase 3β (glycogen synthase kinase 3 beta, GSK3B, NCBI gene ID: 2932), G, Lipican 3 (GPC3, NCBI gene ID: 2719), Gonadotropin-releasing hormone 1 (GNRH1, NCBI gene ID: 2796), Gonadotropin-releasing hormone receptor (GNRHR, NCBI gene ID: 2798), GPNMB glycoprotein nmb (GPNMB, osteoactivin, NCBI gene ID: 10457), Growth differentiation factor 2 (GDF2, BMP9, NCBI gene ID: 2658), Growth factor receptor-binding protein 2 (GRB2, ASH, NCBI gene ID: 2885), Guanylate cyclase 2C (GUCY2C, STAR, MECIL, MUCIL, NCBI gene ID: 2984), H19 (H19, NCBI gene ID: 283120) with maternally derived transcript imprinted, 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 2. HAVCR2, TIM3, CD366, NCBI gene ID: 84868), hepatic Growth factor (hepatocyte growth factor, HGF, NCBI gene ID: 3082), HERV-H LTR related 2 (HHLA2, B7-H7, NCBI gene ID: 11148), histamine receptor H2 (histamine receptor H2, HRH2, NCBI gene ID: 3274), histone deacetylases (e.g., HDAC1, HDAC7, HDAC9, NCBI gene IDs: 3065, 9734, 51564), HRas proto-oncogenes, GTPases (HRAS, NCBI gene ID: 3265), hypoxia-inducible factors (e.g., HIF (hypoxia-inducible factor) 1A, HIF2A (EPAS1), NCBI gene I D:2034, 3091), I-Kappa-B kinase (IKKβ, NCBI gene IDs: 3551, 3553), IKAROS family zinc finger (IKZF1 (LYF1), IKZF3, NCBI gene IDs: 10320, 22806), immunoglobulin superfamily member 11 (IGSF11, NCBI gene ID: 152404), indoleamine 2,3-dioxygenase (e.g., IDO1, IDO2, NCBI gene IDs: 3620, 169355), inducible T cell costimulator (ICOS, CD278, NCBI gene ID: 3551, ID:29851), inducible T cell costimulatory factor ligands (ICOSLG, B7-H2, NCBI gene ID:23308), insulin-like growth factor receptors (e.g., IGF1R, IGF2R, NCBI gene IDs:3480, 3482), insulin-like growth factors (e.g., IGF1, IGF2, NCBI gene IDs:3479, 3481), insulin receptors (INSR, CD220, NCBI gene ID:3643), integrin subunits (e.g., ITGA5 (CD49e), ITGAV (CD51), ITGB1 (CD29), ITGB2 (C) D18, LFA1, MAC1), ITGB7, NCBI gene IDs: 3678, 3685, 3688, 3695, 3698), cell adhesion molecule 1 (ICAM1, CD54, NCBI gene ID: 3383), interleukin-1 receptor-related 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, 35 59, 3560, 3561, 3563, 3570, 58985), interleukins (e.g., IL1A, IL1B, IL2, IL3, IL6(HGF), IL7, IL8(CXCL8), IL10(TGIF), IL12A, IL12B, IL15, IL17A(CTLA8), IL18, IL23A, IL24, IL-29(IFNL1), NCBI gene IDs: 3552, 3553, 3558, 3562, 3565, 3569, 3574, 3586, 3592, 3593, 3600, 3605, 3606, 11009, 51561, 282618),Isocitrate dehydrogenase (NADP(+)1) (e.g., IDH1, IDH2, NCBI gene IDs: 3417, 3418), Janus kinase (e.g., JAK1, JAK2, JAK3, NCBI gene IDs: 3716, 3717, 3718), kallikrein-related peptidase 3 (KLK3, NCBI gene ID: 354), killer cell immunoglobulin-like receptors, Ig domain and long cytoplasmic tail (e.g., KIR2DL1 (CD158A), KIR2DL2 (CD158B1), KIR2DL3 (CD158B), KIR2DL4 (CD158D), KIR2DL5A (CD158F), KIR2DL5B, KIR3DL1 (CD1, 58E1), 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 IDs: 3821, 3822, 3823, 3 824, 8302, 10219, 22914), kinase insertion domain receptors (KDR, CD309, VEGFR2, NCBI gene ID: 3791), kinesin family member 11 (KIF11, NCBI gene ID: 3832), KiSS-1 metastasis suppressor (KISS1, NCBI gene ID: 3814), KIT oncogene, receptor tyrosine kinase (KIT, C-KIT, CD117, NCBI gene ID: 3815), KRAS oncogene, GTPase (KRAS, NCBI gene ID: 3845), lactotransferrin (L TF (NCBI gene ID: 4057), LCK proto-oncogene, Src family tyrosine kinase (LCK, NCBI gene ID: 3932), LDL receptor-related protein 1 (LRP1, CD91, IGFBP3R, NCBI gene ID: 4035), leucine-rich repeat-containing 15 (LRRC15, NCBI gene ID: 131578), leukocyte immunoglobulin-like receptors (e.g., LILRB1 (ILT2, CD85J), LILRB2 (ILT4, CD85D), NCBI gene IDs: 10288, 10859), leukotriene A4 hydro -ase (LTA4H, NCBI gene ID: 4048), linker for T cell activation (LAT, NCBI gene ID: 27040), luteinizing hormone / chorionic gonadotropin receptor (LHCGR, NCBI gene ID: 3973), LY6 / PLAUR domain-containing 3 (LYPD3, NCBI gene ID: 27076), lymphocyte activation 3 (LAG3, CD223, NCBI gene ID: 3902), lymphocyte antigens (e.g., LY9 (CD229), LY75 (CD205), NCBI gene IDs: 4063, 17076), LYN proto-oncogene,Src family tyrosine kinase (LYN, NCBI gene ID: 4067), lymphocyte cytosolic protein 2 (LCP2; NCBI gene ID: 3937), lysine demethylase 1A (KDM1A, NCBI gene ID: 23028), lysophosphatidic acid receptor 1 (LPAR1, EDG2, LPA1, GPR26, NCBI gene ID: 1902), lysyl oxidase (LOX, NCBI gene ID: 4015), lysyl oxidase-like 2 (LOXL2, NCBI gene ID: 4017), macrophage migration inhibitor (MIF, GIF, NCBI gene ID: 4282), macrophage-stimulating receptor 1 (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 complexes (e.g., HLA-A, HLA-E, HLA-F, HLA-G, NCBI gene IDs: 3105, 3133, 3134, 3135), major vault protein, MVP (VAULT1, NCBI gene ID: 9961), MALT1 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 IDs: 2872, 8569), matrix metallopeptidases (e.g., MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP11, MMP12, MMP13, MMP14, MMP1 5, MMP16, MMP17, MMP19, MMP20, MMP21, MMP24, MMP25, MMP26, MMP27, MMP28; NCBI gene IDs: 4312, 4313, 4314, 4316, 4317, 4318, 4319, 4320, 4321, 4322, 4323, 4324, 4325, 4326, 4327, 9313, 10893, 56547, 64066, 64386, 79148, 118856), MCL1 apoptosis regulator, BCL2 family member (MCL1, NCBI gene ID: 4170), MDM2 proto-oncogene) (MDM2, NCBI gene ID: 4193), MDM4 regulator of p53 (MDM4, BMFS6, NCBI gene ID: 4194), mechanistic target of rapamycin kinase (MTOR, FRAP1, NCBI gene ID: 2475), melan-A (MLANA, NCBI gene ID: 2315), melanocortin receptor (MC1R, MC2R, NCBI gene IDs: 4157, 4148), MER proto-oncogene, tyrosine kinase (MERTK, NCBI gene ID: 10461), mesoserine (MSLN, NCBI gene ID: 10232), MET Proto-oncogenes, receptor tyrosine kinases (MET, c-Met, HGFR, NCBI gene ID: 4233), methionyl aminopeptidase 2 (METAP2, MAP2, NCBI gene ID: 10988), MHC class I polypeptide-related sequences (e.g., MICA, MICB, NCBI gene IDs: 4277, 100507436), mitogen-activated protein kinases (e.g., MAPK1 (ERK2), MAPK3 (ERK1), MAPK8 (JNK1), MAPK9 (JNK2), MAPK10 (JNK3), MAPK11 (p38β),MAPK12 (NCBI gene IDs: 5594, 5595, 5599, 5600, 5601, 5602, 819251), mitogen-activated protein kinase 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 kinases (e.g., MAP2K1 (MEK1), MAP2K2 (MEK2), MAP2K7 (MEK7), NCBI gene IDs: 5604, 5605, 5609), MPL Proto-oncogenes, 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 IDs: 4582, 4586, 94025), MYC proto-oncogene, bHLH transcription factor (MYC, NCBI gene ID: 4609), myostatin (MSTN, GDF8, NCBI gene ID: 2660), myristoylated alanine-rich protein kinase C substrate (MARCKS, NCBI gene ID: 4082), natriuretic peptide receptor 3 (NPR3, NC, BI gene ID: 4883), natural killer cytotoxic receptor 3 ligand 1 (NCR3LG1, B7-H6, NCBI gene ID: 374383), Nectin, MAGE family member (NDN, NCBI gene ID: 4692), Nectin cell adhesion molecule (e.g., NECTIN2 (CD112, PVRL2), NECTIN4 (PVRL4), NCBI gene ID: 5819, 81607), neural cell adhesion molecule 1 (neural cell adhesion molecule 1, NCAM1, CD56, NCBI gene ID: 4684), New Ropilin (e.g., NRP1 (CD304, VEGF165R), NRP2 (VEGF165R2), NCBI gene IDs: 8828, 8829), neurotrophic receptor tyrosine kinases (e.g., NTRK1 (TRKA), NTRK2 (TRKB), NTRK3 (TRKC), NCBI gene IDs: 4914, 4915, 4916), NFKB activating protein (NKAP, NCBI gene ID: 79576), NIMA-related kinase 9 (NE K9 (NCBI gene ID: 91754), NLR family pyrin domain-containing 3 (NLRP3, NALP3, NCBI gene ID: 114548), Notch receptor (e.g., NOTCH1, NOTCH2, NOTCH3, NOTCH4, NCBI gene IDs: 4851, 4853, 4854, 4855), NRAS proto-oncogene, GTPase (NRAS, NCBI gene ID: 4893), nuclear factor kappa B (NFKB (nuclear factor kappa B)1, NFKB2, NCBI gene IDs: 4790, 4791), nuclear factor, erythrocyte 2 like 2(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 oligomerized domain-containing 2 (NOD2, NCBI Gene ID: 64127), Nudix Hydrolase 1 (NUDT1, NCBI Gene ID: 4521), O-6-methylguanine-DNA methyltransferase (MGMT, NCBI Gene ID: 4255), Opioid Receptor Delta 1 (OPRD1, NCBI Gene ID: 4985), Ornithine Decarboxylase 1 (ODC1, NCBI Gene ID: 4953), Oxoglutarate Dehydrogenase (OGDH; NCBI Gene ID: 4780), Child 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 receptor (e.g., PPAR (peroxisome proliferator activated receptor) A (PPARα), P PARD (PPARδ), PPARG (PPARγ), NCBI gene IDs: 5465, 5467, 5468), phosphatases and tensin homologs (PTEN, NCBI gene ID: 5728), phosphatidylinositol-4,5-bisphosphate 3-kinases (PIK3CA (PI3Kα), PIK3CB (PI3Kβ), PIK3CD (PI3Kδ), PIK3CG (PI3Kγ), NCBI gene IDs: 5290, 5291, 5293, 5294), phospholipases (e.g., PLA2G1B, PLA PLA2G2A, PLA2G2D, PLA2G3, PLA2G4A, PLA2G5, PLA2G7, PLA2G10, PLA2G12A, PLA2G12B, PLA2G15, 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 (placenta growth factor (PGF, NCBI gene ID: 5228), plasminogen activator, urokinase (PLAU, u-PA, ATF, NCBI gene ID: 5328), platelet-derived growth factor receptor (e.g., PDGFR (platelet-derived growth factor receptor) A( CD140A, PDGFR2), FDGFRB (CD140B, PDGFR1), NCBI gene IDs: 5156, 5159), Plexin B1 (PLXNB1, NCBI gene ID: 53 64) Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155, NCBI gene ID: 5817), polo-like kinase 1 (PLK1, NC NCBI gene ID: 5347), poly(ADP-ribose) polymerase (e.g., PARP (poly(ADP-ribose)polymerase) 1, PARP2, PARP3, NCBI gene ID: 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 (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, N CBI gene ID: 80380), prominin 1 (PROM1, CD133, NCBI gene ID: 8842), promyelocytic leukemia (PML, NCBI gene ID: 5371), propiocin (PSAP, NCBI gene ID: 5660), prostaglandin E receptor 4 (PTGER4, NCBI gene ID: 5734), prostaglandin E synthase (PTGES, NCBI gene ID: 9536), prostaglandin endoperoxide synthase (PTGS1 (COX1), PTGS2 (COX2), NCBI gene IDs: 5742, 5743), proteasome 20S subunit β9 (PSMB9, NCBI gene ID: 5698), protein arginine methyltransferase (e.g., PRMT1, PRMT5, NCBI gene IDs: 3276, 10419), protein kinase N3 (protein Kinase N3, PKN3, NCBI gene (ID:29941), protein phosphatase 2A (PPP2CA, NCBI gene ID:5515), protein tyrosine kinase 7 (inactive) (protein tyrosine kinase 7, PTK7, NCBI gene ID:5754), protein tyrosine phosphatase receptor (PTPRB (PTPB), PTPRC (CD45R); NCBI gene IDs:5787, 5788), prothymosin α (PTMA, NCBI gene ID:5757), purine nucleoside phosphorylase (purine nucleoside phosphorylase, PNP, NC BI 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: 5894), RAR-related orphan receptor gamma (RORC, NCBI gene ID: 6097), ras homolog family members Bar C (RHOC, NCBI gene ID: 389), Ras homolog, mTORC1 binding (RHEB, NCBI gene ID: 6009), RB transcription corepressor 1 (RB1, NCBI gene ID: 5925), receptor interaction serine / threonine protein kinase 1 (RIPK1, NCBI gene ID: 8737), ret oncogene (RET, NCBI gene ID: 5979), retinoic acid early transcript (e.g., RAET (retinoic acid early transcript) 1E, RAET1G, RAET1L, NCBI gene ID: 389), Ras homolog, mTORC1 binding (RHEB, NCBI gene ID: 6009), RB transcription corepressor 1 (RB1, NCBI gene ID: 5925), receptor interaction serine / threonine protein kinase 1 (RIPK1, NCBI gene ID: 8737), retinoic acid proto-on Gene IDs: 135250, 154064, 353091), retinoic acid receptor α (e.g., RARA, RARG, NCBI gene IDs: 5914, 5916), retinoid X receptor (e.g., RXRA, RXRB, RXRG, NCBI gene IDs: 6256, 6257, 6258), Rho-related coiled-coil protein kinase (e.g., ROCK1, ROCK2, NCBI gene IDs: 6093, 9475), ribosomal protein S6 kinase B1 B1, RPS6KB1, S6K-β1, NCBI gene ID: 6198), Ring Finger Protein 128 (RNF128, GRAIL, NCBI gene ID: 79589), ROS Proto-Oncogene 1, Receptor Tyrosine Kinase (ROS1, NCBI gene ID: 6098), Roundabout Guidance Receptor 4 (ROBO4, NCBI gene ID: 54538), RUNX Family Transcription Factor 3 (RUNX3, NCBI gene ID: 864), S100 Calcium-Binding Protein A9 (S100A9, NCBI gene ID: 6280), Secreted Frizzled Related Protein 2 (SFRP2, NCBI gene ID: 6423), Secreted Phosphoprotein 1 (SPP 1. 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 (SEMA4D, CD100, NCBI gene ID: 10507), sialic acid-binding Ig-like lectins (SIGLEC7 (CD328), SIGLEC9 (CD329), SIGL EC10 (NCBI gene IDs: 27036, 27180, 89790), signal regulatory protein α (SIRPA, CD172A, NCBI gene ID: 140885), signaling factors and transcriptional activators (e.g., STAT1, STAT3, STAT5A, STAT5B, NCBI gene IDs: 6772, 6774, 6776, 6777), sirtuin-3 (SIRT3, NCBI gene ID: 23410), signaling lymphocytic activation molecules.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, S LC43A2 (LAT4), SLC44A4, NCBI gene IDs: 6520, 6528, 6530, 8273, 10568, 25800, 80736, 124935), somatostatin receptors (e.g., SSTR1, SSTR2, SSTR3, SSTR4, SSTR5, NCBI gene IDs: 6751, 6752, 6753, 6754, 6755), Sonic Hedgehog signaling molecules (SHH, NCBI gene ID: 6469), Sp1 transcription factor (SP1, NCBI gene ID: 6667), sphingosine kinases (e.g., SPHK1, SPHK2, NCBI gene IDs: 8877, 56848), sphingosine-1-phosphate receptor 1 (S1PR1(sphingosine-1-phosphate receptor1), CD363 (NCBI gene ID: 1901), spleen-associated tyrosine kinase (SYK, NCBI gene ID: 6850), splicing factor 3B-1 (SF3B1, NCBI gene ID: 23451), SRC oncogene, non-receptor tyrosine kinase (SRC, NCBI gene ID: 6714), stabilin 1 (STAB1, CLEVER-1, NCBI gene ID: 23166), STEAP family member 1 (STEAP1, NCBI gene ID: 26872), steroid sulfatase (STS, NCBI gene ID: 412), interferon response cGAMP interactor 1 stimulator (STING1, NCBI gene ID: 340061), superoxide dismutase 1 (SOD1, ALS1, NCBI gene ID: 6647), cytokine signaling suppressors (SOCS (suppressors of cytokine) Signaling receptor 1 (CISH1), SOCS3 (CISH3, NCBI gene IDs: 8651, 9021), Synapsin 3 (SYN3, NCBI gene ID: 8224), Syndecan 1 (SDC1, CD138, Syndecan, NCBI gene ID: 6382), Synuclein α (SNCA, PARK1, NCBI gene ID: 6622), T cell immunoglobulin and mucin domain-containing receptor 4 (TIMD4, SMUCKLER, NCBI gene ID: 91937), T cell immune receptor with Ig and ITIM domains (TIGIT, NCBI gene ID: 201633), Tachykinin receptor (e.g., TACR1, TACR3, NCBI gene IDs: 6869, 6870), TANK-binding kinase 1 (TANK binding kinase)1. TBK1 (NCBI gene ID: 29110), Tankylase (TNKS, NCBI gene ID: 8658), TATA box-binding protein-related factor, RNA polymerase I subunit B (TAF1B, NCBI gene ID: 9014), T-box transcription factor T (TBXT, NCBI gene ID: 6862), TCDD-inducible poly(ADP-ribose) polymerase (TIPARP, PAPR7, NCBI gene ID: 25976), tec protein tyrosine kinase (TEC, NCBI gene ID: 7006), TEK receptor tyrosine kinase (TEK, CD202B, TIE2, NCBI gene ID: 7010), telomerase reverse transcriptase (TERT, NCBI gene ID: 7015), tenascin C (TNC, NCBI gene ID: 3371), 3-prime repair exonuclease (e.g., TREX1, TREX2, NCBI gene IDs: 11277, 11219), thrombomodulin (THBD, CD141, NCBI gene ID: 7056), thymidine kinase (e.g., TK (thymidine kinase) 1) 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), thyroid stimulating hormone receptor (thyroid stimulating hormone) receptor, TSHR, NCBI gene ID: 7253), TNF 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, 7 098, 7099, 10333, 51284, 51311, 54106, 81793), transferrin (TF, NCBI gene ID: 7018), transferrin receptor (TFRC, CD71, NCBI gene ID: 7037), transforming growth factors (e.g., TGFA, TGFB1, NCBI gene IDs: 7039, 7040), transforming growth factor receptors (e.g., TGFBR1, TGFBR2, TGFBR3, NCBI gene IDs: 7046, 7048, 7049), transforming protein E7 (E7, NCBI gene ID: 1489079), transglutaminase 5 (TGM5, NCBI gene ID: 9333), transient receptor latent 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), trigger receptors expressed in bone marrow cells (e.g., TREM1 (CD 354), TREM2, NCBI gene ID: 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 (CD268, BAFFR), TNFRSF14 (CD270, LIGHTR), TNFRSF16, TNFRSF17 (CD269, BCMA), TN FRSF18 (GITR, CD357), TNFRSF19, TNFRSF21, TNFRSF25; NCBI gene IDs: 355, 608, 939, 943, 958, 3604, 4804, 4982, 7132, 7133, 7293, 8718, 8764, 8784, 8792, 8793, 8794, 8795, 8797, 23495, 27242, 51330, 55504), tumor Tumor protein p53 (TP53, NCBI gene ID: 7157), tumor suppressor factor 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 Tyrosine kinases with EGF-like domain 1 (e.g., TIE1, NCBI gene ID: 7075), tyrosine protein phosphatase nonreceptor type 11 (PTPN11, SHP2, NCBI gene ID: 5781), ubiquitin-conjugating enzyme E2 I (UBE2I, UBC9, NCBI gene ID: 7329), ubiquitin C-terminal hydrolase L5 (UCHL5, NCBI gene ID: 51377), ubiquitin-specific peptidase 7 7, USP7, NCBI gene ID: 7874), ubiquitin-like modifier activating enzyme 1 (UBA1, NCBI gene ID: 7317), UL16 binding proteins (e.g., ULBP1, ULBP2, ULBP3, NCBI gene IDs: 79465, 80328, 80328), valosin-containing proteins VCP, CDC48, NCBI gene ID: 7415), vascular cell adhesion molecule 1 (VCAM1, CD106, NCBI gene ID: 7412), vascular endothelial growth factor (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 (VS IR, VISTA, B7-H5 (NCBI gene ID: 64115), WEE1 G2 checkpoint kinase (WEE1, NCBI gene ID: 7465), WRN RecQ-like helicase (WRN, RECQ3, NCBI gene ID: 7486), WT1 transcription factor (WT1, NCBI gene ID: 7490), WW domain-containing transcription regulator 1 (WWTR1, TAZ, NCBI gene ID: 25937), XC motif chemokine ligand 1 (XCL1, ATAC, NCBI gene ID: 6375), XC motif chemokine receptor 1 (XCR1, GPR5, CCXCR1, NCBI gene ID: 2829), Yes1-related transcription regulator (YAP1, NCBI gene ID: 10413), Zeta chain-related protein kinase 70 (ZAP70, NCBI gene ID: 7535).

