MCL1 inhibitors

Abstract

To provide methods of treating diseases.SOLUTION: The present disclosure generally relates to compounds of Formula (I) and pharmaceutical compositions that may be used in methods of treating cancer. This application generally relates to certain compounds that inhibit MCL1, pharmaceutical compositions comprising the compounds, use of the compounds to treat cancers, and methods of making the compounds.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Patent Application No. 62 / 934,400, filed on November 12, 2019. The entire content of the application is incorporated herein by reference.

[0002] (Field of invention) This application generally relates to specific compounds that inhibit MCL1, pharmaceutical compositions containing these compounds, the use of these compounds for treating cancer, and methods for producing these compounds. [Background technology]

[0003] Apoptosis (programmed cell death) is a process that removes undesirable or potentially dangerous cells from an organism. Avoiding apoptosis is crucial for tumor development and sustained growth. Myelocyte leukemia 1 protein (MCL1) is an anti-apoptotic member of the Bcl-2 family of proteins. MCL1 is overexpressed in many cancers. Overexpression of MCL1 prevents cancer cells from undergoing apoptosis. Several studies have shown that MCL1 inhibitors may be used in the treatment of cancer. Therefore, there is a need for new compounds that inhibit MCL1. [Overview of the Initiative] [Means for solving the problem]

[0004] The aforementioned need is addressed by this disclosure. Specifically, inhibitors of MCL1 are provided herein.

[0005] In one embodiment, the present disclosure is given by formula (I): [ka] Compounds by [in the formula, [ka] is a single bond or a double bond, [Chemical Formula] when it is a double bond, R 3~10 , 16 , , 1~6 , 6~10 , 15 , 1~6 , 1~6 , , 1~6 , 1 , 6~10 , 1~6 , 1~6 , 15 , 3~10 does not exist, [Chemical Formula] is a single bond, a double bond, or a triple bond, [Chemical Formula] when it is a triple bond, R 6 and R <00000​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​1~6 Alkylene-5 to 10-membered heteroaryls and -NR 15a R 15b Selected from, R 15 This involves selecting 1 to 5 R's arbitrarily. A Replaced by, Each R 15a and R 15b is hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkylene-C 3~10 Cycloalkyl, -C 1~6 Alkilen-3~12 member heterocyclyl, -C 1~6 Alkylene-C 6~10 Aryl, and -C 1~6 Independently selected from alkylene-5 to 10-membered heteroaryls, R 15a and R 15b Each C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkylene-C 3~10 Cycloalkyl, -C 1~6 Alkilen-3~12 member heterocyclyl, -C 1~6 Alkylene-C 6~10 Aryl, and -C 1~6 Alkylene-5 to 10-membered heteroaryls include halo, hydroxyl, oxo, -CN, and C. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl and C 1~6 The haloalkoxyl is independently and optionally substituted with 1 to 4 groups independently selected, R 16 R is a 3-12 member heterocyclic or 5-12 member heteroaryl, 16 This involves selecting 1 to 5 R's arbitrarily. A Replaced by, R2 is selected from hydrogen, halo, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxyl, and -C 1~4 alkylene-O-C 1~6 alkyl, and is selected from R 3 is selected from hydrogen, halo, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxyl, C 3~10 cycloalkyl, 3- to 12-membered heterocyclyl, and -C 1~4 alkylene-O-5- to 10-membered heteroaryl, and each C of R 3 is optionally substituted with 1 to 4 groups independently selected from halo, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxyl, C 3~10 cycloalkyl, 3- to 12-membered heterocyclyl, and -C 1~4 alkylene-O-5- to 10-membered heteroaryl is optionally substituted with 1 to 4 groups independently selected from halo, C 1~6 alkyl, C 1~6 haloalkyl, and C 1~6 alkoxyl, and each R and R 4 are selected from hydrogen, halo, hydroxyl, C 5 alkyl, C 1~6 ed alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, C 1~6 alkoxyl, C 1~6 haloalkoxyl, -NR aa R bb -NHC(O)-C 1~6 alkyl, -C(O)NH-C 1~6 alkyl, -O-C 2~6 alkynyl, -OC(O)-C 1~6 alkyl, -O-(CH2CH2O) n -C 1~6 alkyl, C 3~10 cycloalkyl, 3- to 12-membered heterocyclyl, -O-C<id= 3~10 cycloalkyl, -O-3- to 12-membered heterocyclyl, -O-C1~4 Alkylene-C 3~10 Cycloalkyl, 5-10 member heteroaryl, -OC 1~4 Alkilen-3 to 12-membered heterocyclyl, -O-5 to 10-membered heteroaryl , and -OC 1~4 Independently selected from alkylene-5 to 10-membered heteroaryls, R 4 and R 5 Each C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, -NHC(O)-C 1~6 Alkyl, -C(O)NH-C 1~6 Alkyl, -OC 2~6 Alkinyl, -OC(O)-C 1~6 Alkyl, -O-(CH2CH2O) n -C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-12 member heterocyclyl, -OC 3~10 Cycloalkyl, -O-3~12 member heterocyclyl, -OC 1~4 Alkylene-C 3~10 Cycloalkyl, 5-10 member heteroaryl, -OC 1~4 Alkylene-3 to 12-membered heterocyclyl, -O-5 to 10-membered heteroaryl, and -OC 1~4 Alkylene-5 to 10-membered heteroaryls are halo, hydroxyl, oxo, and C. 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, -NR aa R bb , C 3~10 Optionally substituted with 1 to 4 groups independently selected from cycloalkyl and 3-12 membered heterocyclyl groups, Each R 6 and R 7 is hydrogen, halo, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6Haloalkyl and C 1~6 Selected independently from haloalkoxyls, R 8 C is hydrogen, halo, hydroxyl, oxo, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, -OC 3~10 Cycloalkyl, -O-3~12 member heterocyclyl, -OC 6~10 Aryl, -O-5~10 member heteroaryl, -OC 1~4 Alkylene-C 3~10 Cycloalkyl, -OC 1~4 Alkilen-3~12 member heterocyclyl, -OC 1~4 Alkylene-C 6~10 Aryl, and -OC 1~4 Selected from alkylene-5 to 10-membered heteroaryls R 9 Either it does not exist, or it is hydrogen, halo, hydroxyl, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, -OC 3~10 Cycloalkyl, -O-3~12 member heterocyclyl, -OC 6~10 Aryl, -O-5~10 member heteroaryl, -OC 1~4 Alkylene-C 3~10 Cycloalkyl, -OC 1~4 Alkilen-3~12 member heterocyclyl, -OC 1~4 Alkylene-C 6~10 Aryl, and -OC 1~4Selected from alkylene-5 to 10-membered heteroaryls R 8 and R 9 Each C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, -OC 3~10 Cycloalkyl, -O-3~12 member heterocyclyl, -OC 6~10 Aryl, -O-5~10 member heteroaryl, -OC 1~4 Alkylene-C 3~10 Cycloalkyl, -OC 1~4 Alkilen-3~12 member heterocyclyl, -OC 1~4 Alkylene-C 6~10 Aryl, and -OC 1~4 Alkylene-5 to 10-membered heteroaryls have 1 to 5 R A It is independently and optionally replaced, or R 2 and R 4 , R 4 and R 6 , R 6 and R 7 , or R 7 and R 8 These, together with the atoms to which they are bonded, form 3-7 membered heterocyclines or 5-6 membered heteroaryls, each 3-7 membered heterocycline and 5-6 membered heteroaryl containing 1-3 heteroatoms, and each 3-7 membered heterocycline and 5-6 membered heteroaryl contains halo, oxo, hydroxyl, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenil, C 2~6 Alkinyl, -NR aa R bb , and -C 1~6 Alkilen-NRaa R bb It is optionally replaced by 1 to 4 bases independently selected from, or R 4 , R 6 , and R 7 These atoms, together with the atoms to which they are bonded, form 8-12 membered condensed heterocyclines, each containing 1-4 heteroatoms, and these heterocyclines are composed of halo, oxo, hydroxyl, and C atoms. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenil, C 2~6 Alkinyl, -NR aa R bb , and -C 1~6 Alkilen-NR aa R bb It is optionally replaced by 1 to 4 bases independently selected from, or R 4 and R 8 These, together with the atoms they are bonded to, form 8-16 member heterocyclines, and each 8-16 member heterocycline contains 1-4 heteroatoms, and each 8-16 member heterocycline is composed of halo, oxo, hydroxyl, and C atoms. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenil, C 2~6 Alkinyl, -NR aa R bb , and -C 1~6 Alkilen-NR aa R bb It is arbitrarily replaced by 1 to 3 bases independently selected from, R 10 is hydrogen, halo, hydroxyl, -CN, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl and C 1~6 Selected from haloalkoxyls, Each R11 , R 12 , R 13 , and R 14 is hydrogen, halo, hydroxyl, -CN, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Independently selected from haloalkyls, or R 11 and R 13 Together with the atoms to which they are bonded, C 3~6 It forms a cycloalkyl or a 3-6 membered heterocycline, and the 3-6 membered heterocycline contains 1-3 heteroatoms, each C 3~6 Cycloalkyl and 3-6 membered heterocyclyls are halo, hydroxyl, -CN, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl and C 1~6 The haloalkoxyl is optionally substituted with 1 to 3 groups independently selected, Each R A is halo, hydroxyl, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxyl, -C 1~4 Alkylene-OC 1~4 Alkyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, and -NR aa R bb Selected independently from, R A Each C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxyl, -C 1~4 Alkylene-OC 1~4 Alkyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C6~10 Aryl, 5-10 member heteroaryl, halo, hydroxyl, -CN, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, and -NR aa R bb It is independently replaced by 1 to 3 elements independently selected from, Each R aa and R bb is hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkylene-C 3~10 Cycloalkyl, -C 1~6 Alkilen-3~12 member heterocyclyl, -C 1~6 Alkylene-C 6~10 Aryl, and -C 1~6 Independently selected from alkylene-5 to 10-membered heteroaryls, R aa and R bb Each C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkylene-C 3~10 Cycloalkyl, -C 1~6 Alkilen-3~12 member heterocyclyl, -C 1~6 Alkylene-C 6~10 Aryl, and -C 1~6 Alkylene-5~10 member heteroaryls are halo, C 1~6 Alkyl, -CN, C 1~6 Alkoxyl, and C 1~6 It is independently and optionally substituted with 1 to 4 groups independently selected from the haloalkyl group. 3- to 12-membered heterocyclines are monocyclic or polycyclic rings having 1 to 4 heteroatoms independently selected from nitrogen, sulfur, phosphorus, -N(O)-, -S(O)-, and S(O)2-, where the polycyclic rings can be condensed, cross-linked, or spiro. A 5-10 membered heteroaryl is an aromatic group having a monocyclic or polycyclic ring, and contains 1 to 4 heteroatoms independently selected from nitrogen, oxygen, sulfur, -N(O)-, -S(O)-, and -S(O)2. however, [ka] When it is a single bond, [ka] At least one of them is a double bond, [ka] When it is a double bond, (a) R 1 is R 16 And, (b) Z 1 is N, (c) Z 1 CR 1a And R 1a Hello, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl and C 1~6 Selected from haloalkoxyls, (d) Each R 4 and R 5 It is not hydrogen, (e) Each R 8 and R 9 It is not hydrogen, (f) R 5 is hydrogen, R 4 C 2~6 Alkenil, C 2~6 Alkinyl and -OC 2~6 Selected from these, each of these is halo, hydroxyl, oxo, C 1~6Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, -NR aa R bb , C 3~10 Optionally substituted with 1 to 4 groups independently selected from cycloalkyl and 3-12 membered heterocyclyl groups, (g) R 9 is hydrogen, R 8 is hydrogen, halo, C 2~6 Alkenil, C 2~6 Alkinyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Selected from aryls and 5-10 membered heteroaryls, R 8 Each C 2~6 Alkinyl, OC 2~6 Alkenyl, -OC 2~6 Alkinyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 aryls and 5-10 member heteroaryls of R have 1-5 R A It is independently and arbitrarily substituted, (h) R 2 and R 4 , R 4 and R 6 , R 6 and R 7 , or R 7 and R 8 These, together with the atoms to which they are bonded, form 3-7 membered heterocyclines or 5-6 membered heteroaryls, each 3-7 membered heterocycline and 5-6 membered heteroaryl containing 1-3 heteroatoms, and each 3-7 membered heterocycline and 5-6 membered heteroaryl contains halo, oxo, hydroxyl, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenil, C 2~6 Alkinyl, -NR aa R bb, and -C 1~6 Alkilen-NR aa R bb It is arbitrarily replaced by 1 to 4 bases independently selected from, (i) R 4 , R 6 , and R 7 These, together with the atoms to which they are bonded, form 8-12 membered condensed heterocyclines, and these 8-12 membered condensed heterocyclines contain 1-3 heteroatoms, and these 8-12 membered condensed heterocyclines are halo, oxo, hydroxyl, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenil, C 2~6 Alkinyl, -NR aa R bb , and -C 1~6 Alkilen-NR aa R bb It is optionally replaced by 1 to 4 bases independently selected from, or (j) R 4 and R 8 These, together with the atoms they are bonded to, form 8-16 member heterocyclines, and 8-16 member condensed heterocyclines contain 1-3 heteroatoms, and 8-16 member condensed heterocyclines contain halo, oxo, hydroxyl, and C atoms. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenil, C 2~6 Alkinyl, -NR aa R bb , and -C 1~6 Alkilen-NR aa R bb The present invention provides a pharmaceutically acceptable salt thereof, which is optionally substituted with 1 to 3 groups independently selected from the present, or a pharmaceutically acceptable salt thereof.

[0006] In some embodiments, pharmaceutical compositions comprising a compound according to formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient are provided herein.

[0007] In some embodiments, methods for inhibiting MCL1 in a patient are provided herein, comprising administering a compound according to formula (I) or a pharmaceutically acceptable salt thereof to the patient.

[0008] In some embodiments, methods for treating cancer in a patient are provided herein, comprising administering to the patient a compound according to formula (I) or a pharmaceutically acceptable salt thereof. [Modes for carrying out the invention]

[0009] Unless otherwise required by context, throughout this specification and the claims, the word “comprise” and its variations, such as “comprises” and “comprising,” are used in an open and comprehensive sense, i.e., “includes, but is not limited to.” It should be interpreted as such.

[0010] "C u~v ", that is (C u ~C v Prefixes such as ) indicate that the following group has u to v carbon atoms, and u and v are integers. For example, "C 1~6 The term "alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0011] A dash ("-") that is not between two letters or symbols is used to indicate a bonding point for a substituent. For example, -C(O)NH2 is bonded via a carbon atom. Dashes at the beginning or end of a chemical group are for convenience only, and chemical groups can be illustrated with or without one or more dashes without losing their usual meaning. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply direction.

[0012] For example, the wavy lines on the chemical group 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.

[0013] The term "substituted" means that one or more hydrogen atoms on a hydrocarbon are substituted by one or more atoms or groups other than hydrogen, provided that the normal valence of the specified carbon atom is not exceeded. A "substituent" is the atom or group that substitutes a hydrogen atom on a hydrocarbon when it is "substituted". Unless otherwise specified, if a group is described as being optionally substituted, any substituent of the group is itself unsubstituted.

[0014] The term "approximately" refers to a value or parameter that is ±10% of the indicated quantity.

[0015] As used herein, "alkyl" refers to a linear or branched saturated monovalent hydrocarbon. Examples of alkyl groups 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), 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), and 2-pentyl (C H(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(-CH-2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3-hexyl(-CH(CH2CH3)(CH2CH2CH3)), 2- Examples include, but are not limited to, methyl-2-pentyl(-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl(CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl(CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl(-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl(CH(CH2CH3)CH(CH3)2), and 2,3-dimethyl-2-butyl(-C(CH3)2CH(CH3)2) and 3,3-dimethyl-2-butyl(-CH(CH3)C(CH3)3).

[0016] "Alkylene" (including those that are part of other groups) refers to branched and unbranched divalent "alkyl" groups. As used herein, alkylene has 1 to 20 carbon atoms (i.e., C 1~20 Alkylenes), having 1 to 8 carbon atoms (i.e., C 1~8 Alkylenes), having 1 to 6 carbon atoms (i.e., C 1~6 Alkylene), or having 1 to 4 carbon atoms (i.e., C 1~4 Alkylenes). Examples include methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, or 1,2-dimethylethylene. Unless otherwise specified, the definitions of propylene and butylene include all possible isomers of the group in question having the same number of carbon atoms. Therefore, for example, propylene also includes 1-methylethylene, and butylene includes 1-methylpropylene, 1,1-dimethylethylene, and 1,2-dimethylethylene.

[0017] An "alkenyl" refers to an aliphatic group containing at least one carbon-carbon double bond. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (such as 1,2-butadienyl and 1,3-butadienyl).

[0018] As used herein, “alkoxy” is defined as formula -OR A This refers to the radical of the expression, where R is located in the formula. A These are alkyl radicals, as defined above. Non-limiting examples of alkoxys include methoxy, ethoxy, propoxy, and butoxy.

[0019] "Alkynyl" refers to an aliphatic group that contains at least one carbon-carbon triple bond.

[0020] "Aryl" refers to a monoradical or diradical aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., polycyclic), such as a fused ring system in which one or more fused rings are completely or partially unsaturated. Non-limiting examples of aryl groups as used herein include phenyl, naphthyl, fluorenyl, indanyl, tetrahydroindanyl, and anthryl. However, aryl does not in any way encompass or overlap with heteroaryls as defined below. When one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is a heteroaryl. The classification of mono or diradical indicates whether the chain terminates with an aryl group (monoradical) or whether the aryl group is within the chain (dirradical). The above definitions do not exclude additional substituents on the aryl group. For example, as used herein, the aryl group in "A-aryl-B" is a diradical, and the aryl group in "AB-aryl" is a monoradical, but additional substituents may be present on each aryl group.

[0021] "Cycloalkyl" refers to monocyclic or spirocyclic systems, including condensed ring systems, bridged ring systems, and spirocyclic systems. This refers to a polycyclic saturated or partially saturated cyclic alkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0022] As used herein, "halo" or "halogen" refers to fluoro(-F), chloro(-Cl), bromo(-Br), and iodine(-I).

[0023] As used herein, the term "haloalkyl" means alkyl as defined herein, where one or more hydrogen atoms of the alkyl are independently substituted with halogen substituents that may or may not be the same. For example, C 1~6 Haloalkyl is C 1~6 It is alkyl, C 1~6 One or more hydrogen atoms of an alkyl group are substituted with a halo substituent. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0024] A "heteroaryl" refers to a radical or diradical aromatic group having a monocyclic, polycyclic, or fused polycyclic structure with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The heteroatoms in a "heteroaryl" can be oxidized to, for example, -N(O)-, -S(O)-, or -S(O)2-. This term includes fused ring systems in which one or more fused rings are completely or partially unsaturated. The classification of mono- or diradical indicates whether the chain terminates with a heteroaryl group (monoradical) or whether the heteroaryl group is present within the chain (dirradical). The above definition does not exclude additional substituents on the heteroaryl group. For example, the heteroaryl group in "A-heteroaryl-B" is a diradical, and the heteroaryl group in "AB-heteroaryl" is a monoradical, but additional substituents may be present on each heteroaryl group. A heteroaryl does not include or overlap with aryl, as defined above.Non-restrictive examples of heteroaryl groups include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoyldolyl, benzodioxolyl, benzofuranil, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzooxypyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, sinnolinil, dibenzofuranil, dibenzothiophenyl, furanil, furanonil, isothiazolyl, imidazolyl, indazolyl, indolyl, inda Examples include, but are not limited to, zolyl, isoindolyl, indolinyl, isoindolyl, isoquinolyl, indolidinyl, isoxazolyl, naphthilidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyranidyl, 1-oxidepyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridadinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl.

[0025] The terms “heterocyclyl,” “heterocyclic,” or “heterocyclic formula” refer to monoradical or diradical saturated or unsaturated groups having a monocyclic or fused ring containing one or more heteroatoms selected from nitrogen, sulfur, phosphorus, and / or oxygen within the ring. Heteroatoms in a “heterocyclyl” can be oxidized, for example, -N(O)-, -S(O)-, -S(O)2-. Heterocyclyls may be monocyclic or polycyclic, and polycyclic rings may be fused, bridging, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of bonding (i.e., carbon atoms or heteroatoms (Can be bonded via a cyclic linkage). Exemplary heterocyclic groups include, but are not limited to, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, thietanyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0026] The term "cyano" refers to the -CN group.

[0027] The term "oxo" refers to the =O group.

[0028] The term "carboxy" refers to the -C(O)-OH group.

[0029] "Isomers" are different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers, and diastereomers.

[0030] "Stereoisomers" are isomers that differ only in the arrangement of atoms in space.

[0031] An "enantiomer" is a pair of stereoisomers that are mirror images of each other and cannot be superimposed. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The symbol "(±)" is used to refer to a racemic mixture as appropriate.

[0032] A "diastelemer isomer" is a stereoisomer that has at least two chiral atoms but is not a mirror image of each other.

[0033] As used herein, “treatment” or “treating” is an approach to obtain a beneficial or desired outcome. For the purposes of this disclosure, beneficial or desired outcomes include, but are not limited to, symptom relief and / or reduction of symptoms associated with a disease or condition. In one embodiment, “treatment” or “treating” includes one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from a disease or condition, and / or reducing the severity of the disease or condition); b) delaying or cessating the onset of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying the worsening or progression of a disease or condition); and c) alleviating a disease or condition, e.g., regression of clinical symptoms, improvement of a disease state, delaying disease progression, improving quality of life, and / or extending survival.

[0034] As used herein, “prevention” or “preventing” means a regimen that protects against the onset of a disease or disorder so that the clinical symptoms of the disease or disorder do not develop. Therefore, “prevention” relates to the administration of treatment to a subject before signs of the disease are detectable in the subject. The subject may be an individual at risk of developing the disease or disorder, such as an individual having one or more risk factors known to be associated with the onset or development of the disease or disorder.

[0035] As used herein, the terms “therapeutic effective dose” or “effective dose” refer to an effective amount to induce a desired biological or medical response, such as an amount sufficient to achieve such treatment of a disease when administered to a subject for the treatment of the disease. The effective dose varies depending on the particular compound, as well as the characteristics of the subject being treated, such as age and weight. The effective dose may include a range of amounts. As understood in the art, the effective dose may be one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. The effective dose may be considered in the context of administering one or more therapeutic agents, where a single agent is considered effective if, or if, a desirable or beneficial outcome may be achieved by combining it with one or more other agents. The appropriate dose of any concurrently administered compound may be selectively reduced due to the combined effects of the compounds (e.g., additive or synergistic effects).

[0036] As used herein, “concurrent administration” includes administering 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).

[0037] This specification also provides pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein. "pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other materials suitable for veterinary use or human pharmaceutical use.

[0038] The compounds described herein may be prepared and / or formulated as pharmaceutically acceptable salts. 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 acids, organic acids, or 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, caprinates, heptanoates, propioates, oxalates, malons, succinates, suberates, sebacinates, fumarates, maleates, butin-1,4-dioate, and hexyl Examples include 1,6-dioate, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, tylsulfonates, propylsulfonates, besilates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, and mandelates. A list of other pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21. st Seen in Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0039] Non-limiting examples of “pharmaceutically acceptable salts” of the compounds disclosed herein also include alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and NX4 + This includes salts derived from appropriate bases, such as (wherein X is a C1-C4 alkyl group). It also includes base addition salts, such as sodium or potassium salts.

[0040] A "stereoisomer" refers to a compound that has the same atoms bonded together by the same bonds but has different three-dimensional structures that are not interchangeable. This disclosure intends various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are mirror images of each other and cannot be superimposed.

[0041] "Tautomerism" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. This disclosure includes tautomers of any such compound.

[0042] A "solvate" is formed by the interaction of 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.