[0258] In some embodiments, one or more additional therapeutic agents include, for example, 5'-nucleotidase ectopropyl alcohol (NT5E or CD73, NCBI gene ID: 4907), adenosine A 2A Receptor (ADORA2A, NCBI gene ID: 135), adenosine A 2B Receptor (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 (IA) P, CD47, NCBI gene ID: 961), interleukin-2 (IL2, NCBI gene ID: 3558), interleukin-2 receptor (IL2RA, IL2RB, IL2RG, NCBI gene ID: 3559, 3560, 3561), Kirsten rat sarcoma virus (KRAS, NCBI gene ID: 3845, including mutations such as KRAS G12C or G12D), mitogen-activated protein kinase kinase kinase 1 (MAP4K1) (also called hematopoietic progenitor kinase 1 (HPK1), NCBI gene ID: 11184), myelocyte 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 cell death ligand 1 (PD-L1, CD274, NCBI gene ID: 29126), programmed cell death protein 1 (PD-1, CD279, NCBI gene ID: 5133), proto-oncogene c-KIT (KIT, CD117, NCBI gene ID: 3815), signal regulatory protein α (SIRPA, CD172A, NCBI gene ID: 140885), TCDD-inducible poly(ADP-ribose) polymerase (TIPARP, PARP7, NCBI gene ID: 25976), T cell immune receptor with Ig and ITIM domains (TIGIT, NCBI gene ID: 201633), bone Trigger receptor 1 (TREM1, NCBI gene ID: 54210) expressed on myelocytes, trigger receptor 2 (TREM2, NCBI gene ID: 54209) expressed on bone marrow cells, 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), WRN Examples include drugs targeting RecQ-like helicase (WRN, NCBI gene ID: 7486) and zinc finger protein Helios (IKZF2, NCBI gene ID: 22807).