[0043] As used herein, the term "prodrug" refers to a biologically inactive derivative of a drug that, upon administration to the human body, is converted to a biologically active parent drug via several chemical or enzymatic pathways. [Table 1] compound

[0044] In some embodiments, this disclosure relates to formula (I): [ka] Compounds by [in the formula, [ka] These are single or double bonds, [ka] When R is a double bond, 5 It does not exist. [ka] These are single bonds, double bonds, or triple bonds. [ka] When R is a triple bond, 6 and R 7 It does not exist. [ka] These are single or double bonds, [ka] When R is a double bond, 9 It does not exist. Z 1 CR 1a or N, R 1a is hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl and C 1~6 Selected from haloalkoxyls, R 1 -C(O)R 15 , or R 16 And, R 15 C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, C 1~6 Alkylene-OC 3~10 Cycloalkyl, -C 1~6 Alkilen-O-3~12 member heterocycline, C 1~6 Alkylene-OC 6~10 Ariel, -C 1~6Alkylene-5 to 10-membered heteroaryls and -NR 15a R 15b Selected from, R 15 This involves selecting 1 to 5 R's arbitrarily. A Replaced by, Each R 15a and R 15b is hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkylene-C 3~10 Cycloalkyl, -C 1~6 Alkilen-3~12 member heterocyclyl, -C 1~6 Alkylene-C 6~10 Aryl, and -C 1~6 Independently selected from alkylene-5 to 10-membered heteroaryls, R 15a and R 15b Each C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkylene-C 3~10 Cycloalkyl, -C 1~6 Alkilen-3~12 member heterocyclyl, -C 1~6 Alkylene-C 6~10 Aryl, and -C 1~6 Alkylene-5 to 10-membered heteroaryls include halo, hydroxyl, oxo, -CN, and C. 1~6 Alkyl, C 2~6 Al Kenil, C 2~6 Alkinyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl and C 1~6 The haloalkoxyl is independently and optionally substituted with 1 to 4 groups independently selected, R 16 R is a 3-12 member heterocyclic or 5-12 member heteroaryl, 16 This involves selecting 1 to 5 R's arbitrarily. A Replaced by, R2 is hydrogen, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, and -C 1~4 Alkylene-OC 1~6 Selected from alkyl groups, R 3 is hydrogen, halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, and -C 1~4 Selected from alkylene-O-5~10 member heteroaryls, R 3 Each C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, and -C 1~4 Alkylene-O-5~10 member heteroaryls are halos, C 1~6 Alkyl, C 1~6 Haloalkyl and C 1~6 It is optionally substituted with 1 to 4 groups independently selected from the alkoxyl, Each R 4 and R 5 is hydrogen, halo, hydroxyl, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, -NR aa R bb , -NHC(O)-C 1~6 Alkyl, -C(O)NH-C 1~6 Alkyl, -OC 2~6 Alkinyl, -OC(O)-C 1~6 Alkyl, -O-(CH2CH2O) n -C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-12 member heterocyclyl, -OC 3~10 Cycloalkyl, -O-3~12 member heterocyclyl, -OC1~4 Alkylene-C 3~10 Cycloalkyl, 5-10 member heteroaryl, -OC 1~4 Alkylene-3 to 12-membered heterocyclyl, -O-5 to 10-membered heteroaryl, and -OC 1~4 Independently selected from alkylene-5 to 10-membered heteroaryls, R 4 and R 5 Each C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, -NHC(O)-C 1~6 Alkyl, -C(O)NH-C 1~6 Alkyl, -OC 2~6 Alkinyl, -OC(O)-C 1~6 Alkyl, -O-(CH2CH2O) n -C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-12 member heterocyclyl, -OC 3~10 Cycloalkyl, -O-3~12 member heterocyclyl, -OC 1~4 Alkylene-C 3~10 Cycloalkyl, 5-10 member heteroaryl, -OC 1~4 Alkylene-3 to 12-membered heterocyclyl, -O-5 to 10-membered heteroaryl, and -OC 1~4 Alkylene-5 to 10-membered heteroaryls are halo, hydroxyl, oxo, and C. 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, -NR aa R bb , C 3~10 Optionally substituted with 1 to 4 groups independently selected from cycloalkyl and 3-12 membered heterocyclyl groups, Each R 6 and R 7 is hydrogen, halo, hydroxyl, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl and C 1~6Selected independently from haloalkoxyls, R 8 C is hydrogen, halo, hydroxyl, oxo, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, -OC 3~10 Cycloalkyl, -O-3~12 member heterocyclyl, -OC 6~10 Aryl, -O-5~10 member heteroaryl, -OC 1~4 Alkylene-C 3~10 Cycloalkyl, -OC 1~4 Alkilen-3~12 member heterocyclyl, -OC 1~4 Alkylene-C 6~10 Aryl, and -OC 1~4 Selected from alkylene-5 to 10-membered heteroaryls R 9 Either it does not exist, or it is hydrogen, halo, hydroxyl, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, -OC 3~10 Cycloalkyl, -O-3~12 member heterocyclyl, -OC 6~10 Aryl, -O-5~10 member heteroaryl, -OC 1~4 Alkylene-C 3~10 Cycloalkyl, -OC 1~4 Alkilen -3-12 member heterocycline, -OC 1~4 Alkylene-C 6~10 Aryl, and -OC 1~4Selected from alkylene-5 to 10-membered heteroaryls R 8 and R 9 Each C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, -OC 3~10 Cycloalkyl, -O-3~12 member heterocyclyl, -OC 6~10 Aryl, -O-5~10 member heteroaryl, -OC 1~4 Alkylene-C 3~10 Cycloalkyl, -OC 1~4 Alkilen-3~12 member heterocyclyl, -OC 1~4 Alkylene-C 6~10 Aryl, and -OC 1~4 Alkylene-5 to 10-membered heteroaryls have 1 to 5 R A It is independently and optionally replaced, or R 2 and R 4 , R 4 and R 6 , R 6 and R 7 , or R 7 and R 8 These, together with the atoms to which they are bonded, form 3-7 membered heterocyclines or 5-6 membered heteroaryls, each 3-7 membered heterocycline and 5-6 membered heteroaryl containing 1-3 heteroatoms, and each 3-7 membered heterocycline and 5-6 membered heteroaryl contains halo, oxo, hydroxyl, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenil, C 2~6 Alkinyl, -NR aa R bb , and -C 1~6 Alkilen-NRaa R bb It is optionally replaced by 1 to 4 bases independently selected from, or R 4 , R 6 , and R 7 These atoms, together with the atoms to which they are bonded, form 8-12 membered condensed heterocyclines, each containing 1-4 heteroatoms, and these heterocyclines are composed of halo, oxo, hydroxyl, and C atoms. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenil, C 2~6 Alkinyl, -NR aa R bb , and -C 1~6 Alkilen-NR aa R bb It is optionally replaced by 1 to 4 bases independently selected from, or R 4 and R 8 These, together with the atoms they are bonded to, form 8-16 member heterocyclines, and each 8-16 member heterocycline contains 1-4 heteroatoms, and each 8-16 member heterocycline is composed of halo, oxo, hydroxyl, and C atoms. 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenil, C 2~6 Alkinyl, -NR aa R bb , and -C 1~6 Alkilen-NR aa R bb It is arbitrarily replaced by 1 to 3 bases independently selected from, R 10 is hydrogen, halo, hydroxyl, -CN, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl and C 1~6 Selected from haloalkoxyls, Each R 11 , R12 , R 13 , and R 14 is hydrogen, halo, hydroxyl, -CN, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Independently selected from haloalkyls, or R 11 and R 13 Together with the atoms to which they are bonded, C 3~6 It forms a cycloalkyl or a 3-6 membered heterocycline, and the 3-6 membered heterocycline contains 1-3 heteroatoms, each C 3~6 Cycloalkyl and 3-6 membered heterocyclyls are halo, hydroxyl, -CN, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl and C 1~6 The haloalkoxyl is optionally substituted with 1 to 3 groups independently selected, Each R A is halo, hydroxyl, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxyl, -C 1~4 Alkylene-OC 1~4 Alkyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, and -NR aa R bb Selected independently from, R A Each C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxyl, -C 1~4 Alkylene-OC 1~4 Alkyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10Aryl, 5-10 member heteroaryl, halo, hydroxyl, -CN, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxyl, C3 ~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, and -NR aa R bb It is independently replaced by 1 to 3 elements independently selected from, Each R aa and R bb is hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkylene-C 3~10 Cycloalkyl, -C 1~6 Alkilen-3~12 member heterocyclyl, -C 1~6 Alkylene-C 6~10 Aryl, and -C 1~6 Independently selected from alkylene-5 to 10-membered heteroaryls, R aa and R bb Each C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkylene-C 3~10 Cycloalkyl, -C 1~6 Alkilen-3~12 member heterocyclyl, -C 1~6 Alkylene-C 6~10 Aryl, and -C 1~6 Alkylene-5~10 member heteroaryls are halo, C 1~6 Alkyl, -CN, C 1~6 Alkoxyl, and C 1~6 It is independently and optionally substituted with 1 to 4 groups independently selected from the haloalkyl group. 3- to 12-membered heterocyclines are monocyclic or polycyclic rings having 1 to 4 heteroatoms independently selected from nitrogen, sulfur, phosphorus, -N(O)-, -S(O)-, and S(O)2-, where the polycyclic rings can be condensed, cross-linked, or spiro. A 5-10 membered heteroaryl is an aromatic group having a monocyclic or polycyclic ring, and contains 1 to 4 heteroatoms independently selected from nitrogen, oxygen, sulfur, -N(O)-, -S(O)-, and -S(O)2, however, [ka] When it is a single bond, [ka] At least one of them is a double bond, [ka] When it is a double bond, (a) R 1 is R 16 And, (b) Z 1 is N, (c) Z 1 CR 1a And R 1a Hello, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl and C 1~6 Selected from haloalkoxyls, (d) Each R 4 and R 5 It is not hydrogen, (e) Each R 8 and R 9 It is not hydrogen, (f) R 5 is hydrogen, R 4 C 2~6 Alkenil, C 2~6 Alkinyl and -OC 2~6 Selected from these, each of these is halo, hydroxyl, oxo, C 1~6 Alkyl, C 1~6Alkoxyl, C 1~6 Haloalkoxyl, -NR aa R bb , C 3~10 Optionally substituted with 1 to 4 groups independently selected from cycloalkyl and 3-12 membered heterocyclyl groups, (g) R 9 is hydrogen, R 8 is hydrogen, halo, C 2~6 Alkenil, C 2~6 Alkinyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Selected from aryls and 5-10 membered heteroaryls, R 8 Each C 2~6 Alkinyl, OC 2~6 Alkenyl, -OC 2~6 Alkinyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 aryls and 5-10 member heteroaryls of R have 1-5 R A It is independently and arbitrarily substituted, (h) R 2 and R 4 , R 4 and R 6 , R 6 and R 7 , or R 7 and R 8 These, together with the atoms to which they are bonded, form a 3-7 member heterocycline or a 5-6 member heteroaryl compound. Each 3-7 membered heterocyclyl and 5-6 membered heteroaryl forms a compound containing 1-3 heteroatoms, and each 3-7 membered heterocyclyl and 5-6 membered heteroaryl contains halo, oxo, hydroxyl, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenil, C 2~6 Alkinyl, -NR aa R bb , and -C1~6 Alkilen-NR aa R bb It is arbitrarily replaced by 1 to 4 bases independently selected from, (i) R 4 , R 6 , and R 7 These atoms, together with the atoms to which they are bonded, form 8-12 membered condensed heterocyclines, and these 8-12 membered condensed heterocyclines contain 1-3 heteroatoms, and these 8-12 membered condensed heterocyclines are halo, oxo, hydroxyl, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenil, C 2~6 Alkinyl, -NR aa R bb , and -C 1~6 Alkilen-NR aa R bb It is optionally replaced by 1 to 4 bases independently selected from, or (j) R 4 and R 8 These, together with the atoms they are bonded to, form 8-16 member heterocyclines, and 8-16 member condensed heterocyclines contain 1-3 heteroatoms, and 8-16 member heterocyclines are halo, oxo, hydroxyl, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, C 2~6 Alkenil, C 2~6 Alkinyl, -NR aa R bb , and -C 1~6 Alkilen-NR aa R bb The present invention provides a pharmaceutically acceptable salt thereof, which is optionally substituted with 1 to 3 groups independently selected from the present, or a pharmaceutically acceptable salt thereof.

[0045] In some embodiments of formula (I), this disclosure relates to formula (Ia): [ka] The compound or a pharmaceutically acceptable salt thereof is provided. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 This is defined as described above or elsewhere in this disclosure.