[0259] Illustrative mechanism of action Immune checkpoint modulator In some embodiments, the compounds provided herein are administered together with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors, and / or one or more stimulants, activators, or agonists of one or more stimulating immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can positively modulate T cell or NK cell activation and prevent immune evasion of cancer cells within the tumor microenvironment. Activation or stimulation of stimulating immune checkpoints can enhance the effects of immune checkpoint inhibitors in cancer treatment. In some embodiments, immune checkpoint proteins or receptors modulate T cell responses (as outlined, e.g., Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In some embodiments, immune checkpoint proteins or receptors modulate the NK cell response (see, e.g., Davis, et al., Semin Immunol. (2017) 31:64-75 and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688). Inhibition or depletion of regulatory T cells (Tregs) may mitigate the suppression of their antitumor immune response and have anticancer effects (see, e.g., Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77 and Tanaka and Sakaguchi, Eur. J. Immunol. (2019) 49:1140-1146).

[0260] 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 (N CBI 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 inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptor (VSIR, B7H5, VISTA, NCBI gene ID: 64115), immunoglobulin superfamily member 11 (IGSF11, VSIG3, NCBI gene ID: 152404), natural killer cytotoxic receptor 3 ligand 1 (NCR3LG1, B7H6, NCBI gene ID: 374383), HERV-H LTR-related 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 CBI 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-related (BTLA), NCBI gene ID: 151888), TNFRSF17 (BCMA, CD269, NCBI gene ID: 608), TNFSF13B (BAFF, NCBI gene ID: 10673), TNFRSF18 (GITR, NCBI gene ID: 8784), TNFSF18 (GITRL, NCBI gene ID: 8995), MHC class I polypeptide-related sequence A (MICA, NCBI gene ID: 100507436), MHC class I polypeptide-related sequence B (MICB, NCBI gene ID: 4277), CD274 (CD274, PDL1, PD-L1, NCBI gene ID: 29126), programmed cell death 1 (PDCD1, PD1, PD-1, NCBI gene ID: 5133), cytotoxic T lymphocyte-related 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 immune receptor with Ig and ITIM domains (TIGIT, NCBI gene ID: 20 1633), T cell immunoglobulin and mucin domain-containing 4 (TIMD4, TIM4, NCBI gene ID: 91937), hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3, NCBI gene ID: 84868), galectin 9 (LGALS9, NCBI gene ID: 3965), lymphocyte activation 3 (LAG3, CD223, NCBI gene ID: 3902), signal transduction lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150, NCBI gene ID: 6504), lymphocyte antigen 9 (LY9, CD229,SLAMF3 (NCBI gene ID: 4063), SLAM family member 6 (SLAMF6, CD352, NCBI gene ID: 114836), SLAM family member 7 (SLAMF7, CD319, NCBI gene ID: 57823), UL16-binding protein 1 (ULBP1, NCBI gene ID: 80329), UL16-binding protein 2 (ULBP2, NCBI gene ID: 80328), UL16-binding protein 3 (ULBP3, NCBI gene ID: 79465), retinoic acid early transcript 1E (RAET1E; ULBP4, NCBI gene ID: 135250, ), retinoic acid early transcript 1G (RAET 1G;ULBP5, NCBI gene ID:353091), retinoic acid early transcript 1L (RAET1L;ULBP6, NCBI gene Child ID: 154064), killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic tail 1 (KIR, CD158E1, NCBI gene ID: 3811, e.g., lirirumab (IPH-2102, IPH-4102)), killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A, NCBI gene ID: 3821), killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314 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, and long cytoplasm Tail 1 (KIR2DL1, NCBI gene ID: 3802), killer cell immunoglobulin-like receptor, 2 Ig domains, and long cytoplasmic tail 2 (KIR2DL2, NCBI gene ID: 3803), killer cell immunoglobulin-like receptor, 2 Ig domains, and long cytoplasmic tail 3 (KIR2DL3, NCBI gene ID: 3804), killer cell immunoglobulin-like receptor, 3 Ig domains, and long cytoplasmic tail 1 (K Examples include IR3DL1; 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).

[0261] In some embodiments, the compounds provided herein are administered together with one or more T-cell inhibitory immune checkpoint proteins or receptor blockers or inhibitors. Examples of T cell inhibitory immune checkpoint proteins or receptors include CD274 (CD274, PDL1, PD-L1); programmed cell death ligand 1 (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 T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-associated immunoglobulin domain-containing (PVRIG, CD1 Examples include 12R); T cell immune receptor having 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 with three Ig domains and a long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin-like receptor with three Ig domains and a long cytoplasmic tail 1 (KIR3DL1). In some embodiments, the compounds provided herein are administered together with one or more agonists or activators of one or more T cell-stimulating immune checkpoint proteins or receptors.Examples of T cell-stimulating immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T cell costimulatory molecules (ICOS, CD278); inducible T cell costimulatory molecule ligands (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). For example, see Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0262] In some embodiments, the compounds provided herein are administered together with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Illustrative NK cell inhibitory immune checkpoint proteins or receptors include: killer cell immunoglobulin-like receptor, 3 Ig domains, and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, 2 Ig domains, and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin-like receptor, 2 Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, 2 Ig domains, and long cytoplasmic tail 3 Examples include (KIR2DL3); killer cell immunoglobulin-like receptor, with three Ig domains and a 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-bound Ig-like lectin 7 (SIGLEC7); and sialic acid-bound Ig-like lectin 9 (SIGLEC9). In some embodiments, the compounds provided herein are administered together with one or more agonists or activators of one or more NK cell-stimulating immune checkpoint proteins or receptors. Examples of NK cell-stimulated immune checkpoint proteins or receptors include CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). See, for example, Davis, et al., Semin Immunol. (2017) 31:64-75, Fang, et al., Semin Immunol. (2017) 31:37-54, and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0263] In some embodiments, one or more immune checkpoint inhibitors include protein-based inhibitors (e.g., antibodies or fragments thereof, or antibody mimics) of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, one or more immune checkpoint inhibitors include small organic molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), CTLA4, or TIGIT. In some embodiments, one or more immune checkpoint inhibitors include protein-based inhibitors (e.g., antibodies or fragments thereof, or antibody mimics) of LAG3.

[0264] Examples of CTLA4 inhibitors that can be administered concurrently include ipilimumab, tremelimumab, BMS-986218, AGEN1181, zarifremab (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. Examples include 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).

[0265] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be administered concurrently include pembrolizumab, nivolumab, semiprimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, cosiberimab (CK-301), sasamrimab (PF-06801591), tislerizumab (BGB-A317), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, and HLX-1. 0, Retifan Limab (MGA-012), BI-754091, Valstilimab (AGEN-2034), AMG-404, Tripalimab (JS-001), Cetrelimab (JNJ-63723283), Genolimuzumab (CBT-501), LZM-009, Prorugolimab (BCD-100), Rhodapolimab (LY-3300054), SHR-1201, Camrelizumab (SHR-1210), Sym-021, Buzigalimab (ABBV-181), PD1-PIK, BAT-1306, Avelumab (MSB0010718C), CX-072, CBT-502, Dostallumab (TSR-042), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155), Embafolimab (KN-035), Syntilimab (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, Zimbererimab (AB122), Spartali Zumab (PDR-001), and compounds disclosed in International Publication Nos. 2018195321, 2020014643, 2019160882, or 2018195321, as well as the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), RO-7247669 (PD-1 / LAG-3), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4),MEDI-5752 (CTLA4 / PD-1), RO-7121661 (PD-1 / TIM-3), RG7769 (PD-1 / TIM-3), TAK-252 (PD-1 / OX4) 0L), XmAb-20717(PD-1 / CTLA4), AK-104(CTLA4 / PD-1), FS-118(LAG-3 / PD-L1), FPT-155(CTLA4 / Examples include PD-L1 / CD28), GEN-1046 (PD-L1 / 4-1BB), vintrafusp α (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 razertinib (GNS-1480, PD-L1 / EGFR).

[0266] Examples of TIGIT inhibitors that can be administered concurrently include tiragolumab (RG-6058), vivostrimab, dombanalimab, dombanalimab (AB154), AB308, BMS-986207, AGEN-1307, COM-902, or etigirimab.

[0267] An example of a LAG3 inhibitor that can be administered concurrently is relamirimab (LAG525).

[0268] Inhibition of regulatory T cell (Treg) activity or Treg depletion may mitigate the suppression of the antitumor immune response and have an anticancer effect. For example, Plitas and Rudensky, Annu. Rev. Cancer Biol. (2020) 4:459-77, Tanaka See and Sakaguchi, Eur.J.Immunol.(2019)49:1140-1146. In some embodiments, the compounds provided herein are administered together with one or more inhibitors of Treg activity or Treg depletors. Inhibition or depletion of Tregs can enhance the effects of immune checkpoint inhibitors in cancer treatment.