[0046] In some embodiments, this disclosure relates to (II), (III), (IV), and (V): [ka] Compounds by formulas selected from [wherein, Z 1 CR 1a or N, Z 2 CR 2a R 2b , S, NR 2c Selected from , and O, Each R 1a , R 2a , and R 2b Hydrogen, halo, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl and C 1~6 Selected independently from haloalkoxyls, R 2c is hydrogen, C 1~6 Alkyl and C 1~6 Selected from haloalkyl groups, R 1 -C(O)R 15 , or R 16 And, R 15 C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, C 1~6 Alkylene-OC 3~10Cycloalkyl, -C 1~6 Alkilen-O-3~12 member heterocycline, C 1~6 Alkylene-OC 6~10 Ariel, -C 1~6 Alkylene-5 to 10-membered heteroaryls and -NR 15a R 15b Selected from, R 15 This involves selecting 1 to 5 R's arbitrarily. A Replaced by, Each R 15a and R 15b is hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkylene-C 3~10 Cycloalkyl, -C 1~6 Alkilen-3~12 member heterocyclyl, -C 1~6 Alkylene-C 6~10 Aryl, and -C 1~6 Independently selected from alkylene-5 to 10-membered heteroaryls, R 15a and R 15b Each C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkylene-C 3~10 Cycloalkyl, -C 1~6 Alkilen-3~12 member heterocyclyl, -C 1~6 Alkylene-C 6~10 Aryl, and -C 1~6 Alkylene-5 to 10-membered heteroaryls include halo, hydroxyl, oxo, -CN, and C. 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl and C 1~6 The haloalkoxyl is independently and optionally substituted with 1 to 4 groups independently selected, R 16is a 3- to 12-member heterocyclic or 5- to 12-member heteroaryl, and R 16 is optionally substituted with 1 to 5 R A groups, and R 2 is selected from hydrogen, halo, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy group, and -C 1~4 alkylene-O-C 1~6 alkyl, R 3 is selected from hydrogen, halo, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxyl, C 3~10 cycloalkyl, 3- to 12-member heterocyclyl, and -C 1~4 alkylene-O-5- to 10-member heteroaryl, and each C 3 of R 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxyl, C 3~10 cycloalkyl, 3- to 12-member heterocyclyl, and -C 1~4 alkylene-O-5- to 10-member heteroaryl is optionally substituted with 1 to 4 groups independently selected from halo, C 1~6 alkyl, C 1~6 haloalkyl, and C 1~6 alkoxyl, each R 4 and R 5 is selected from hydrogen, halo, hydroxyl, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, C 1~6 alkoxyl, C 1~6 haloalkoxyl, -NR aa R bb group, -NHC(O)-C 1~6 alkyl, -C(O)NH-C 1~6 alkyl, -O-C 2~6 alkynyl, -OC(O)-C 1~6 alkyl, -O-(CH2CH2O) n-C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-12 member heterocyclyl, -OC 3~10 Cycloalkyl, -O-3~12 member heterocyclyl, -OC 1~4 Alkylene-C 3~10 Cycloalkyl, 5-10 member heteroaryl, -OC 1~4 Alkylene-3 to 12-membered heterocyclyl, -O-5 to 10-membered heteroaryl, and -OC 1~4 Independently selected from alkylene-5 to 10-membered heteroaryls, R 4 and R 5 Each C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, -NHC(O)-C 1~6 Alkyl, -C(O)NH-C 1~6 Alkyl, -OC 2~6 Alkinyl, -OC(O)-C 1~6 Alkyl, -O-(CH2CH2O) n -C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-12 member heterocyclyl, -OC 3~10 Cycloalkyl, -O-3~12 member heterocyclyl, -OC 1~4 Alkylene-C 3~10 Cycloalkyl, 5-10 member heteroaryl, -OC 1~4 Alkylene-3 to 12-membered heterocyclyl, -O-5 to 10-membered heteroaryl, and -OC 1~4 Alkylene-5 to 10-membered heteroaryls are halo, hydroxyl, oxo, and C. 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, -NR aa R bb , C 3~10 Optionally substituted with 1 to 4 groups independently selected from cycloalkyl and 3-12 membered heterocyclyl groups, Each R 6 and R7 is independently selected from hydrogen, halo, hydroxyl, C 1~6 alkyl, C 1~6 alkoxyl, C 1~6 haloalkyl, and C 1~6 haloalkoxyl, and R 8 is hydrogen, halo, hydroxyl, oxo, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkoxyl, -O-C 2~6 alkenyl, -O-C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 十二-membered heterocyclyl, C 6~10 aryl, 5- to 十-membered heteroaryl, -O-C 3~10 cycloalkyl, -O-3- to 十二-membered heterocyclyl, -O-C 6~10 aryl, -O-5- to 十-membered heteroaryl, -O-C 1~4 alkylene-C 3~10 cycloalkyl, -O-C 1~4 alkylene-3- to 十二-membered heterocyclyl, -O-C 1~4 alkylene-C 6~10 aryl, and -O-C 1~4 alkylene-5- to 十-membered heteroaryl, and is selected from R 9 is absent or is hydrogen, halo, hydroxyl, C 1~6 alkyl, C<00°0979>alkenyl, C 2~6 alkynyl, C 1~6 alkoxyl, -O-C 2~6 alkenyl, -O-C 2~6 alkynyl, C 3~10 cycloalkyl, 3- to 十二-membered heterocyclyl, C 6~10 aryl, 5- to 十-membered heteroaryl, -O-C 3~10 cycloalkyl, -O-3- to 十二-membered heterocyclyl, -O-C 6~10 aryl, -O-5- to 十-membered heteroaryl, -O-C 1~4 alkylene-C 3~10 cycloalkyl, -O-C 1~4 It should be noted that there may be some inaccuracies in the original text like "十二" which might be a typo. If it's supposed to be a specific number in Chinese characters, it needs to be corrected for a more accurate translation. Also, some chemical-related terms might need more context for a more precise rendering.Alkilen-3~12 member heterocyclyl, -OC 1~4 Alkylene-C 6~10 Aryl, and -OC 1~4 Selected from alkylene-5 to 10-membered heteroaryls R 8 and R 9 Each C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, -OC 3~10 Cycloalkyl, -O-3~12 member heterocyclyl, -OC 6~10 Aryl, -O-5~10 member heteroaryl, -OC 1~4 Alkylene-C 3~10 Cycloalkyl, -OC 1~4 Alkilen-3~12 member heterocyclyl, -OC 1~4 Alkylene-C 6~10 Aryl, and -OC 1~4 Alkylene-5 to 10-membered heteroaryls have 1 to 5 R A It is independently and arbitrarily substituted, R 10 is hydrogen, halo, hydroxyl, -CN, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl and C 1~6 Selected from haloalkoxyls, Each R 11 , R 12 , R 13 , and R 14 is hydrogen, halo, hydroxyl, -CN, C 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Independently selected from haloalkyls, or R 11 and R 13Together with the atoms to which they are bonded, C 3~6 Forming cycloalkyl or 3-6 membered heterocyclines, each C 3~6 Cycloalkyl and 3-6 membered heterocyclyls are halo, hydroxyl, -CN, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl and C 1~6 The haloalkoxyl is optionally substituted with 1 to 3 groups independently selected, Each R A is halo, hydroxyl, oxo, -CN, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxyl, -C 1~4 Alkylene-OC 1~4 Alkyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, and -NR aa R bb Selected independently from, R A Each C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxyl, -C 1~4 Alkylene-OC 1~4 Alkyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, halo, hydroxyl, -CN, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, and -NR aa Rbb It is independently replaced by 1 to 3 elements independently selected from, Each R aa and R bb is hydrogen, C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkylene-C 3~10 Cycloalkyl, -C 1~6 Alkilen-3~12 member heterocyclyl, -C 1~6 Alkylene-C 6~10 Aryl, and -C 1~6 Independently selected from alkylene-5 to 10-membered heteroaryls, R aa and R bb Each C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, -C 1~6 Alkylene-C 3~10 Cycloalkyl, -C 1~6 Alkilen-3~12 member heterocyclyl, -C 1~6 Alkylene-C 6~10 Aryl, and -C 1~6 Alkylene-5~10 member heteroaryls are halo, C 1~6 Alkyl, -CN, C 1~6 Alkoxyl, and C 1~6 It is independently and optionally substituted with 1 to 4 groups independently selected from the haloalkyl group. 3- to 12-membered heterocyclines are monocyclic or polycyclic rings having 1 to 4 heteroatoms independently selected from nitrogen, sulfur, phosphorus, -N(O)-, -S(O)-, and S(O)2-, where the polycyclic rings can be condensed, cross-linked, or spiro. A 5-10 membered heteroaryl is an aromatic group having a monocyclic or polycyclic ring, and the 5-10 membered heteroaryl contains 1 to 4 heteroatoms independently selected from nitrogen, oxygen, sulfur, -N(O)-, -S(O)-, and -S(O)2, or provides a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, this disclosure relates to formula (II): [ka] The compound or a pharmaceutically acceptable salt thereof is provided. 1 , Z 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , and R 16 This is defined as described above or elsewhere in this disclosure.

[0048] In some embodiments of formula (II), the present disclosure relates to formula (IIa): [ka] The compound or a pharmaceutically acceptable salt thereof is provided. 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 10 , , and R 16 This is defined as described above or elsewhere in this disclosure.

[0049] In some embodiments of formula (II), this disclosure relates to formula (IIb): [ka] The compound or a pharmaceutically acceptable salt thereof is provided. 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 10 , , and R 16This is defined as described above or elsewhere in this disclosure.

[0050] In some embodiments, this disclosure relates to formula (III): [ka] The compound or a pharmaceutically acceptable salt thereof is provided. 1 , R 1 , R 2 , R 3 ,R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 13 This is defined as described above or elsewhere in this disclosure.

[0051] In some embodiments of formula (III), this disclosure relates to formula (IIIa): [ka] The compound or a pharmaceutically acceptable salt thereof is provided. 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , and R 10 This is defined as described above or elsewhere in this disclosure.

[0052] In some embodiments of formula (III), this disclosure relates to formula (IIIb): [ka] The compound or a pharmaceutically acceptable salt thereof is provided. 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , and R 10This is defined as described above or elsewhere in this disclosure.

[0053] In some embodiments, this disclosure relates to formula (IV): [ka] The compound or a pharmaceutically acceptable salt thereof is provided. 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 13 This is defined as described above or elsewhere in this disclosure.

[0054] In some embodiments of formula (IV), this disclosure relates to formula (IVa): [ka] The compound or a pharmaceutically acceptable salt thereof is provided. 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , and R 10 This is defined as described above or elsewhere in this disclosure.

[0055] In some embodiments of formula (IV), this disclosure relates to formula (IVb): [ka] The compound or a pharmaceutically acceptable salt thereof is provided. 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , and R 10This is defined as described above or elsewhere in this disclosure.

[0056] In another embodiment, the present disclosure relates to formula (V): [ka] The compound or a pharmaceutically acceptable salt thereof is provided. 1 , Z 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 13 This is defined as described above or elsewhere in this disclosure.

[0057] In some embodiments of formula (V), this disclosure relates to formula (Va): [ka] The compound or a pharmaceutically acceptable salt thereof is provided. 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , and R 10 This is defined as described above or elsewhere in this disclosure.

[0058] In some embodiments of formula (V), this disclosure relates to formula (Vb): [ka] The compound or a pharmaceutically acceptable salt thereof is provided. 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , and R10 This is defined as described above or elsewhere in this disclosure.

[0059] In some embodiments of formulas (I), (II), (III), or (V), Z 1 In some embodiments, Z 1 In some embodiments, Z 1 CR 1a C 1a is a halo. In some embodiments, Z 1 It is CF.

[0060] In some embodiments of formula (II), (IV), or (V), Z 2 In some embodiments, Z 2 S is.

[0061] In some embodiments of formula (II) or (V), Z 1 CH is, Z 2 In some embodiments, Z 1 CH is, Z 2 is CH2. In some embodiments, Z 1 is N, Z 2 It is CH2.

[0062] In some embodiments of formula (II), (III), or (IV), R 11 and R 13 is C 3~6 Forms a cycloalkyl group. In some embodiments, R 11 and R 13 It forms a cyclopropyl group.

[0063] In some embodiments of formula (II) or (III), Z 1 CH is, R 11 and R 13 C 3~6 Forms a cycloalkyl group. In some embodiments, R 11 and R 13 It forms a cyclopropyl group.

[0064] In some embodiments of formula (II) or (IV), Z 2 It is CH2, and R 11 and R 13 C 3~6 Forms a cycloalkyl group. In some embodiments, R 11 and R 13 It forms a cyclopropyl group.

[0065] In some embodiments of equation (II), Z 1 CH is, Z 2 It is CH2, and R 11 and R 13 C 3~6 Forms a cycloalkyl group. In some embodiments, R 11 and R 13 It forms a cyclopropyl group.

[0066] In some embodiments of formulas (I), (Ia), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), R 1 -C(O)R 15 And R 15 The following are selected from -CH3, -CH2CH3, cyclopropyl, cyclobutyl, -NH-cyclopropyl, -NH-cyclobutyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyridinyl, pyrimidinyl, and pyridazinyl, each R 15 is F, Cl, -OH, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -C H2OCH3, -OCH3, -OCH2CH3, -O-CH2CH2CH3, -OCH(CH3)2, -OC(CH3)3, -NH2, -NHCH3, -N(CH3)2, [ka] 1 to 3 R selected independently from A It is optionally replaced by R. In some embodiments, 15 teeth, [ka] Selected from, each R 15 is F, Cl, -OH, -CN, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2F, -CHF2, -CF3, -CH2OCH3, -OCH3, -OCH2CH3, -O-CH2CH2CH3, -OCH(CH3)2, -OC(CH3)3, [ka] 1 to 3 R selected independently from A It is optionally replaced.

[0067] In some embodiments of formulas (I), (Ia), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), R 1 -C(O)R 15 And R 15 teeth, [ka] Selected from.

[0068] In some embodiments of formulas (I), (Ia), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), R 1 -C(O)R 15 And R 15 This is 1 to 3 R A It is a 5- to 10-membered heteroaryl that is optionally substituted with R. In some embodiments, 15 teeth [ka] Therefore, 1 to 3 R can be selected arbitrarily. A It will be replaced with.

[0069] In some embodiments of formulas (I), (Ia), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), R 1 -C(O)R 15 And R 15 teeth [ka] That is the case.

[0070] In some embodiments of formulas (I), (Ia), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), R 1 -C(O)R 15 And R 15 teeth, [ka] Selected from.

[0071] In some embodiments of formulas (I), (Ia), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), R 1 teeth, [ka] Selected from, each R 1 These are F, Cl, -OH, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -NHCH3, and -N(CH3)2, and [ka] 1 to 3 R selected independently from A It is optionally replaced.

[0072] In some embodiments of formulas (I), (Ia), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), R 1 teeth, [ka] Selected from. In some embodiments, R 1 teeth [ka] That is the case.

[0073] In some embodiments of formulas (I), (Ia), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), R 1 teeth, [ka] Selected from, each R 1 These are F, Cl, -OH, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -NHCH3, and -N(CH3)2, and [ka] 1 to 3 R selected independently from A It is optionally replaced.

[0074] In some embodiments of formula (II), (IIa), or (IIb), R 16 teeth, [ka] Selected from.

[0075] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), R 2 is hydrogen or C 1~3 It is alkyl. In some embodiments, R 2 It is hydrogen.

[0076] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), R 3 is hydrogen or C 1~3 It is alkyl. In some embodiments, R 3 It is -CH3.

[0077] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), R 4 is hydrogen, hydroxyl, halo, C 1~6 Alkoxyl, -NHC(O)-C 1~6 Alkyl, -OC 2~6 Alkinyl, -OC(O)-C 1~6 Alkyl, -O-(CH2CH2O) n -C 1~6 Alkyl, -OC 1~4 Alkylene-C 3~10 Cycloalkyl, -OC 1~4 Alkylene-3 to 12-membered heterocyclyl, -O-5 to 10-membered heteroaryl, and -OC 1~4 Selected from alkylene-5 to 10-membered heteroaryls. In some embodiments, R 4 is hydrogen, hydroxyl, F, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, [ka] Selected from.

[0078] In some embodiments of formulas (I), (II), (III), (IV), or (V), R 5 R is selected from hydrogen, hydroxyl, and -OCH3. In some embodiments, R 5 It is hydrogen.

[0079] In some embodiments of formulas (I), (II), (III), (IV), or (V), each R 4 and R 5 is hydrogen, halo, hydroxyl, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, -NR aa R bb ,-NHC(O)-C 1~6 Alkyl, -C(O)NH-C 1~6 Alkyl, -OC 2~6 Alkinyl, -OC(O)-C 1~6 Alkyl, -O-(CH2CH2O) n -C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-12 member heterocyclyl, -OC 3~10 Cycloalkyl, -O-3~12 member heterocyclyl, -OC 1~4 Alkylene-C 3~10 Cycloalkyl, 5-10 member heteroaryl, -OC 1~4 Alkylene-3 to 12-membered heterocyclyl, -O-5 to 10-membered heteroaryl, and -OC 1~4 Independently selected from alkylene-5 to 10-membered heteroaryls, R 4 and R 5 Each C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Haloalkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, -NHC(O)-C 1~6 Alkyl, -C(O)NH-C 1~6 Alkyl, -OC 2~6 Alkinyl, -OC(O)-C 1~6 Alkyl, -O-(CH2CH2O) n -C 1~6 Alkyl, C 3~10 Cycloalkyl, 3-12 member heterocyclyl, -OC 3~10Cycloalkyl, -O-3~12 member heterocyclyl, -OC 1~4 Alkylene-C 3~10 Cycloalkyl, 5-10 member heteroaryl, -OC 1~4 Alkylene-3 to 12-membered heterocyclyl, -O-5 to 10-membered heteroaryl, and -OC 1~4 Alkylene-5 to 10-membered heteroaryls are halo, hydroxyl, oxo, and C. 1~6 Alkyl, C 1~6 Alkoxyl, C 1~6 Haloalkoxyl, -NR aa R bb , C 3~10 It is optionally substituted with 1 to 3 groups independently selected from cycloalkyl and 3- to 12-membered heterocyclines.

[0080] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), R 4 is hydroxyl, C 1~6 Alkoxyl, -NHC(O)-C 1~6 Alkyl, -OC 2~6 Alkinyl, -OC(O)-C 1~6 Alkyl, -O-(CH2CH2O) n -C 1~6 Alkyl, -OC 1~4 Alkylene-C 3~10 Cycloalkyl, -OC 1~4 Alkilen-3~12 member heterocyclyl, -O-5 ~10-membered heteroaryl and -OC 1~4 Selected from alkylene-5 to 10-membered heteroaryls, R 5 The group is selected from hydroxyl and -OCH3.

[0081] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), R 2 and R 4Together with the atoms to which they are bonded, C 5~10 Forming a cycloalkyl or 5-7 membered heterocycline, C 5~10 Cycloalkyl or 5-7 membered heterocyclyls are classified as halo, hydroxyl, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, -NR aa R bb , and -C 1~6 Alkilen-NR aa R bb It is optionally replaced.

[0082] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), R 6 It is hydrogen.

[0083] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), R 4 and R 6 Together with the atoms to which they are bonded, C 5~10 They form cycloalkyl, 3-7 membered heterocyclil, or 5-6 membered heteroaryl compounds, and the 3-7 membered heterocyclil compounds are halo, oxo, hydroxyl, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, -NR aa R bb , and -C 1~6 Alkilen-NR aa R bb It is optionally substituted with 1 to 3 groups independently selected from R. In some embodiments, R 4 and R 6These, together with the atoms to which they are bonded, form tetrahydrofuranyl, which is optionally substituted with one group selected from hydroxyl, oxo, -CH3, -CH2CH2N(CH3)2, and -CH2CH=CH2.

[0084] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), R 7 It is hydrogen.

[0085] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), R 6 and R 7 Together with the atoms to which they are bonded, C 5~10 They form cycloalkyl, 3-7 membered heterocyclil, or 5-6 membered heteroaryl compounds, and the 3-7 membered heterocyclil compounds are halo, oxo, hydroxyl, and C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, -NR aa R bb , and -C 1~6 Alkilen-NR aa R bb It is arbitrarily replaced by 1 to 3 elements selected independently of it.

[0086] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), R 7 and R 8 Together with the atoms to which they are bonded, C 5~10 They form cycloalkyl, 3-7 membered heterocyclil, or 5-6 membered heteroaryl compounds, and the 3-7 membered heterocyclil compounds are halo, oxo, hydroxyl, and C 1~6Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, -NR aa R bb , and -C 1~6 Alkilen-NR aa R bb It is optionally substituted with 1 to 3 groups independently selected from R. In some embodiments, R 7 and R 8 These atoms, together with the atoms to which they are bonded, form tetrahydrofuran or tetrahydropyranyl, which are selected from hydroxyl, oxo, and -CH3. It is optionally substituted by one of the bases being replaced.

[0087] In some embodiments of formulas (I), (II), (III), (IV), or (V), each R 8 and R 9 is halo, hydroxyl, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxyl, -OC 2~6 Alkenyl, -OC 2~6 Alkinyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, -OC 3~10 Cycloalkyl, -O-3~12 member heterocyclyl, -OC 6~10 Aryl, -O-5~10 member heteroaryl, -OC 1~4 Alkylene-C 3~10 Cycloalkyl, -OC 1~4 Alkilen-3~12 member heterocyclyl, -OC 1~4 Alkylene-C 6~10 Aryl, and -OC 1~4 Independently selected from alkylene-5~10 member heteroaryls, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkoxyl, -OC2~6 Alkenyl, -OC 2~6 Alkinyl, C 3~10 Cycloalkyl, 3-12 membered heterocyclyl, C 6~10 Aryl, 5-10 member heteroaryl, -OC 3~10 Cycloalkyl, -O-3~12 member heterocyclyl, -OC 6~10 Aryl, -O-5~10 member heteroaryl, -OC 1~4 Alkylene-C 3~10 Cycloalkyl, -OC 1~4 Alkilen-3~12 member heterocyclyl, -OC 1~4 Alkylene-C 6~10 Aryl, and -OC 1~4 Each alkylene-5 to 10-membered heteroaryl has 1 to 5 R A It is independently and arbitrarily substituted.

[0088] In some embodiments of formulas (I), (II), (III), (IV), or (V), each R 8 and R 9 OH, F, -CH3, [ka] It is selected independently of others.

[0089] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), R 8 teeth, [ka] That is the case.

[0090] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), R 4 and R 8These, together with the atoms they are bonded to, form a 10-membered heterocycline, and a 10-membered heterocycline is a halo, oxo, hydroxyl, C 1~6 Alkyl and C 1~6 It is optionally substituted with 1 to 3 groups independently selected from the haloalkyl group.

[0091] In some embodiments of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), R 10 R is selected from F, Cl, -CH3, and -CH2CH3. In some embodiments, R 10 It is Cl.

[0092] In some embodiments of equation (I), [ka] It is a single bond. In some embodiments, [ka] It is a double bond. In some embodiments, [ka] It is a double bond, R 9 It does not exist. In some embodiments, [ka] It is a triple bond, R 6 and R 7 It does not exist.

[0093] In some embodiments, the present disclosure provides compounds selected from Examples 1 to 211.

[0094] In some embodiments, isotopically labeled forms of compounds of formula (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb) are provided herein. In some embodiments, isotopically labeled forms of compounds of formula (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (V), (Va), (IVb), or (Vb) are provided herein. The isotopically labeled compounds have the structure shown by the formulas given herein, except that one or more atoms are replaced by isotopes having selected atomic masses or mass numbers. The isotopically labeled compounds have the structure shown by the formulas given herein, except that one or more atoms are replaced by isotopes having selected atomic masses or mass numbers. Examples of isotopes that can be incorporated into the compounds disclosed herein include: 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 Isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as I, are included, but are not limited to these. Various isotope-labeled compounds of this disclosure include, for example, 3 H, 13 C, and 14 Radioactive isotopes such as 1C are incorporated, and this is within the scope of this disclosure. These isotope-labeled compounds are used in metabolic studies, reaction kinetic studies, positron emission tomography (PET), and single-photon emission computed tomography (S) including drug or substrate tissue distribution assays. Such isotope-labeled analogs of the compounds disclosed herein may be useful in detection or imaging techniques such as PECT, or in the treatment of patients. These isotope-labeled analogs may also be useful in the treatment of the diseases disclosed herein, as they may offer improved pharmacokinetic and / or pharmacodynamic properties compared to the unlabeled forms of the same compounds. Such isotope-labeled forms of the compounds disclosed herein are within the scope of this disclosure. Those skilled in the art can prepare and use such isotope-labeled forms by following the procedures of the isotope-labeled compounds or embodiments of the compounds to obtain isotopes or radiolabeled analogs of the compounds disclosed herein.

[0095] The compounds disclosed herein may contain one or more chiral centers and thus may 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)- for amino acids. This disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or may be 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 separation of racemic compounds (or racemic compounds of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC). Similarly, all tautomeric forms are also intended to be included.

[0096] In certain embodiments, the Disclosure provides a pharmaceutical composition comprising a compound of the Disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises one or more additional therapeutic agents, as fully described below.

[0097] Pharmaceutical compositions comprising the compounds disclosed herein or pharmaceutically acceptable salts thereof may be prepared with one or more pharmaceutically acceptable excipients, which may be selected according to common practice. "pharmaceutically acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, lubricants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers approved by the U.S. Food and Drug Administration as permissible for use in humans or livestock.

[0098] In certain embodiments, the pharmaceutical composition is provided in solid dosage forms, including solid oral dosage forms such as tablets. Tablets may contain excipients, including lubricants, fillers, and binders. Aqueous compositions may be prepared in a sterile form and may generally be isotonic if intended for delivery by means other than oral administration. All compositions are based on Rowe et al, Handbook of Pharmaceutical Excipients, 6. th Excipients may be included, such as those described in edition, American Pharmacists Association, 2009. Examples of excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, and carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, and stearic acid.

[0099] The pharmaceutical compositions disclosed herein include those suitable for various routes of administration, including oral administration. The compositions may be presented in unit dosage forms and may be prepared by any method known in the field of pharmacy. Such methods include associating an active ingredient (e.g., a compound of this disclosure or a pharmaceutically acceptable salt thereof) with one or more pharmaceutically acceptable excipients. The compositions may also be prepared by homogeneously and closely associating the active ingredient with a liquid excipient or a finely divided solid excipient or both, and then, if necessary, forming a product. (Technical and) Formulations are generally described in Remington: The Science and Practice of Pharmacy, 21 stSeen in Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0100] The compositions described herein, suitable for oral administration, may be presented as separate units (unit dosage forms), including but not limited to capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient. In one embodiment, the pharmaceutical composition is a tablet.

[0101] The pharmaceutical compositions disclosed herein comprise one or more of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, together with pharmaceutically acceptable excipients and optionally other therapeutic agents. The pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. For example, when used orally, tablets, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more excipients, including sweeteners, flavorings, colorings, and preservatives, 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, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch, or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. The 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 materials such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with wax.

[0102] The amount of active ingredient that can be combined with an inactive ingredient to produce a dosage form may vary depending on the intended therapeutic target and the specific mode of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain about 1 to 1000 mg of the active ingredient, formulated with an appropriate and convenient amount of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutically acceptable excipients may vary from about 5 to about 95% (by weight) of the total composition. method

[0103] In some embodiments, the Disclosure provides methods for inhibiting MCL1. In some embodiments, the Disclosure provides methods for inhibiting MCL1, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual (e.g., a human).