[0269] In some embodiments, the compounds provided herein are administered together with one or more Treg inhibitors. In some embodiments, Treg inhibitors can suppress the migration of Tregs into the tumor microenvironment. In some embodiments, Treg inhibitors can reduce the immunosuppressive function of Tregs. In some embodiments, Treg inhibitors can modulate the cellular phenotype and induce the production of inflammatory cytokines. Exemplary Treg inhibitors include, but are not limited to, CCR4 (NCBI gene ID: 1233) antagonists and degradants of 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).

[0270] Examples of Helios-degrading agents that may be administered concurrently include, but are not limited to, I-57 (Novartis) and the compounds disclosed in International Publication Nos. 2019038717, 2020012334, 20200117759, and 2021101919.

[0271] In some embodiments, the compounds provided herein are administered together with one or more Treg depletion agents. In some embodiments, the Treg depletion agent is an antibody. In some embodiments, the Treg depletion antibody has antibody-dependent cell-mediated cytotoxicity (ADCC) activity. In some embodiments, the Treg depletion antibody is Fc gene-engineered to have enhanced ADCC activity. In some embodiments, the Treg depletion antibody is an antibody-drug conjugate (ADC). Examples of typical targets for Treg depletion 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).

[0272] In some embodiments, Treg inhibitors or Treg depletors that may be administered concurrently include CC-motif chemokine receptor 4 (CCR4), CC-motif chemokine receptor 7 (CCR7), CC-motif chemokine receptor 8 (CCR8), CXC-motif chemokine receptor 4 (CXCR4, CD184), TNFRSF4 (OX40), TNFRSF18 (GITR, CD357), TNFRSF9 (4-1BB, CD137), cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152), programmed cell death 1 (PDCD1, PD-1), and sialyl Lewis. x (CD15s), CD27, ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, ​​CD39), protein tyrosine phosphatase receptor type C (PTPRC, CD45), neuronal cell adhesion molecule 1 (NCAM1, CD56), selectin L (SELL, CD62L), integrin subunit αE (ITGAE, CD103), interleukin 7 receptor (IL7R, CD127), CD40 ligand (CD40LG, CD154), folate receptor α (FOLR1), folate receptor β (FOLR2), leucine-rich repeat containing 32 (LRRC32, GARP), IKAROS family zinc finger 2 (IKZF 2, HELIOS), inducible T cell costimulatory factor (ICOS, CD278), lymphocyte activation 3 (LAG3, CD223), transforming growth factor β1 (transforming growth factor beta 1, TGFB1), hepatitis A virus cell receptor 2 (HAVCR2, CD366) The present invention comprises an antibody or antigen-binding fragment thereof that selectively binds to a cell surface receptor selected from the group consisting of TIM3, T cell immune receptors having Ig and ITIM domains (TIGIT), TNF receptor superfamily member 1B (CD120b, TNFR2), IL2RA (CD25), or combinations thereof.

[0273] Examples of Treg depletion anti-CCR8 antibodies that may be administered include, but are not limited to, JTX-1811 (GS-1811) (Jounce Therapeutics, Gilead Sciences) and BMS-986340 (Bristol Meyers). Examples include antibodies disclosed in International Publication Nos. Squibb, S-531011 (Shionogi), FPA157 (Five Prime Therapeutics), SRF-114 (Surface Oncology), HBM1022 (Harbor BioMed), IO-1 (Oncurious), and International Publication Nos. 2021163064, 2020138489, and 2021152186.

[0274] An example of a Treg-depleting anti-CCR4 antibody that can be administered is mogamulizumab.

[0275] Inhibition, depletion, or reprogramming of non-stimulated myeloid cells in the tumor microenvironment can enhance the anti-cancer immune response (see, e.g., Binnewies et al., Nat. Med. (2018) 24(5):541-550, International Publication No. 2016049641). Exemplary targets for depleting or reprogramming non-stimulated myeloid cells include trigger receptors expressed on myeloid cells, TREM-1 (CD354, NCBI gene ID: 54210) and TREM-2 (NCBI gene ID: 54209). In some embodiments, the compounds provided herein are administered together with one or more myeloid depletion or reprogramming agents, such as an anti-TREM-1 antibody (e.g., PY159, the antibody disclosed in International Publication No. 2019032624) or an anti-TREM-2 antibody (e.g., PY314, the antibody disclosed in International Publication No. 2019118513).

[0276] Agonists or activators of differentiation clusters In some embodiments, the compounds provided herein are administered together with agents targeting differentiation cluster (CD) markers. Exemplary CD marker-targeting agents that may be co-administered include, but are not limited to, A6, AD-IL24, neratinib, tucatinib (ONT 380), mobocertinib (TAK-788), tesevatinib, trastuzumab (HERCEPTIN®), trastuzumab biosimimer (HLX-02), margetuximab, BAT-8001, pertuzumab (Perjeta), pegfilgrastim, RG6264, zanidatamab (ZW25), cavatak, AIC-100, tagraxofusp (SL-401), HLA-A2402 / HLA-A0201 restriction epitope peptide vaccine, dasatinib, and i Matinib, nilotinib, sorafenib, lenvatinib mesylate, ofranergene ovadenovec, cabozantinib malate, AL-8326, ZLJ-33, KBP-7018, sunitinib malate, pazopanib derivative, AGX-73, levastinib, NMS-088, lucitanib hydrochloride, midostaurin, cejiranib, dovitinib, citravatinib, tivozanib, masitinib, regorafenib, olberenvatinib 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, 2006009755, and Applications No. 2007078034, No. 2007092403, No. 2007127317, No. 2008005877, No. 2012154480, No. 2014100620, No. 2014039714, No. 2015134536, No. 2017167182, No. 2018112136, No. 2018112140, No. 2019155067, No. 2020076105, International Application PCT / US2019 / 063091, International Publication No. 19173692,Same as No. 2016179517, No. 2017096179, No. 2017096182, No. 2017096281, No. 2018089628, No. 2017096179, No. 2018089628, No. 2018195321, No. 2020014643, No. 2019160882, No. 2018195321, No. 200140307, ​​No. 2002092784, No. 2007133811, No. 2009046541, No. 2010083253, No. 20110767 No. 81, No. 2013056352, No. 2015138600, No. 2016179399, No. 2016205042, No. 2017178653, No. 2018026600, No. 2018057669, No. 2018107058, No. 2018190719, No. 2018210793, No. 2019023347, No. 2019042470, No. 2019175218, No. 2019183266, No. 2020013170, 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) revealed the use of されている compounds. ,

[0277] In some embodiments, the CD marker-targeting drugs that may be administered concurrently include small molecule inhibitors, such as PBF-1662, BLZ-945, pemigatinib (INCB-054828), logalatinib (BAY-1163877), AZD4547, robritinib (FGF-401), quizartinib dihydrochloride, SX-682, AZD-5069, PLX-9486, avapritinib (BLU-285), ripretinib (DCC-2618), imatinib mesylate, JSP-191, BL Examples include U-263, CD117-ADC, AZD3229, teratinib, bororanib, GO-203-2C, AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708, HM-30181A, motixafortide (BL-8040), LY2510924, tinxafor (TG-0054), X4P-002, mavolixafor (X4P-001-IO), prelixafor, CTX-5861, or REGN-5678 (PSMA / CD28).

[0278] In some embodiments, the drugs targeting the CD marker that may be administered concurrently include small molecule agonists, such as interleukin-2 receptor subunit gamma, eltrombopag, lintatrimod, polyICLC (NSC-301463), riboxone, apoxime, RIBOXXIM®, MCT-465, MCT-475, G100, PEPA-10, eftozanermin α (ABBV-621), and E-6. Examples include 887, Motrimod, Reshikimod, Sergantrimod (GS-9688), VTX-1463, NKTR-262, AST-008, CMP-001, Kobitrimod, Chilsotrimod, Litenimod, MGN-1601, BB-006, IMO-8400, IMO-9200, Agatrimod, DIMS-9054, DV-1079, Refitrimod (MGN-1703), CYT-003, and PUL-042.

[0279] In some embodiments, the CD marker-targeting agents that can be administered concurrently include antibodies such as tafacitamab (MOR208, MorphoSys AG), inebilizumab (MEDI-551), obinutuzumab, IGN-002, rituximab biosimilar (PF-05280586), valrirumab (CDX-1127), AFM-13 (CD16 / CD30), AMG330, otreltuzumab (TRU-016), isatuximab, ferzaltamab (MOR-202), TAK-079, and T AK573, Daratumumab (DARZALEX®), TTX-030, Sericrelumab (RG7876), APX-005M, ABBV-428, ABBV-927, Mitazarimab (JNJ-64457107), Renzrumab, Alemtuzumab, Emactuzumab, AMG-820, FPA-008 (Cabilizumab), PRS-343 (CD-13 7 / HER2), AFM-13 (CD16 / CD30), verantamab mahodotin (GSK-2857916), AFM26 (BCMA / CD16A), Simulcaphusp α (RG7461), urerumab, utomirumab (PF-05082566), AGEN2373, ADG-106, BT-7480, PRS-343 (CD-137 / HER2), FA P-4-IBBL (4-1BB / FAP), ramucirumab, CDX-0158, CDX-0159 and FSI-174, relatrimab (ONO-4482), LAG-525, MK-4280, fianlimab (REGN-3767), INCAGN2385, enserimab (TSR-033), atipotuzumab, BrevaRex (Mab-AR-20).5) MEDI-9447 (Olecumab), CPX-006, IPH-53, BMS-986179, NZV-930, CPI-006, PAT-SC1, Lirirumab (IPH-2102), Lactamab (IPH-4102), Monalizumab, BAY-1834942, NEO-201 (CEACAM 5 / 6), Iodine (131I) apamistamab (131I-BC8 (iomab-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, C Examples include TB-006, INBRX-109, GEN-1029, pepinemab (VX-15), voplaterimab (JTX-2011), GSK3359609, covolimab (TSR-022), MBG-453, INCAGN-2390, and compounds disclosed in International Publication Nos. 2017096179, 2017096276, 2017096189, and 2018089628.

[0280] In some embodiments, CD marker-targeting agents that may be administered concurrently include cell therapies such as CD19-ARTEMIS, TBI-1501, CTL-119 huCART-19 T cells, iso-cel, lysocabactene maralucel (JCAR-017), axicapbutazine siroleucel (KTE-C19, Yescarta®), axicapbutazine siroleucel (KTE-X19), US7741465, US6319494, UCART-19, taberecureucel (EBV-CTL), T tisagenlecroucel-T (CTL019), CD19CAR-CD28-CD3ζ-EGFRt-expressing T cells, and CD19 / 4-1BBL armored CAR. T cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28ζ T cells, PCAR-019, MatchCART, DSCAR-01, IM19 CAR-T, TC-110, anti-CD19 CAR T-cell therapy (B-cell acute blastocystic leukemia, Universiti Kebangsaan Malaysia), anti-CD19 CAR T-cell therapy (acute blastocystic leukemia / non-homogeneous blastocystic leukemia, University Hospital Heidelberg), anti-CD19 CAR T-cell therapy (silent IL-6 manifestation, Shanghai Unicar-Therapy Bio-medicine Technology), MB-CART2019.1 (CD19 / CD20), GC-197 (CD19 / CD7), CLIC-1901, ET-019003, anti-CD19-STAR-T cells, AVA-001, BCMA-CD19 cCAR(CD19 / APRIL), ICG-134, ICG-132(CD19 / CD20), CTA-101, WZTL-002, デュアルanti-CD19 / anti-CD20 CAR T-cell (chronic leukemia / B-cell leukemia), HY-001, ET-019002, YTB-323, GC-012 (CD19 / APRIL), GC-022 (CD19 / CD22), CD19CAR-CD28-CD3ζ-EGFRt-emergent Tn / mem, UCAR-011, ICTCAR-014, GC-007F, PTG-01, CC-97540, GC-007G, TC-310, GC-197, cisagecroicel-T, CART-19, cisagecroicel (CTL-019)), anti-CD20 CAR T-cell therapy (non-hojikin rinpa), 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 nock-and-away T-cell therapy (NSCLC), ICTCAR-052, Tn Examples include 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 therapies disclosed in International Publication No. 2012079000 or No. 2017049166.

[0281] Differentiation cluster 47 (CD47) inhibitors In some embodiments, the compounds provided herein are administered together with an inhibitor of CD47 (IAP, MER6, OA3, NCBI gene ID: 961). Examples of CD47 inhibitors include anti-CD47 mAb (Vx-1004), anti-human CD47 mAb (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibody or CD47 blocker, NI-1701, NI-1801, RCT-1938, ALX148, SG-404, SRF-231, and TTI-621.Additional exemplary anti-CD47 antibodies include CC-90002, maglorimab (Hu5F9-G4), AO-176 (Vx-1004), retaprimab (IBI-188), remzopalimab (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. 19972. No. 7873, No. 199940940, No. 2002092784, No. 2005044857, No. 2009046541, Same No. 2010070047, Same No. 2011143624, Same No. 2012170250, Same No. 2013109752, Same No. 2013 119714, 2014087248, 2015191861, 2016022971, 201602304 No. 0, No. 2016024021, No. 2016081423, No. 2016109415, No. 2016141328, No. 2 No. 016188449, No. 2017027422, No. 2017049251, No. 2017053423, No. 201712 No. 1771, No. 2017194634, No. 2017196793, No. 2017215585, No. 2018075857, Same No. 2018075960, No. 2018089508, No. 2018095428, No. 2018137705, No. 201 No. 8233575, No. 2019027903, No. 2019034895, No. 2019042119, No. 201904228 Examples of compounds disclosed in No. 5, No. 2019042470, No. 2019086573, No. 2019108733, No. 2019138367, No. 2019144895, No. 2019157843, No. 2019179366, No. 2019184912, No. 2019185717, No. 2019201236, No. 2019238012, No. 2019241732, No. 2020019135, No. 2020036977, No. 2020043188, and No. 2020009725 include those disclosed in No. 5, No. 2019042470, No. 2019086573, No. 2019108733, No. 20191387, No. 2019144895, No. 2019157843, No. 2019179366, No. 2019184912, No. 2019185717, No. 2019201236, No. 2019238012, No. 2019241732, No. 2020019135, No. 2020036977, No. 2020043188, and No. 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 maglorimab.

[0282] In some embodiments, the CD47 inhibitor is a bispecific antibody targeting CD47, such as IBI-322 (CD47 / PD-L1), IMM-0306 (CD47 / CD20), TJ-L1C4 (CD47 / PD-L1), HX-009 (CD47 / PD-1), PMC-122 (CD47 / PD-L1), PT-217 (CD47 / DLL3), IMM-26011 (CD47 / These include FLT3), IMM-0207 (CD47 / VEGF), IMM-2902 (CD47 / HER2), BH29xx (CD47 / PD-L1), IMM-03 (CD47 / CD20), IMM-2502 (CD47 / PD-L1), HMBD-004B (CD47 / BCMA), HMBD-004A (CD47 / CD33), TG-1801 (NI-1701), or NI-1801.

[0283] Drugs that target SIRPa In some embodiments, the compounds provided herein are administered together with a SIRPa-targeting agent (NCBI gene ID: 140885, UniProt P78324). Examples of SIRPa-targeting agents include SIRPa inhibitors such as AL-008, RRx-001, and CTX-5861, as well as anti-SIRPa antibodies such as FSI-189 (GS-0189), ES-004, BI-765063, ADU1805, CC-95251, and Q-1801 (SIRPa / PD-L1). The additional SIRPα-targeting drugs used include, for example, International Publication Nos. 200140307, ​​2002092784, 2007133811, 2009046541, 2010083253, 2011076781, 2013056352, 2015138600, 2016179399, 2016205042, and 20 It is listed in documents No. 17178653, No. 2018026600, No. 2018057669, No. 2018107058, No. 2018190719, No. 2018210793, No. 2019023347, No. 2019042470, No. 2019175218, No. 2019183266, No. 2020013170, and No. 2020068752.

[0284] FLT3R Agonist In some embodiments, the compounds provided herein are administered with an FLT3R agonist. In some embodiments, the compounds provided herein are administered with an FLT3 ligand. In some embodiments, the compounds provided herein are administered with, for example, the FLT3L-Fc fusion protein described in International Publication No. 2020263830. In some embodiments, the compounds provided herein are administered with GS-3583 or CDX-301. In some embodiments, the compounds provided herein are administered with GS-3583.

[0285] Agonists or activators of members of the TNF receptor superfamily (TNFRSF). In some embodiments, the compounds provided herein are agonists of one or more members of the TNF receptor superfamily (TNFRSF), for example, 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), TNFR SF7 (CD27, NCBI gene ID; 939), TNFRSF8 (CD30, NCBI gene ID; 943), TNFRSF9 (4-1BB, CD137, NCBI gene ID; 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID; 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID; 8795), TNFRSF10C (CD263, TRAILR3, NCBI gene ID; 8794) ), TNFRSF10D (CD264, TRAILR4, NCBI gene ID; 8793), TNFRSF11A (CD265, RANK, NCBI gene ID; 8792), TNFRSF11B (NCBI gene ID; 4982), TNFRSF12A (CD266, NCBI gene ID; 51330), TNFRSF13B (CD267, NCBI gene ID; 23495), TNFRSF13C (CD268, NCBI gene ID; 115650), TNFRSF16 ( It is administered with one or more agonists from among 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).

[0286] Examples of anti-TNFRSF4 (OX40) antibodies that can be administered concurrently include MEDI6469, MEDI6383, tavorixizumab (MEDI0562), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and antibodies described in International Publication Nos. 2016179517, 2017096179, 2017096182, 2017096281, and 2018089628.

[0287] Exemplary anti-TNFRSF5 (CD40) antibodies that can be administered concurrently include RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0288] In some embodiments, the anti-TNFRSF7 (CD27) antibody varylumab (CDX-1127) is administered concurrently.

[0289] Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that may be administered concurrently include urelumab, utomirumab (PF-05082566), AGEN-2373, and ADG-106.

[0290] In some embodiments, the anti-TNFRSF17(BCMA) antibody GSK-2857916 is administered concurrently.

[0291] Examples of anti-TNFRSF18(GITR) antibodies that may be co-administered include MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and antibodies described in International Publication Nos. 2017096179, 2017096276, 2017096189, and 2018089628. In some embodiments, antibodies or fragments thereof that simultaneously target TNFRSF4(OX40) and TNFRSF18(GITR) are co-administered. Such antibodies are described, for example, in International Publication Nos. 2017096179 and 2018089628.

[0292] Examples of bispecific antibodies targeting TNFRSF family members that can be administered concurrently include PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), AFM-13 (CD16 / CD30), odronexutamab (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).

[0293] Bispecific T cell engagers In some embodiments, the compounds provided herein are administered together with a bispecific T cell engager (e.g., without Fc) or an anti-CD3 bispecific antibody (e.g., with Fc). Exceptional anti-CD3 bispecific antibodies or BiTEs that may 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), odronexutamab (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 (XmA b-18087(SSTR2 / CD3)), JNJ-63709178(CD123 / CD3), MGD-007(CD3 / gpA33), MGD-009(CD3 / B7H3), IMCg p100 (CD3 / gp100), XmAb-14045 (CD123 / CD3), XmAb-13676 (CD3 / CD20), Tidutamab (XmAb-18087, SSTR2 / CD 3) Examples include catumakisomab (CD3 / EpCAM), REGN-4018 (MUC16 / CD3), mosnetuzumab (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). The anti-CD3 binding bispecific molecule may or may not have an Fc, as needed. Exemplary bispecific T cell engagers that can be administered concurrently target CD3 and tumor-associated antigens described herein, such as CD19 (e.g., blinatumomab), CD33 (e.g., AMG330), CEA (e.g., MEDI-565), and receptor tyrosine kinase-like orphan receptor 1 (ROR1) (Gohil, et al., Oncoimmunology. (2017) May Examples include 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).

[0294] Bispecific and tripspecific natural killer (NK) cell engineering Ja In some embodiments, the compounds provided herein are bi-specific NK-cell engagers (BiKE) or triplicate NK-cell engagers. It is administered together with gagers (tri-specific NK-cell engagers, TriKE) (e.g., those without Fc) or bispecific antibodies against NK cell activation receptors (e.g., those with Fc), such as CD16A, type C lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), innate cytotoxic receptors (NKp30, NKp44, and NKp46), killer cell type C lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (mediates antibody-dependent cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), DNAM-1, and CD137 (41BB). Exemplary anti-CD16 bispecific antibodies, BiKEs, or TriKEs that may be administered concurrently include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). The anti-CD16 binding bispecific molecule may or may not have an Fc, as required. Exemplary bispecific NK cell engagers that may be administered concurrently target CD16 and one or more tumor-associated antigens described herein, such as CD19, CD20, CD22, CD30, CD33, CD123, EGFR, EpCAM, ganglioside GD2, HER2 / neu, HLA class II, and FOLR1. BiKEs and TriKEs are described, for example, in Felices, et al., Methods Mol Biol. (2016) 1441:333-346 and Fang, et al., Semin Immunol. (2017) 31:37-54.

[0295] MCL1 apoptosis regulator, BCL2 family member (MCL1) inhibitor In some embodiments, the compounds provided herein are administered together with inhibitors of MCL1 apoptosis regulators and BCL2 family members (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 International Publications 2018183418, 2016033486, and 2017147410.

[0296] SHP2 inhibitors In some embodiments, the compounds provided herein are administered together with inhibitors of protein tyrosine phosphatase nonreceptor 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 International Publication Nos. 2018172984 and 2017211303.