[0104] In some embodiments, the Disclosure provides a method for treating or preventing cancer. In certain embodiments, the Disclosure provides a method for treating or preventing cancer comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual. In some embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is selected from the group consisting of breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, and leukemia.

[0105] The compounds disclosed herein may be administered by any route suitable for use in the methods described herein. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), and transdermal. Examples include the skin, vagina, and parenteral (subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural) routes.

[0106] The compounds disclosed herein may be administered to an individual according to an effective administration plan for a desired period or duration, such as at least one week, 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 one modification, the compounds may be administered daily or on an intermittent schedule over the lifespan of the individual.

[0107] 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.

[0108] The therapeutically effective dose of the compounds disclosed herein is 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 μg to approximately 30 mg per day, or for example, approximately 0.3 μg to approximately 30 mg per day.

[0109] Compounds of formulas (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), or pharmaceutically acceptable salts thereof, may be combined with one or more additional therapeutic agents in any dose of the compounds of this disclosure (e.g., 1 mg to 1000 mg of the compounds). The therapeutically effective dose of a compound of formula (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), or a pharmaceutically acceptable salt thereof, may range from approximately 0.01 mg to approximately 1000 mg per dose, for example, from approximately 0.01 mg to approximately 100 mg per dose, or for example, from approximately 0.1 mg to approximately 100 mg per dose, or for example, from approximately 1 mg to approximately 100 mg per dose, or for example, from approximately 1 mg to approximately 100 mg per dose. Other effective therapeutic doses of compounds of formula (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb) are approximately 1 mg per dose, or approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or approximately 100 mg per dose. Other effective therapeutic doses of compounds of formula (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IIIb), (V), (Va), or (Vb) are approximately 100 mg per dose, or approximately 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or approximately 500 mg per dose.

[0110] The therapeutically effective dose of a compound of formula (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb), or a pharmaceutically acceptable salt thereof, may range from approximately 0.01 mg to approximately 1000 mg per dose, for example, from approximately 0.01 mg to approximately 100 mg per dose, or for example, from approximately 0.1 mg to approximately 100 mg per dose, or for example, from approximately 1 mg to approximately 100 mg per dose, or for example, from approximately 1 mg to approximately 100 mg per dose. Other therapeutically effective doses of compounds of formula (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), or (Vb) are 1 dose. The effective doses are approximately 1 mg per dose, or approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or approximately 100 mg per dose. Other effective therapeutic doses of compounds of formula (I), (Ia), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IIIb), (V), (Va), or (Vb) are approximately 100 mg per dose, or approximately 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or approximately 500 mg per dose.

[0111] A single dose can be administered hourly, daily, or weekly. For example, a single dose can be administered once every 1, 2, 3, 4, 6, 8, 12, or 16 hours, or once every 24 hours. A single dose can also be administered once every 1, 2, 3, 4, 5, or 6 days, or once every 7 days. A single dose can also be administered once every 1, 2, or 3 weeks, or once every 4 weeks. In certain embodiments, a single dose may be administered once a week. A single dose may also be administered once a month. In some embodiments, the compounds disclosed herein are administered once daily in the manner disclosed herein. In some embodiments, the compounds disclosed herein are administered twice daily in the manner disclosed herein.

[0112] The frequency of administration of the compounds disclosed herein is determined by the individual patient's needs and may be, for example, once per day, twice per day, or more times. Administration of the compounds is continued for as long as necessary to treat the cancer. For example, the compounds disclosed herein may be administered to a person with cancer over a period of 20 to 180 days, or, for example, 20 to 90 days, or, for example, 30 to 60 days.

[0113] Administration may be intermittent, with the patient receiving a daily dose of the compound disclosed herein for several days or more, followed by a period of several days or more without administration of the compound. For example, the patient may receive the compound every other day or three times a week. In a more non-limiting example, the patient may receive the compound daily for a period of 1 to 14 days, followed by a period of 7 to 21 days without administration of compound I, followed by a period of the following days (e.g., 1 to 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 many times as clinically necessary to treat the patient. Combination therapy

[0114] In various embodiments, the compounds described herein may be one or more additional therapeutic agents, such as 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 (including, but not limited to, single and multispecific antibodies and their fragments in any format (e.g., DART®, Duobodies®, BiTEs®, BiKEs, TriKEs, XmAbs®, TandAbs®, scFvs, Fabs, Fab derivatives)), bispecific antibodies, non-immunoglobulin antibody mimetic (e.g., adnectin, afibody molecules, affin, affimer, afitin, alphabody, antikalin, peptide aptamers, armadillo repeat proteins) This includes, but is not limited to, proteins (ARM), atrimers, avimers, designed ankyrin repeat proteins (DARPins®), finomers, Notchin, Knitz domain peptides, monobodies, and nanoCLAMPs), antibody-drug conjugates (ADCs), antibody-peptide conjugates), oncolytic viruses, gene modifiers or editors, and chimeric antigen receptors. Cells containing antigen receptors (CARs) (e.g., T cell immunotherapy agents, NK cell immunotherapy agents) It is used in combination with a therapeutic agent, or a macrophage immunotherapy agent (including cells containing engineered T cell receptors (TCR-T)), or any combination thereof. Exemplary target