[0297] Hematopoietic progenitor cell kinase 1 (HPK1) inhibitors and degrading agents In some embodiments, the compounds provided herein are administered together with inhibitors of mitogen-activated protein kinase kinase kinase 1 (MAP4K1, HPK1, NCBI gene ID: 11184). Examples of hematopoietic progenitor cell kinase 1 (HPK1) inhibitors include, but are not limited to, those described in International Publication Nos. 2020092621, 2018183956, 2018183964, 2018167147, 2018049152, 2020092528, 2016205942, 2016090300, 2018049214, 2018049200, 2018049191, 2018102366, 2018049152, and 2016090300.

[0298] Apoptosis signal-regulating kinase (ASK) inhibitors In some embodiments, the compounds provided herein are administered together with ASK inhibitors, such as inhibitors of mitogen-activated protein kinase kinase 5 (MAP3K5, ASK1, MAPKKK5, MEKK5, NCBI gene ID: 4217). Examples of ASK1 inhibitors are described in International Publication No. 2011008709 (Gilead Sciences) and No. 2013112741 (Gilead Sciences).

[0299] Bruton's tyrosine kinase (BTK) inhibitors In some embodiments, the compounds provided herein are administered together with inhibitors of Bruton's tyrosine kinases (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA, NCBI gene ID: 695). Examples of BTK inhibitors include (S)-6-amino-9-(1-(buta-2-inoyl)pyrrolidine-3-yl)-7-(4-phenoxyphenyl)-7H-purine-8(9H)-one, acalabrutinib (ACP-196), zanubrutinib (BGB-3111), CB988, HM71224, ibrutinib, M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebralutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, PCI-32765, and TAS-5315.

[0300] Cyclin-dependent kinase (CDK) inhibitors In some embodiments, the compounds provided herein are 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: It is administered together with an inhibitor of 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, arbocidicib (HMR-1275, flavopyridol), AT-7519, dinacilib, Ibrance, FLX-925, LEE001, palbociclib, samuracilib, ribociclib, rigosertib, selinexol, UCN-01, SY1365, CT-7001, SY-1365, G1T38, milcilib, trilaciclib, simrosertib hydrate (TAK931), and TG-02.

[0301] Discoidine domain receptor (DDR) inhibitors In some embodiments, the 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, as well as International Publication No. 2014 / 047624 (Gilead Sciences), U.S. Patent Application Publication No. 2009-0142345 (Takeda Pharmaceutical), U.S. Patent Application Publication No. 2011-0287011 (Oncomed Pharmaceuticals), International Publication No. 2013 / 027802 (Chugai Pharmaceutical), and U.S. Patent Application Publication No. 2013 / 034933 (Imperial Innovations). Examples of those disclosed include:

[0302] Targeted E3 ligase ligand conjugate In some embodiments, the compounds provided herein are administered together with a targeted E3 ligase ligand conjugate. Such a conjugate has a target protein binding moiety and an E3 ligase binding moiety (e.g., an apoptotic protein inhibitor (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, a mouse double micro2 homolog (MDM2) E3 ubiquitin ligase binding moiety) and can be used to promote or increase the degradation of the targeted protein, for example, via the ubiquitin pathway. In some embodiments, the targeted E3 ligase ligand conjugate comprises a target moiety or binding moiety that targets or binds to the proteins described herein, and an E3 ligase ligand or binding moiety. In some embodiments, the targeted E3 ligase ligand conjugate includes a target or binding moiety that targets or binds to a protein selected from the Cbl proto-oncogene B (CBLB, Cbl-b, Nbla00127, RNF56, NCBI gene ID: 868) and hypoxia-inducible factor 1 subunit α (HIF1A, NCBI gene ID: 3091). In some embodiments, the targeted E3 ligase ligand conjugate includes a kinase inhibitor (e.g., a small molecule kinase inhibitor of BTK and the E3 ligase ligand or binding moiety). See, for example, International Publication No. 2018098280. In some embodiments, the targeted E3 ligase ligand conjugate comprises a binding site that targets or binds to interleukin-1 (IL-1) receptor-associated kinase 4 (IRAK-4), rapidly accelerating fibrosarcoma proteins (such as c-RAF, A-RAF, and / or B-RAF), c-Met / p38, or BRD proteins, and an E3 ligase ligand or binding site. See, for example, International Publication Nos. 2019099926, 2018226542, 2018119448, 2018223909, and 2019079701.Additional targeted E3 ligase ligand conjugates that can be administered concurrently are described, for example, in International Publications 2018237026, 2019084026, 2019084030, 2019067733, 2019043217, 2019043208, and 2018144649.

[0303] Histone deacetylase (HDAC) inhibitors In some embodiments, the compounds provided herein are administered together with inhibitors of histone deacetylase, such as histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR, gene ID: 9734). Examples of HDAC inhibitors include avexinostat, ACY-241, AR-42, BEBT-908, bellinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, dibinostat, mosetinostat, panobinostat, prasinostat, xinostat (JNJ-26481585), resminostat, licorinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamstine, remetinostat, and entinostat.

[0304] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors In some embodiments, the compounds provided herein are administered together with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1, NCBI gene ID: 3620). Examples of IDO1 inhibitors include BLV-0801, epacadostat, linrhodostat (F-001287, BMS-986205), GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919 vaccine, PF-06840003, pyranonaphthoquinone derivative (SN-35837), resminostat, SBLK-200802, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

[0305] Janus kinase (JAK) inhibitors In some embodiments, the compounds provided herein are administered together with inhibitors 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), restaurtinib, momerotinib (CYT0387), irginatinib maleate (NS-018), pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019.

[0306] Lysyl oxidase-like protein (LOXL) inhibitors In some embodiments, the compounds provided herein are administered together with inhibitors of LOXL proteins, such as LOXL1 (NCBI gene ID: 4016), LOXL2 (NCBI gene ID: 4017), LOXL3 (NCBI gene ID: 84695), LOXL4 (NCBI gene ID: 84171), and / or LOX (NCBI gene ID: 4015). Examples of LOXL2 inhibitors are described in International Publication No. 2009017833 (Arresto Biosciences), No. 2009035791 (Arresto Biosciences), and No. 2011097513 (Gilead Examples of antibodies listed in Biologics include those mentioned above.

[0307] 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: 4312). It is administered together with inhibitors of MMP15 (NCBI gene ID: 4323), MMP16 (NCBI gene ID: 4325), MMP17 (NCBI gene ID: 4326), MMP19 (NCBI gene ID: 4327), MMP20 (NCBI gene ID: 9313), MMP21 (NCBI gene ID: 118856), MMP24 (NCBI gene ID: 10893), MMP25 (NCBI gene ID: 64386), MMP26 (NCBI gene ID: 56547), MMP27 (NCBI gene ID: 64066), and / or MMP28 (NCBI gene ID: 79148). Examples of MMP9 inhibitors include marimastat (BB-2516), cipestat (Ro 32-3555), GS-5745 (andecaliximab), and those described in International Publication No. 2012027721 (Gilead Biologics).

[0308] RAS and RAS pathway inhibitors In some embodiments, the compounds provided herein are 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, It is administered together with an inhibitor of the NCMS, ALPS4, N-ras, NRAS1 (NCBI gene ID: 4893), or HRAS proto-oncogene, or 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)). Ras inhibitors 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 the following: EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT, and mTOR. Examples of K-Ras inhibitors that can be administered concurrently include sotrasib (AMG-510), COTI-219, ARS-3248, WDB-178, BI-3406, BI-1701963, SML-8-73-1 (G12C), adaglasib (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). Examples of KRAS mRNA inhibitors include anti-KRAS U1 adapters, AZD-4785, siG12D-LODER®, and siG12D exosomes.Examples of MEK inhibitors that can be administered concurrently include binimetinib, cobimetinib, PD-0325901, pimacertib, RG-7304, selumetinib, trametinib, and those described below and in this specification. Examples of Raf dimer inhibitors that can be administered concurrently include BGB-283, HM-95573, LXH-254, LY-3009120, RG7304, and TAK-580. Examples of ERK inhibitors that can be administered concurrently include LTT-462, LY-3214996, MK-8353, labocertinib, and urixertinib. Examples of Ras GTPase inhibitors that can be administered concurrently include rigosertib. Examples of PI3K inhibitors that can be administered concurrently include idelalisib (Zydelig®), alpelisib, buparlisib, pitilisib, inavolisib (RG6114), and ASN-003. Examples of AKT inhibitors that can be administered concurrently include capivacertib and GSK2141795. Examples of PI3K / mTOR inhibitors that can be administered concurrently include dactricib, omiparisib, voxtalisib, gedatricib, GSK2141795, GSK-2126458, inavolisib (RG6114), sapanicertib, ME-344, sirolimus (oral nanoamorphous formulation, cancer), and racemethyrosine (TYME-88 (mTOR / cytochrome P450). Examples include 3A4), temsirolimus (TORISEL®, CCI-779), CC-115, onatasertib (CC-223), SF-1126, and PQR-309 (vimiralisib). In some embodiments, Ras-driven cancers with CDKN2A mutations (e.g., NSCLC) can be inhibited by co-administration of the MEK inhibitor selumetinib and the CDK4 / 6 inhibitor palbociclib. See, for example, Zhou, et al., Cancer Lett. 2017 Nov 1;408:130-137. In addition, K-RAS and mutant N-RAS can be reduced by the irreversible ERBB1 / 2 / 4 inhibitor neratinib. See, for example, Booth, et al., Cancer See Biol Ther. 2018 Feb 1;19(2):132-137.

[0309] Mitogen-activated protein kinase (MEK) inhibitors In some embodiments, the compounds provided herein are administered together with inhibitors 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 antroquinonol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosetib + trametinib, PD-0325901, pimacertib, LTT462, AS703988, CC-90003, and refametinib.

[0310] Phosphatidylinositol 3-kinase (PI3K) inhibitors In some embodiments, the compounds provided herein are phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunits, for example, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA, CLAPO, CLOVE, CWS5, MCAP, MCM, MCMTC, PI3K, PI3K-alpha, p110-alpha, NCBI gene ID: 5290), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit β (PIK3CB, P11 It is administered together with inhibitors of 0β (PI3K, PI3KBETA, PIK3C1, NCBI gene ID: 5291), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit γ (PIK3CG, PI3CG, PI3K, PI3Kγ, PIK3, p110γ, p120-PI3K, gene ID: 5494), and / or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit δ (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, buparlisib (BKM120), BYL719 (alperisib), CH5132799, and copanlisib (BAY 80-6946), Duverisib, 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, R G7604, ligoseltib, RP5090, RP6530, SRX3177, tasericib, TG100115, TGR-1202 (umbralicib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, Waltmannin, ZSTK474, and International Publication No. 2005113556 (ICOS), and International Publication No. 2013 / 052699 (Gilead Examples include the compounds described in Calistoga, Gilead Calistoga (No. 2013116562), Gilead Calistoga (No. 2014100765), Gilead Calistoga (No. 2014100767), and Gilead Sciences (No. 2014201409).

[0311] Spleen tyrosine kinase (SYK) inhibitors In some embodiments, the compounds provided herein are administered together with inhibitors of spleen-associated tyrosine kinase (SYK, p72-Syk, NCBI gene ID: 6850). Examples of SYK inhibitors include 6-(1H-indazole-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazine-8-amine, BAY-61-3606, celduratinib (PRT-062607), enstopretinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), gusacitinib (ASN-002), and those described in U.S. Patent No. 8,450,321 (Gilead Connecticut) and U.S. Patent Application Publication No. 20150175616.

[0312] Toll-like receptor (TLR) agonist In some embodiments, the compounds provided herein are administered together with agonists of Toll-like receptors (TLRs), such as 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 can be administered concurrently include DS-0509, GS-9620 (besatrimod), besatrimod analogues, LHC-165, TMX-101 (imiquimod), GSK-2245035, reciquimod, 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 U.S. Patent Application Publication No. 20100143301 (Gilead Sciences), and U.S. Patent Application Publication No. 20110098248 (Gilead Sciences). (Sciences), and Patent No. 20090047249 (Gilead Sciences), Patent No. 20140045849 (Janssen), Patent No. 20140073642 (Janssen), International Publication No. 2014056953 (Janssen), International Publication No. 2014076221 (Janssen), International Publication No. 2014128189 (Janssen), US Patent Application Publication No. 20140350031 (Janssen), International Publication No. 2014023813 (Janssen), US Patent Application Publication No. 20080234251 (Array Biopharma), International Publication No. 20080306050 (Array Biopharma), International Publication No. 20100029585 (Ventirx Examples of compounds disclosed include those listed in (Pharma), (Ventirx Pharma) No. 20110092485, (Ventirx Pharma) No. 20110118235, (Ventirx Pharma) No. 20120082658, (Ventirx Pharma) No. 20120219615, (Ventirx Pharma) No. 20140066432, (Ventirx Pharma) No. 20140088085, (Ventirx Pharma) No. 20140275167, and (Novira Therapeutics) No. 20130251673. The TLR7 / TLR8 agonist that can be administered concurrently is NKTR-262.Examples of TLR8 agonists that can be administered concurrently include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motlimod, reciquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and U.S. Patent Application Publication No. 20140045849 (Janssen), No. 201400736. 42 (Janssen), International Publication No. 2014 / 056953 (Janssen), International Publication No. 2014 / 076221 (Janssen), International Publication No. 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), International Publication No. 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Examples of compounds disclosed in Biopharma, No. 20080306050 (Array Biopharma), No. 20100029585 (Ventirx Pharma), No. 20110092485 (Ventirx Pharma), No. 20110118235 (Ventirx Pharma), No. 20120082658 (Ventirx Pharma), No. 20120219615 (Ventirx Pharma), No. 20140066432 (Ventirx Pharma), No. 20140088085 (Ventirx Pharma), No. 20140275167 (Novira Therapeutics), and No. 20130251673 (Novira Therapeutics). Examples of TLR9 agonists that can be administered concurrently include AST-008, CMP-001, IMO-2055, IMO-2125, ritenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatrimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), CYT-003, CYT-003-QbG10, and PUL-042.Examples of TLR3 agonists include lintatrimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.

[0313] Tyrosine kinase inhibitors (TKIs) In some embodiments, the compounds provided herein are administered together with tyrosine kinase inhibitors (TKIs). TKIs are used to target epidermal growth factor receptor (EGFR), as well as fibroblast growth factor (FGF) and platelet-derived growth factors. platelet-derived growth factor (PDGF), and vascular endothelial growth factor (vascular endothelial growth factor) It may target the receptor for endothelial growth factor (VEGF). An example of a TKI is... However, this is not limited to afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, cejiranib, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, K Examples include X2-391(Src), lapatinib, restaurtinib, lenvatinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, quizartinib, radotinib, rosiletinib, sulfatinib (HMPL-012), sunitinib, famitinib, L-malate (MAC-4), tiboanib, TH-4000, and MEDI-575 (anti-PDGFR antibody). Examples of EGFR-targeting drugs include neratinib, tucatinib (ONT-380), tesevatinib, mobocertinib (TAK-788), DZD-9008, baritinib, avivertinib (ACEA-0010), EGF816 (nazartinib), olmutinib (BI-1482694), osimertinib (AZD-9291), AMG-596 (EGFRvIII / CD3), rifirafenib (BGB-283), vectibix, razertinib (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 sarotalocan (RM-1929), cerivanthumab, necitumumab, depatuxizumab mafodotin (ABT-414), tomzotuximab, depatuxizumab (ABT-806), and cetuximab.

[0314] Chemotherapy agents In some embodiments, the compounds provided herein are administered together with chemotherapeutic agents or antineoplastic agents.

[0315] As used herein, the terms “chemotherapeutic agent” or “chemotherapeutic drug” (or “chemotherapy” when referring to treatment with a chemotherapeutic agent) mean to encompass any non-proteinogenic (e.g., non-peptidogenic) compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents, e.g., thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates, e.g., busulfan, improsulfan, and pigosulfan; aziridines, e.g., benzodepa, carboquan, meturedepa, and uredepa; ethyleneimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimemiloromelamamine; acetogenins, e.g., bratacin and bratacinone; camptothecin, including the synthetic analog topotecan; bryostatin, callistatin; CC-1065, including adzeresin, karzeresin, and bizeresin synthetic analogs; cryptophycin, in particular, Liptophycin 1 and cryptophycin 8; dorastatin; duocalmycin including synthetic analogs KW-2189 and CBI-TMI; eloiterobin; 5-azacitidine; pancratistatin; sarcodictiin; spongstatin; nitrogen mustards, e.g., chlorambucil, chlornafadin, cyclophosphamide, gluphosphamide, evophosphamide, bendamustine, estramustine, ifosfamide, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobembitin, fenesterine, prednimustine, trophosphamide, and uracil mustard; nitrosoureas, e.g., carmustine, chlorozotosine, foremustine, lomustine, nimustine, and ranimustine;Antibiotics, such as engineeric antibiotics (e.g., Calichemycin, in particular Calichemycin Gamma II and Calichemycin Phi I1), dinemycin containing dinemycin A, bisphosphonates such as clodronate, esperamycin, neocardinostatin chromophores and related chromoprotein engineeric antibiotic chromophores, acrasinomycin, actinomycin, anthramycin, azaserin, bleomycin, kactinomycin, carabicin, carminomycin, cardinophilin, chromomycin, dactinomycin, dauno Rubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin such as mitomycin C, mycophenolic acid, nogaramycin, olibomycin, peplomycin, porphyromycin, puromycin, keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidine, ube Nimex, dinostatin, and zolubicin; antimetabolites, e.g., methotrexate and 5-fluorouracil (5-FU); folate analogs, e.g., demopterin, methotrexate, pteropterin, and trimethrexate; purine analogs, e.g., cladribine, pentostatin, fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs, e.g., ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and phloxuridine; a Endogens, such as carsterone, dromostanolone propionate, epithiostanol, mepithiostan, and testotractone; anti-adrenal drugs, such as aminoglutethimide, mitotane, and trilostane; folic acid supplements, such as phloric acid; radiotherapy agents such as radium-223; trichothecenes, especially T-2 toxin, beraclin A, loridine A, and anguidin; taxoids such as paclitaxel (TAXOL®), abraxane, docetaxel (TAXOTERE®), cabazitaxel, BIND-014, and tesetaxel;Sabizabrin (Veru-111), platinum analogs, e.g., cisplatin and carboplatin, NC-6004 nanoplatin; acegraton; aldofamide glycoside; aminolevulinic acid; enyluracil; amsacrin; hestrabusyl; bisanthren; edatraxate; defofamine; demecoltin; diaziquan; elformutin; eriptinium acetate; epotilon; etogluside; gallium nitrate; hydroxyurea; lentinan; leucovorin; ronidamine; meitansinoids, e.g., meitansin and ansamitosine; mitogwazone; mitoxantrone; mopidamol; nitracrin; pentostatin; fenamet; pirarubicin; losoxantrone; fluoropyrimidine; folic acid; podophyllic acid, 2-ethylhydrazide; procarbazine; polysaccharide K (PSK); ra Zoxane; Rhizoxin; Schizophyllan; Spirogermanium; Tenuazonic acid; Trabectedin, Triadiquan; 2,2',2''-Trichlorotriemylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitractol; Pipobroman; Gacitosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiopeta; Chlorambucil; Gemcitabine (GEMZAR (Registered Trademark)); 6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitroxantrone; bancristine; vinorelbine (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; zeoloda; ibandronate; CPT-11, topoisomerase inhibitor RFS 2000; difluoromethylornithine (DFMO); retinoids, e.g., retinoic acid; capecitabine; NUC-1031; FOLFOX (folic acid, 5-fluorouracil, oxaliplatin); FOLFIRI (folic acid, 5-fluorouracil, irinotecan);Examples include, but are not limited to, FOLFOXIRI (folic acid, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (folic acid, 5-fluorouracil, irinotecan, oxaliplatin), and any pharmaceutically acceptable salts, acids, or derivatives of the above. Such agents may be conjugated to an antibody or any targeted agent described herein to create an antibody-drug conjugate (ADC) or a targeted drug conjugate.

[0316] Anti-hormone drugs The definition of "chemotherapeutic agents" includes anti-hormonal agents such as anti-estrogens and selective estrogen receptor modulators (SERMs), enzyme aromatase inhibitors, anti-androgens, and any pharmaceutically acceptable salts, acids, or derivatives of any of the above that act to modulate or inhibit the hormonal effects on tumors.

[0317] Examples of anti-estrogen agents and SERMs include tamoxifen (including NOLVADEXTM), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxyfen, keoxyfen, LY117018, onapristone, and toremifene (FARESTON®).

[0318] Inhibitors of the enzyme aromatase regulate estrogen production in the adrenal gland. Examples include 4(5)-imidazole, aminoglutethimide, megestrol acetate (MEGACE®), exemestane, formestan, fadrozole, borozole (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®).

[0319] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, ODM-204, enovotherm (GTX-024), darolutamide, and IONIS-AR-2.5Rx (antisense).

[0320] An example of a progesterone receptor antagonist is onapristone. Additional progesterone-targeting drugs include TRI-CYCLEN LO (norethindrone + ethinylestradiol), norgestimate + ethinylestradiol (Tri-Cyclen), and levonorgestrel.

[0321] Anti-angiogenic agents In some embodiments, the compounds provided herein are administered together with anti-angiogenic agents. Anti-angiogenic agents that may be administered concurrently include retinoid acids and their derivatives, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®, regorafenib, nekparanib, suramin, squalamine, tissue inhibitors of metalloproteinase-1, tissue inhibitors of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitors, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulfate (clepein), sulfated chitin derivatives (prepared from snow crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, and l-azetidine-2-carboxylic acid. Matrix metabolism regulators including proline analogs such as acid, LACA, cis-hydroxyproline, d,I-3,4-dehydroproline, thiaproline, α,α'-dipyridyl, beta-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2-macroglobulin-serum, metalloproteinase-3 chicken inhibitor (ChIMP-3), chymostatin, beta-silicon Examples of anti-angiogenic agents include clodextrin tetradecasulfate, eponemycin, fumagiline, sodium aurantithiomalate, d-penicillamine, beta-1 anticollagenase serum, alpha-2 antiplasmin, bisanthren, lobenzalit disodium, n-2-carboxyphenyl-4-chloroantonylate disodium or "CCA", thalidomide, angiogenesis-inhibiting steroids, carboxyaminoimidazole, metalloproteinase inhibitors such as BB-94, and S100A9 inhibitors such as tascinimod. Other anti-angiogenic agents include antibodies, preferably monoclonal antibodies against angiogenic growth factors such as β-FGF, α-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF / SF, and Ang-1 / Ang-2.Examples of anti-VEGFA antibodies that can be administered concurrently include bevacizumab, vanucizumab, falisimab, zilpasimab (ABT-165, DLL4 / VEGF), or nabisikizumab (OMP-305B83, DLL4 / VEGF).