[0115] In some embodiments, one or more additional therapeutic agents include, but are not limited to, inhibitors, agonists, antagonists, ligands, modulators, stimulants, blockers, target activators or inhibitors (e.g., polypeptides or polynucleotides), and these therapeutic agents include, but are not limited to, Abelson mouse leukemia virus oncogene homolog 1 genes (ABL, such as ABL1), acetyl-CoA carboxylase (such as ACC1 / 2), activated CDC kinase (ACK, such as ACK1), adenosine deamylase, adenosine receptor (A2BR, A2a) (e.g., R, A3aR), adenylyl cyclase, ADP-ribosyl cyclase-1, adrenocortical hormone receptor (ACTH), aerolidine, AKT1 gene, Alk-5 protein kinase, alkaline phosphatase, alpha-1 adrenergic receptor, alpha-2 adrenergic receptor, alpha-ketoglutarate dehydrogenase (KGDH), aminopeptidase N, AMP-activated protein kinase, anaplastic lymphoma kinase (ALK1, etc.), androgen receptor, angiopoietin (ligand-1, ligand-2, etc.), angiotenoid Synogen (AGT) gene, mouse thymoma virus oncogene homolog 1 (AKT) protein kinase (AKT1, AKT2, AKT3, etc.), apolipoprotein AI (APOA1) gene, apoptosis inducer, apoptotic proteins (1, 2, etc.), apoptosis signal regulating kinase (ASK1, etc.), arginase (I), arginine deiminase, aromatase, asteroid homolog 1 (ASTE1) gene, telangiectasia and Rad3-related (ATR) serine / threonine protein kinase, Aurol Laprotein kinases (1, 2, etc.), Axl tyrosine kinase receptor, 4-1 BB ligand (CD137L), baculovirus IAP repeat-containing 5 (BIRC5) gene, basigin, B-cell lymphoma 2 (BCL2) gene, Bcl2 binding component 3, Bcl2 protein, BCL2L11 gene, BCR (breakpoint cluster region) protein and gene, β-adrenergic receptor, β-catenin, B lymphocyte antigen CD19, B lymphocyte antigen CD20, B lymphocyte cell adhesion molecule, B lymphocyte-stimulating factor ligand, osteomorphonectomy protein-10 ligand,Bone morphogenetic protein-9 ligand modifier, brachyuriprotein, bradykinin receptor, B-Raf proto-oncogene (BRAF), Brc-Abl tyrosine kinase, bromodomain and extradomain (BET) bromodomain-containing proteins (BRD2, BRD3, BRD4), Bruton's tyrosine kinase (BTK), calmodulin, calmodulin-dependent protein kinases (CaMK such as CAMKII), cancer testis antigen 2, cancer testis antigen NY-ESO-1, cancer / testis antigen 1B (CTAG1) gene, cancer Navinoid receptors (CB1, CB2, etc.), carbonic anhydrase, casein kinases (CKI, CKII, etc.), caspases (caspase-3, caspase-7, caspase-9, etc.), caspase-8 apoptosis-related cysteine ​​peptidase CASP8-FADD-like regulator, caspase recruitment domain protein-15, cathepsin G, CCR5 gene, CDK-activated kinase (CAK), checkpoint kinases (CHK1, CHK2, etc.), chemokine (CC motif) receptors (CCR2, CCR4, CCR5) CD4, CD40 ligand receptors, CD40 ligands, CD40LG Differentiation antigens (CDs) such as the genes CD44, CD45, CD47, CD49b, CD51, CD52, CD55, CD58, CD66e (CEACAM6), CD70, CD74, CD79, CD79b, CD79B, CD80, CD95, CD99, CD117, CD122, CDw123, CD134, CDw137, CD158a, CD158b1, CD158b2, CD223, CD276 antigens; clusterin (CLU) gene, clusterin, c-Met (hepatocyte growth, Factor receptor (hepatocyte growth factor receptor, HGFR), complement C3, connective tissue growth factor, COP9 signalosome subunit 5, CSF-1 (colony-stimulating factor 1 receptor), CSF2 gene, CTLA-4 (cytotoxic T lymphocyte protein 4) receptor, C-type lectin domain protein 9A (CL EC9A), cyclin D1, cyclin G1, cyclin-dependent kinase (CDK, e.g., COX1, COX2), CYP2B1 gene, cysteine ​​palmitoyltransferase porcupine, cytochrome P450 11B2, cytochrome P450 17, cytochrome P450 17A1, cytochrome P450 2D6, cytochrome P450 3A4, cytochrome P450 reductase, cytokine signaling 1, cytokine signaling 3, cytoplasmic isocitrate dehydrogenase, cytosine deaminase, cytosine DNA methyltransferase, cytotoxic T lymphocyte protein 4, DDR2 gene, DEAD-box helicase (DEAD-box helicase 6, DD X6), Death receptor 5 (DR5, TRAILR2), Death receptor 4 (DR4, TRAILR1), Delta-like protein ligands (3, 4, etc.), Deoxyribonuclease, Deubiquitinating enzyme (DUB), Dickkopf-1 ligand, Dihydrofolate reductase (DHFR), Dihydropyrimidine dehydrogenase, Dipeptidyl peptidase IV, Discoidin domain receptor (DDR, e.g., DDR1), Diacylglycerol kinase Zeta (DGKZ), DNA-binding proteins (HU-β, etc.), DNA-dependent protein kinases, DNA gyrases, DNA methyltransferases, DNA polymerases (α, etc.), DNA primers, dUTP pyrophosphatase, L-dopachrome tautomerase, E3 ubiquitin protein ligases (RNF128, CBL-B, etc.), echinoderm microtubule-like protein 4, EGFR tyrosine kinase receptor, elastase, elongation factor 1α2, elongation factor 2, endoglin, endonuclease, endoplasmic reticulum aminopeptidase (ERAP, e.g., ERAP1, ERAP2, etc.), endoplasmin, endosialin, endostatin, endothelin (ET-A, ET-B, etc.), enhancer of zeste homolog 2 (EZH2), ephrin (EPH) tyrosine kinase (Epha3, Ep (e.g., hb4), ephrin B2 ligand, epidermal growth factor, epidermal growth factor receptor (epidermal growth factor receptors, EGFR, epidermal growth factor receptor (EGFR) gene Epigen, epithelial cell adhesion molecule (EpCAM), Erb-b2 (v-erb-b2 avian erythroblastic leukemia virus cancer homolog 2), tyrosine kinase receptor, Erb-b3 tyrosine kinase receptor, Erb-b4 tyrosine kinase receptor, E-selectin, estradiol 17β dehydrogenase, estrogen receptors (α, β, etc.), estrogen-related receptors, eukaryotic translation initiation factor 5A (EIF5A) gene, exportin 1, extracellular signal-related kinases (1, 2, etc.), extracellular signal-regulated kinase (ERK), hypoxia-inducible factor prolyl hydroxylase (HIF-PH or EGLN), factors (Xa, VIIa, etc.), farnesoid x receptor (FXR), Fas ligand, fatty acid synthase (Fatty acid Synthase (FASN), ferritin, FGF-2 ligand, FGF-5 ligand, fibroblast growth factor (FGF, e.g., FGF1, FGF2, FGF4), fibronectin, focal adhesion kinase (FAK, e.g., FAK2), folate hydrolase prostate-specific membrane antigen 1 (FOLH1), folate receptor (α, etc.), folate, folate transporter 1, FYN tyrosine kinase, base-paired amino acid cleavage enzyme (FURIN), β-glucuronidase, galactosyltransferase, galectin-3, ganglioside GD2, glucocorticoid, glucocorticoid-inducible TNFR-related protein GITR receptor, glutamine Acid carboxypeptidase II, glutaminase, glutathione S-transferase P, glycogen synthase kinase (GSK, e.g., 3-β), glypican 3 (GPC3), gonadotropin-releasing hormone (GNRH), granulocyte macrophage colony-stimulating factor (GM-CSF) receptor, granulocyte-colony-stimulating factor (GCSF) ligand, growth factors Growth factor receptor-bound protein 2 (GRB2), Grp78 (78kDa glucose regulatory protein), calcium-binding protein, molecular chaperone groEL2 gene, heme oxygenase 1 (HO1), heme oxygenase 2 (HO2), heat shock proteins (27, 70, 90α, β, etc.), heat shock protein gene, heat-stable enterotoxin receptor, hedgehog protein, heparanase, hepatocyte growth factor, HERV-HLTR associated protein 2, hexose kinase, histamine H2 receptor, histone methyltransferase (DOT1L), histone deacetylase (HDAC, e.g., 1, 2, 3, 6, 10, 11, etc.), histone H1, histone H3, HLA class I antigen (A-2α), HLA class II antigen, HLA class I antigen αG (HLA class I antigen alpha HLA-G, non-classical HLA, homeobox protein NANOG, HSPB1 gene, human leukocyte antigen HLA, human papillomavirus (E6, E7, etc.) proteins, hyaluronic acid, hyaluronidase, hypoxia-inducible factor-1 alpha (HIF) 1α), imprinted maternal expression transcript (H19) gene, mitogen-activated protein kinase kinase 1, M AP4K1), tyrosine protein kinase HCK, I-κ-B kinase (IKK, e.g., IKKbe), IL-1α, IL-1β, IL-12, IL-12 gene, IL-15, IL-17, IL-2 gene, IL-2 receptor α subunit, IL-2, IL-3 receptor, IL-4, IL-6, IL-7, IL-8, immunoglobulins (G, G1, G2, K, M, etc.), immunoglobulin Fc receptor, immunoglobulin γFc receptor (I, III, IIIA, etc.), indoleamine 2,3-dioxygenase (IDO, e.g., IDO1, IDO2, etc.), indoleamine pyrrole 2,3-dioxygenase 1 inhibitor, Integrins receptor, insulin-like growth factor (e.g., 1, 2), integrin α-4 / β-1, integrin α-4 / β-7, integrin α-5 / β-1, integrin α-V / β-3, integrin α-V / β-5, integrin α-V / β-6, intercellular adhesion molecule 1 (ICAM-1), interferons (α, α2, β, γ, etc.), interferon-inducing protein (AIM2) not present in melanoma 2, type I interferon receptor, interleukin-1 ligand, interleukin-13 receptor α2, interleukin-2 ligand, interleukin-1 receptor-associated kinase 4 (IRAK4), interleuk N-2, Interleukin-29 ligand, Interleukin 35, IL-35), isocitrate dehydrogenase (IDH1, IDH2, etc.), Janus kinase (JAK, e.g., JAK1, JAK2, etc.), Jun N-terminal kinase, kallikrein-related peptidase 3 (KLK3) gene, killer cell Ig-like receptor, kinase insert domain receptor (KDR), kinesin-like protein KIF11, Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, kisspeptin (KiSS-1) receptor, KIT gene, vk It Hardy-Zuckerman 4 feline sarcoma virus oncogene homolog (KIT) tyrosine kinase, lactoferrin, lanosterol-14 demethylase, LDL receptor-related enzymes. Protein-1, leukocyte immunoglobulin-like receptor subfamily B member 1 (ILT2), leukocyte immunoglobulin-like receptor subfamily B member 2 (ILT4), leukotriene A4 hydrolase, listeriolisin, L-selectin, luteinizing hormone receptor, lyase, lymphocyte activation gene 3 protein (L-selectin), L AG-3), lymphocyte antigen 75, lymphocyte functional antigen 3 receptor, lymphocyte-specific protein tyrosine kinase (LCK), lymphotactin, Lyn(Lck / Yes novel) tyrosine kinase, lysine demethylase (KDM1, KDM2, KDM4, KDM5, KDM6, A / B / C / D, etc.), lysophosphatidic acid-1 receptor, lysosomal-associated membrane protein family (LAMP) genes, lysine Luoxidase homolog 2, lysyl oxidase protein (LOX) Protein, lipoxygenase (5-LOX), hematopoietic precursor kinase 1 Progenitor Kinase 1 (HPK1), hepatocyte growth factor receptor (MET) gene, macro macrophage colony-stimulating factor (MCSF) ligand, macrophage migration inhibitor, MAGEC1 gene, MAGEC2 gene, major vault protein, MAPK-activated protein kinase (MK2, etc.), Mas-related G protein-coupled receptor, matrix metalloprotease (MMP, e.g., MMP2, MMP9, etc.), MCL1 differentiation protein, Mdm2 p53 binding protein, Mdm4 protein, Melan-A (MART-1) melanoma antigen, melanocyte protein Pmel17, melanocyte-stimulating hormone ligand, melanoma antigen family A3 (MAGEA3) gene, melanoma-related antigens (1, 2, 3, 6, etc.), copper membrane amine oxidase, mesoserine, MET tyrosine kinase, metabotropic glutamate receptor 1, metalloreductase STEAP1 (prostate 6-transmembrane epithelial antigen 1), metastine, methionine aminopeptidase-2, methyltransferase, mitochondrial 3-ketoacyl-CoA thiolase, mitogen-activate protein kinase (MAPK), mitogen activity Mitogen-activated protein kinases (MEK, e.g., MEK1, MEK2), mTOR (mechanistic target of rapamycin (serine / threonine kinase)), mTOR complexes (1, 2, etc.), mucins (1, 5A, 16, etc.), mutT homologs (MTH, e.g., MTH1, etc.), Myc proto-oncogene protein, myeloid cell leukemia 1 (MCL1) gene, myristoylated alanine-rich protein kinase C substrate (MARCKS) protein, NAD ADP ribosyltransferase, natriuretic peptide receptor C, neuronal adhesion molecule 1, neurokinin 1 (NK1) receptor Neurokinin receptor, neuropilin 2, NFκB activating protein, NIMA-related kinase 9 (NEK9), nitric oxide synthase, NK cells Receptors, NK3 receptor, NKG2AB activated NK receptor, NLRP3 (NACHT LRR PYD domain protein 3) modulator, norepinephrine transporter, Notch (Notch-2 receptor, Notch-3 receptor, Notch-4 receptor, etc.), nucleoretic cell 2-related factor 2, nuclear factor (NF) κB, nucleolin, nucleo Fosmin, nucleofosmin anaplastolymphoma kinase (NPM-ALK), 2-oxoglutarate dehydrogenase, 2,5-oligoadenylate synthetase, O-methylguanine DNA methyltransferase, opioid receptors (δ, etc.), ornithine decarboxylase, orotate phosphoribosyltransferase, orphan nuclear hormone receptor NR4A1, osteocalcin, osteocrust differentiation factor, osteopontin, OX-40 (tumor necrosis factor receptor superfamily member 4 TNFRSF4, or CD134) receptor, P3 protein, p38 kinase, p38MAP kinase, p53 tumor suppressor protein, parathyroid hormone ligand, peroxisome proliferator-activated receptor (PPAR, e.g., α, β, γ, etc.), P-glycoprotein (1, etc.), phos Phosphatase and tensin (PTEN) homologs, phosphatidylinositol 3-kinase (PI3K), phosphoinositide-3 kinase (PI3K, e.g., α, β, γ), phosphorylase kinase (P3K) K), PKN3 gene, placental growth factor, platelet-derived growth factor (PDGF, e.g., α, β, etc.), platelet-derived growth factor (PDGF, α, β, etc.), pleomorphic drug resistance transporter, plexin B1, PLK1 gene, polo-like kinase (PLK), polo-like kinase 1, Poly(ADP-ribose) polymerase (PARP, e.g., PARP1, 2, and 3), genes for antigens preferentially expressed in melanoma (PRAME), prenyl-binding protein (PrPB), and transcription factor P ML, progesterone receptor, programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1) inhibitor, prosaposin (PSAP) gene, prostanoid receptor (EP4), prostaglandin E2 synthase, prostate-specific antigen, prostatin acid phosphatase, proteasome, protein E7, protein farnesyltransferase, protein kinase (PK, e.g., A, B, C, etc.), protein tyrosine kinase, protein tyrosine phosphatase β, proto-oncogene serine / threonine-protein kinase (PIM-1, PIM-2, PIM-3, etc.), P-selectin, purine nucleoside phosphorylase, purinergic receptor P2X ligand-gated ion channel 7 (P2X7), pyruvate dehydrogenase (Pyruvate dehydrogenase (PDH), pyruvate dehydrogenase kinase, pyrvi Pyruvate kinase (PYK), 5α-reductase, Raf protein kinase (1, B, etc.), RAF1 gene, Ras gene, Ras GTPase, RET gene, Ret tyrosine kinase receptor, retinoblastoma-related protein, retinoic acid receptor (γ, etc.), retinoid X receptor, Rheb (a brain-abundant Ras homolog) GTPase, Rho (Ras homolog)-related protein kinase 2, ribonuclease, ribonucleotide reductase (M2 subunit, etc.), ribosomal protein S6 kinase, RNA polymerase (I, II, etc.), Ron (Recepteur d'Origine Nantais tyrosine kinase, ROS1 (ROS oncogene 1, receptor tyrosine kinase) gene, Ros1 tyrosine kinase, Runt-related transcription factor 3, γ-secretase, S100 calcium-binding protein A9, sarcoplasmic reticulum calcium ATPase, Second mitochondria-derived caspase activator (S MAC proteins, secreted frizzled-associated protein-2, secreted phospholipase A2, semaphorin-4D, serine proteases, serine / threonine kinase (STK), serine / threonine-protein kinase (TBK, e.g., TBK1), signal transduction and transcription (STAT, e.g., STAT-1, STAT-3, STAT-5), Signaling lymphocytic activation molecule (SLAM) family member 7, six-transmembrane epithelial antigen of the prostate (STEAP) gene, SL cytokine ligand, blunting (SMO) receptor, sodium iodide cotransporter, sodium phosphate cotransporter 2B, somatostatin receptors (1, 2, 3, 4, 5, etc.), Sonic Hedgehog protein, Son of Sevenless (SOS), Specific protein 1 1, Sp1) transcription factor, sphingomyelin synthase, sphingosine kinase (1, 2, etc.), sphingosine-1-phosphate receptor-1, spleen tyrosine kinase (SYK), SRC gene, Src tyrosine kinase, Stabilin-1 (STAB1), STAT3 gene, sterol Idosulfatase, Stimulator of interferon genes (STING) receptor, interferon gene stimulator protein, stromal cell Derived from factor I ligand, SUMO (small ubiquitin-like modifier), superoxide dismutase, suppressor of cytokine signaling modulators (SOCS), survivor protein, synapsin 3, syndecane-1, synucle In α, T cell surface glycoprotein CD28, tank-binding kinase (TBK), TATA box-binding protein-related factor RNA polymerase I subunit B (TAF1B) gene, T cell CD3 glycoprotein ζ chain, T cell differentiation antigen CD6, T cell immunoglobulin and mucin domain-containing-3 (TIM-3), T cell surface glycoprotein CD8, Tec protein tyrosine kinase, Tek tyrosine kinase receptor, telomerase, telomerase Reverse transcriptase (Telomerase reverse transcriptase, TERT) gene, tenascin, Three prime repair exonuclease 1 (TREX1), Three prime repair exonuclease 2 (TREX2), thrombopoietin receptor, thymidine kinase, thymidine phosphorylase, thymidylate synthase, thymosine (α1, etc.), thyroid hormone receptor, thyroid-stimulating hormone receptor, tissue factor, TNF-related apoptosis-inducing ligand, TNFR1-related death domain protein, TNF-related apoptosis-inducing ligand (TRAIL) receptor, TNFSF11 gene, TNFSF9 Genes, Toll-like receptors (TLRs, e.g., 1-13), topoisomerases (I, II, III, etc.), transcription factors, transferases, transferrin (TF), transforming growth factor alpha (TGFα), transforming growth factor beta (TGFB) and its isoforms, TGFβ2 ligand, transforming growth factor TGF-β receptor kinase, transglutaminase, translocation-related proteins, transmembrane glycoprotein NMB, Trop-2 calcium signal transducer, trophoblast glycoprotein (TPBG) gene, trophoblast glycoprotein, tropomyosin receptor Kinase (Tropomyosin receptor kinase, Trk) receptor (TrkA, TrkB, T) rkC, etc.), tryptophan 2,3-dioxygenase (TDO), tryptophan 5-hydroxylase, tubulin, tumor necrosis factor (TNF, e.g., α, β, etc.), tumor necrosis factor 13C receptor, tumor progression locus 2 (TPL2), tumor protein 53 (TP53) gene, tumor suppressor candidate 2 (TU SC2) gene, tumor-specific neoantigen, tyrosinase, tyrosine hydroxynase, tyrosine kinase (TK), tyrosine kinase receptor, tyrosine kinase with immunoglobulin-like and EGF-like domains (TIE) receptor, tyrosine protein kinase ABL1 inhibitor, ubiquitin, ubiquitin carboxylase hydrolase isozyme L5, ubiquitin thioesterase-14, ubiquitin-conjugating enzyme E2I (UBE2I, UBC9), ubiquitin-specific-processing protease 7 7, USP7), urease, urokinase plasminogen activator, uteroglomerate Vanilloid VR1, vascular cell adhesion protein 1, vascular endothelial growth factor receptor (vascular Endothelial growth factor receptor (VEGFR), V domain of T cell activation Ig inhibitor (V-domain Ig suppressor of T-cell activation, VISTA), VEGF-1 receptor, VEGF-2 receptor, VEGF-3 receptor, VEGF-A, VEGF-B, vimentin, vitamin D3 receptor, proto-oncogene tyrosine protein kinase, Mer (Mer tyrosine kinase receptor modulator), YAP (Yes-related protein modulator), Wee-1 protein kinase, Werner Syndrome RecQ-like helicase (WRN), Wilms tumor antigen 1, Wilms tumor Examples include proteins, WW domain-containing transcription regulatory protein 1 (TAZ), X-linked apoptosis inhibitory proteins, zinc finger protein transcription factors, or any combination thereof. Exemplary mechanism of action