[0322] Antifibrotic agents In some embodiments, the compounds provided herein are administered together with antifibrotic agents. Antifibrotic agents that may be administered concurrently include compounds such as β-aminopropionitrile (BAPN), as well as compounds disclosed in U.S. Patent No. 4,965,288, relating to lysyl oxidase inhibitors and their use in the treatment of diseases and conditions associated with abnormal collagen deposition, and U.S. Patent No. 4,997,854, relating to compounds that inhibit LOX for the treatment of various pathological fibrous conditions, which are incorporated herein by reference. Further exemplary inhibitors are described in U.S. Patents 4,943,593, 5021,456, 5059,714, 5120,764, and 5182,297 relating to compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine, U.S. Patent 5,252,608 relating to 2-(1-naphthyloxymemyl)-3-fluoroallylamine, and U.S. Patent Application Publication 20040248871, which are incorporated herein by reference.

[0323] Examples of antifibrotic agents include primary amines that react with the carbonyl group of the active site of lysyl oxidase, more specifically, those that, after binding to carbonyl, produce resonance-stabilized products, such as emylenemamine, hydrazine, phenylhydrazine, and their derivatives; semicarbazides and urea derivatives; aminonitriles, such as BAPN or 2-nitroethylamine; unsaturated or saturated haloamines, such as 2-bromoethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, and p-halobenzylamine; and primary amines such as selenohomocysteine ​​lactone.

[0324] Other antifibrotic agents are copper chelating agents that either penetrate or do not penetrate cells. Exemplary compounds include indirect inhibitors that inhibit aldehyde derivatives derived from the oxidative deamination of lysyl and hydroxylysyl residues by lysyl oxidase. Examples include thiolamins, particularly D-penicillamine and its analogues, such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulfate, 2-acetamidoethyl-2-acetamidoethanethiol sulfanate, and sodium-4-mercaptobutane sulfinate trihydrate.

[0325] Anti-inflammatory drugs In some embodiments, the compounds provided herein are administered together with anti-inflammatory agents. Examples of such anti-inflammatory agents include, but are not limited to, arginases (ARG1 (NCBI gene ID: 383), ARG2 (NCBI gene ID: 384)), carbonic anhydrases (CA (carbonic anhydrase) 1 (NCBI gene: 759), CA2 (NCBI gene: 759)). Prostaglandin endoperoxide synthase (NCBI gene ID: 760), CA3 (NCBI gene ID: 761), CA4 (NCBI gene ID: 762), CA5A (NCBI gene ID: 763), CA5B (NCBI gene ID: 11238), CA6 (NCBI gene ID: 765), CA7 (NCBI gene ID: 766), CA8 (NCBI gene ID: 767), CA9 (NCBI gene ID: 768), CA10 (NCBI gene ID: 56934), CA11 (NCBI gene ID: 770), CA12 (NCBI gene ID: 771), CA13 (NCBI gene ID: 377677), CA14 (NCBI gene ID: 23632) Examples of inhibitors include one or more of the following: 1 (PTGS1, COX-1, NCBI gene ID: 5742), prostaglandin endoperoxide synthase 2 (PTGS2, COX-2, NCBI gene ID: 5743), secreted phospholipase A2, prostaglandin E synthase (PTGES, PGES, gene ID: 9536), arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX, NCBI gene ID: 240), soluble epoxide hydrolase 2 (EPHX2, SEH, NCBI gene ID: 2053), and / or mitogen-activated protein kinase kinase 8 (MAP3K8, TPL2, NCBI gene ID: 1326). In some embodiments, the inhibitor is a dual inhibitor, for example, a dual inhibitor of COX-2 / COX-1, COX-2 / SEH, COX-2 / CA, or COX-2 / 5-LOX.

[0326] Examples of prostaglandin endoperoxide synthase 1 (PTGS1, COX-1, NCBI gene ID: 5742) inhibitors that can be administered concurrently include mofezolac, GLY-230, and TRK-700.

[0327] Examples of prostaglandin endoperoxide synthase 2 (PTGS2, COX-2, NCBI gene ID: 5743) inhibitors that can be administered concurrently include diclofenac, meloxicam, parecoxib, etoricoxib, AP-101, celecoxib, AXS-06, diclofenac potassium, DRGT-46, AAT-076, maesoshri, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimeslid, anitrazafen, apricoxib, simicoxib, delacoxib, flumizole, firocoxib, mavacoxib, NS-398, pamicogrel, parecoxib, robenacoxib, rofecoxib, lutecarpine, chilmacoxib, and zaltoprofen. Examples of dual COX1 / COX2 inhibitors that can be administered concurrently include HP-5000, lornoxicam, ketrolactromethamine, bromfenac sodium, ATB-346, and HP-5000. Examples of dual COX-2 / carbonic anhydrase (CA) inhibitors that can be administered concurrently include polmacoxib and imurecoxib.

[0328] Examples of inhibitors of secretory phospholipase A2 and prostaglandin E synthase (PTGES, PGES, gene ID: 9536) that can be administered concurrently include LY3023703, GRC27864, and International Publication Nos. 2015158204, 2013024898, 2006063466, 2007059610, and 20071. 24589, 2010100249, 2010034796, 2010034797, 2012022793, 2012076673, 2012076672, 2010034798, 2010034799, 2012022792, 2009103778, 201104800 No. 4, No. 2012087771, No. 2012161965, No. 2013118071, No. 2013072825, No. 2014167444, No. 2009 138376, 2011023812, 2012110860, 2013153535, 2009130242, 2009146696, Examples of compounds listed are those described in Nos. 2013186692, 2015059618, 2016069376, 2016069374, 2009117985, 2009064250, 2009064251, 2009082347, 2009117987, and 2008071173. Metformin has been further found to inhibit the COX2 / PGE2 / STAT3 axis and can be administered concurrently. See, for example, Tong, et al., Cancer Lett. (2017) 389:23-32 and Liu, et al., Oncotarget. (2016) 7(19):28235-46.

[0329] Carbonic anhydrases that can be administered simultaneously (e.g., CA1 (NCBI gene ID: 759), CA2 (NCBI gene ID: 760), CA3 (NCBI gene ID: 761), CA4 (NCBI gene ID: 762), CA5A (NCBI gene ID: 763), CA5B (NCBI gene ID: 11238), CA6 (NCBI gene ID: 765), CA7 (NCBI gene ID: 766), CA8 (NCBI gene ID: 767), C Examples of inhibitors for one or more of the following: A9 (NCBI gene ID: 768), CA10 (NCBI gene ID: 56934), CA11 (NCBI gene ID: 770), CA12 (NCBI gene ID: 771), CA13 (NCBI gene ID: 377677), and CA14 (NCBI gene ID: 23632) include acetazolamide, metazolamide, dorzolamide, zonisamide, brinzolamide, and diclofenamide. CG100649 is an example of a dual COX-2 / CA1 / CA2 inhibitor that can be administered concurrently.

[0330] Examples of arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX, NCBI gene ID:240) inhibitors that can be administered concurrently include meclofenamate sodium and dilauton.

[0331] Examples of soluble epoxide hydrolase 2 (EPHX2, SEH, NCBI gene ID: 2053) that can be administered concurrently include compounds described in International Publication No. 2015148954. Examples of COX-2 / SEH dual inhibitors that can be administered concurrently include compounds described in International Publication No. 2012082647. Examples of SEH and fatty acid amide hydrolase dual inhibitors (FAAH, NCBI gene ID: 2166) that can be administered concurrently include compounds described in International Publication No. 2017160861.

[0332] Examples of mitogen-activated protein kinase kinase 8 (MAP3K8, tumor progression locus 2, TPL2, NCBI gene ID: 1326) inhibitors that can be administered concurrently include GS-4875, GS-5290, BHM-078, and International Publication Nos. 2006124944, 2006124692, 2014064215, 2018005435, as well as Teli, et al., J Enzyme Inhib Med Chem. (2012) 27(4):558-70, Gangwall, et al., Curr Top Med Chem. (2013) 13(9):1015-35, Wu, et al., Bioorg Med Chem Lett. (2009) 19(13):3485-8, and Kaila, et al., Bioorg Examples include those described in Med Chem. (2007) 15(19):6425-42 and Hu, et al., Bioorg Med Chem Lett. (2011) 21(16):4758-61.

[0333] Tumor oxygenation agent In some embodiments, the compounds provided herein are administered together with agents that promote or increase tumor oxygenation or reoxygenation, or prevent or reduce tumor hypoxia. Illustrative agents that may be administered concurrently include, for example, hypoxia-inducible factor-1 alpha (HI) such as PT-2977 and PT-2385. Examples include VEGF inhibitors such as F-1α) inhibitors, bevacizumab, IMC-3C5, GNR-011, tanibirumab, LYN-00101, and ABT-165, as well as oxygen carrier proteins (e.g., heme nitric oxide and / or oxygen-binding protein (HNOX)) such as OMX-302 and HNOX proteins described in International Publication Nos. 2007137767, 2007139791, 2014107171, and 2016149562.

[0334] Immunotherapy agents In some embodiments, the compounds provided herein are administered together with an immunotherapy agent. In some embodiments, the immunotherapy agent is an antibody.Examples of immunotherapeutic agents that can be administered concurrently include avagovomab, AB308, ABP-980, adecatumumab, aftumumab, alemtuzumab, altumomab, amatsuximab, anatumomab, alsitumomab, atezolizumab, bavituximab, vectumomab, bevacizumab, vibatuzumab, blinatumomab, brentuximab, camidanlumab, cantuzumab, catumakisomab, CC49, cetuximab, sitatuzumab, xixtumumab, cribatuzumab, conatumumab, dacetuzumab, darotuzumab, daratumumab, detumomab. Dinutuximab, dombanarimab, dorodizumab, durigotumab, dusigitumab, eclomeximab, elotuzumab, emibetuzumab, encituximab, erzumaxomab, etalacizumab, falletuzumab, ficratuzumab, figitumumab, frambotumab, futuximab, ganituzumab, gemtuzumab, girentuximab, glenbatumumab, ibritumomab, igobomab, imugatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab (YERVOY®, MDX-010, BMS-7) 34016, and MDX-101), Iratumumab, Labetuzumab, Lexatumumab, Lintuzumab, Rorbotuzumab, Lucatumumab, Mapatumumab, Matuzumab, Miratuzumab, Minretum...

Claims

[Claim 1] The invention described herein.

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