[0116] In various embodiments, one or more additional therapeutic agents may be classified into the following groups, for example, based on their mechanism of action:

[0117] Antimetabolites / anticancer agents such as pyrimidine analogs phloxuridine, capecitabine, cytarabine, CPX-351 (liposomalcytarabine, daunorubicin), and TAS-118;

[0118] Purine analogs, folate antagonists (such as pralatrexate), cladribine, pentostatins, fludarabine, and related inhibitors;

[0119] Microtubule inhibitors such as vinca alkaloids (vinblastine, vincristine) and taxanes (paclitaxel, docetaxel), and antiproliferative / antimitotic agents including natural products such as vinblastine, nocodazole, epotilon, vinorelbine (NAVELBINE®), and epipodophyllotoxin (etoposide, teniposide);

[0120] DNA damaging agents such as actinomycin, amsacrin, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide (CYTOXAN®), dactinomycin, daunorubicin, doxorubicin, DEBDOX, epirubicin, ifosfamide, melphalan, mechloretamine, mitomycin C, mitoxantrone, nitrosourea, procarbazine, taxol, taxotere, teniposide, etoposide, and triethylenethiophosphoramide;

[0121] DNA hypomethylating agents such as guadecitabine (SGI-110) and ASTX727;

[0122] Antibiotics such as dactinomycin, daunorubicin, doxorubicin, idarubicin, anthracyclines, mitoxantrone, bleomycin, and primycin (mitramycin);

[0123] Enzymes such as L-asparaginase metabolize L-asparagine throughout the body and remove cells that lack the ability to synthesize asparagine themselves;

[0124] DNAi oligonucleotides that target Bcl-2, such as PNT2258; drugs that activate or reactivate latent human immunodeficiency virus (HIV), such as panobinostat and romidepsin;

[0125] Asparaginase-stimulating factors such as chrysanthan spase (Erwinase®) and GRASPA (ERY-001, ERY-ASP), GRASPA pegol, and GRASPA pegaspargase;

[0126] Entrectinib, and pan-Trk, ROS1, and ALK inhibitors such as TPX-0005;

[0127] Anaplastic lymphoma kinase (ALK) inhibitors such as alectinib, ceritinib, Alecensa (RG7853), and ALUNBRIG® (brigatinib);

[0128] Antiproliferative / antimitotic alkylating agents such as nitrogen mustard cyclophosphamide and analogs (e.g., melphalan, chlorambucyl, hexamethylmelamine, thiotepa), alkylnitrosourea (e.g., carmustine) and analogs, streptozocin, and triazines (e.g., dacarbazine);

[0129] Antiproliferative / antimitotic antimetabolites such as folic acid analogs (methotrexate);

[0130] Platinum-coordinated complexes (e.g., cisplatin, oxyloplatinim, and carboplatin), procarbazine, hydroxyurea, mitotane, and aminoglutethimide;

[0131] Hormones, hormone analogs (e.g., estrogen, tamoxifen, goserelin, bicalutamide, and nilutamide), and aromatase inhibitors (e.g., letrozole and anastrozole);

[0132] Antiplatelet agents; anticoagulants such as heparin, synthetic heparin salts, and other thrombin inhibitors;

[0133] Fibrinolytic agents such as tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamol, ticlopidine, and clopidogrel;

[0134] Anti-mobility agent;

[0135] Antisecretors (e.g., breveldin);

[0136] Immunosuppressants such as tacrolimus, sirolimus, azathioprine, and mycophenolate;

[0137] Growth factor inhibitors and vascular endothelial growth factor inhibitors;

[0138] Fibroblast growth factor inhibitors such as FPA14;

[0139] AMP-activated protein kinase stimulants such as metformin hydrochloride;

[0140] Alpha-1 adrenergic receptor / alpha-2 adrenergic receptor antagonists such as phenoxybenzamine hydrochloride (injectable, for pheochromocytoma);

[0141] androgen receptor antagonists such as nilutamide;

[0142] Anti-VEGFR antibodies such as IMC-3C5, GNR-011, tanibirumab, and LYN-00101; anti-VEGF / DDL4 antibodies such as ABT-165;

[0143] Anti-cadherin antibodies such as HKT-288;

[0144] Anti-leucine rich repeat-containing antibody 15 (LRRC15), such as ABBV-085. ARGX-110;

[0145] Angiotensin receptor blockers, nitric oxide donors;

[0146] AEG35156, IONIS-KRAS-2.5Rx, EZN-3042, RX-0201, IONIS-AR-2.5Rx, BP-100 (Plexigeversen), and I Antisense oligonucleotides such as ONIS-STAT3-2.5Rx;

[0147] DNA interfering oligonucleotides such as PNT2258 and AZD-9150;

[0148] Anti-angiopoietin (ANG)-2 antibodies such as MEDI3617 and LY3127804;

[0149] Anti-ANG-1 / ANG-2 antibodies such as AMG-780;

[0150] Anti-CSF1R antibodies such as emactumab, LY3022855, AMG-820, and FPA-008 (kabilalizumab);

[0151] Anti-endoglin antibodies such as TRC105 (carotuximab);

[0152] Anti-MET / EGFR antibodies such as LY3164530;

[0153] Anti-EGFR antibodies such as ABT-414, AMG-595, necitumumab, ABBV-221, depatuxizumab mahodotin (ABT-414), tomzotuximab, ABT-806, vectibix, modotuximab, and RM-1929;

[0154] Anti-HER2 antibodies such as HERCEPTIN® (trastuzumab), trastuzumab biosimilars, margetuximab, MEDI4276, BAT-8001, pertuzumab (Perjeta), RG6264, and ZW25 (a bispecific HER2-targeting antibody targeting extracellular domains 2 and 4); Cancer Discov. 2019 Jan;9(1):8; PMID:30504239;

[0155] Anti-HLA-DR antibodies such as IMMU-114;

[0156] Anti-IL-3 antibodies such as JNJ-56022473;

[0157] Antibodies of anti-TNF receptor superfamily member 4 (TNFRSF4, OX40; NCBI gene ID: 7293) (MEDI6469, MEDI6383, MEDI0562 (tavorixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, etc.); and those described in International Publication Nos. 2016 / 179517, 2017 / 096179, 2017 / 096182, 2017 / 096281, and 2018 / 089628;

[0158] Antibodies of anti-TNF receptor superfamily member 18 (TNFRSF18, GITR; NCBI gene ID: 8784) (MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, etc.); as well as those described, for example, in International Publication Nos. 2017 / 096179, 2017 / 096276, 2017 / 096189, and 2018 / 089628;

[0159] Anti-TNFRSF4(OX40) / TNFRSF18(GITR) bispecific antibodies, such as those described in International Publication Nos. 2017 / 096179 and 2018 / 089628;

[0160] Anti-EphA3 antibodies such as KB-004;

[0161] Anti-CD37 antibodies such as AGS67E and otreltuzumab (TRU-016);

[0162] Anti-ENPP3 antibodies such as AGS-16C3F;

[0163] Anti-FGFR-3 antibodies such as LY3076226 and B-701;

[0164] Anti-FGFR-2 antibodies such as GAL-F2;

[0165] Anti-C5 antibodies such as ALXN-1210;

[0166] Anti-TROP-2 antibodies such as IMMU-132;

[0167] Anti-EpCAM antibodies such as VB4-845;

[0168] Antibodies against TNF receptor superfamily member 17 (TNFRSF17, BCMA), such as GSK-2857916;

[0169] Anti-CEA antibodies such as RG-7813;

[0170] Anti-surface antigen classification 3 (CD3) antibodies such as MGD015; anti-folate receptor α antibodies such as IMGN853;

[0171] Antibodies targeting anti-TNF receptor superfamily member 10b (TNFRSF10B, DR5, TRAILR2), such as DS-8273, CTB-006, INBRX-109, and GEN-1029;

[0172] Anticancer embryogenic antigen-associated cell adhesion molecule 6 (CEACAM6, CD66C) antibodies such as BAY-1834942 and NEO-201 (CEACAM 5 / 6);

[0173] Anti-GD2 antibodies such as APN-301;

[0174] Anti-interleukin-17 (IL-17) antibodies such as CJM-112;

[0175] Anti-interleukin-1 beta antibodies such as canakinumab (ACZ885) and VPM087;

[0176] Anticarbonic anhydrase 9 (CA9, CAIX) antibodies such as TX-250;

[0177] Anti-CD38 antibodies such as isatuximab, MOR-202, and TAK-079;

[0178] Anti-CD38 attenukine such as TAK573;

[0179] Gatipotuzumab and anti-mucin 1 (MUC1) antibodies such as Mab-AR-20.5;

[0180] Anti-CD33 antibodies such as IMGN-779;

[0181] Anti-KMA antibodies such as MDX-1097;

[0182] Anti-CD55 antibodies such as PAT-SC1;

[0183] Anti-PSMA antibodies such as ATL-101;

[0184] Anti-CD100 antibodies such as VX-15;

[0185] Anti-EPHA3 antibodies such as fibatuzumab;

[0186] Anti-APRIL antibodies such as BION-1301;

[0187] Anti-fibroblast-activating protein (FAP) / IL-2R antibodies such as RG7461;

[0188] Anti-fibroblast-activating protein (FAP) / TRAIL-R2 antibodies such as RG7386;

[0189] Anti-fucosyl-GM1 antibodies such as BMS-986012;

[0190] Anti-TGFb antibodies such as SAR439459;

[0191] ADP-ribosylcyclase-1 inhibitors such as daratumumab (DARZALEX®);

[0192] Caspase-recruiting domain protein-15 stimulants such as mifamultide (liposome);

[0193] CCR5 chemokine antagonists such as MK-7690 (Bikribirock);

[0194] CDC7 protein kinase inhibitors such as TAK-931;

[0195] Cholesterol side-chain cleavage enzyme inhibitors such as ODM-209;

[0196] Dihydropyrimidine dehydrogenase / orotinate phosphoribosyltransferase inhibitors such as cephezone (tegafur + gimeracil + oteracil potassium);

[0197] DNA polymerase / ribonucleotide reductase inhibitors such as clopharabine;

[0198] Estrogen receptor modulators such as bazedoxifene;

[0199] Estrogen receptor agonists / progesterone receptor antagonists such as TRI-CYCLEN LO (norethindrone + ethinylestradiol);

[0200] HLA class I antigen A-2 alpha modulators such as FH-MCVA2TCR;

[0201] MART-1 F5 TCR-modified PBMCs and other HLA class I antigen A-2 alpha / MART-1 melanoma antigen modifiers;

[0202] Human granulocyte colony-stimulating factors such as PF-06881894;

[0203] GNRH receptor agonists such as leuprorelin acetate, leuprorelin acetate sustained-release depot (ATRIGEL), triptrelyn pamoate, and goserelin acetate;

[0204] GNRH receptor antagonists such as Eragolix, Relugolix, and Degarelix;

[0205] Endoplasmin modifiers such as analotinib;

[0206] H+K+ATPase inhibitors such as omeprazole and esomeprazole;

[0207] ICAM-1 / CD55 modifiers such as cavatak (V-937);

[0208] IL-15 / IL-12 modifiers such as SAR441000;

[0209] Interleukin-23A inhibitors such as guselkumab;

[0210] Lysine-specific histone demethylase 1 inhibitors such as CC-90011;

[0211] IL-12 Mrna, such as MEDI 1191;

[0212] Progesterone receptor agonists such as levonorgestrel;

[0213] Protein cereblon regulators such as CC-92480 and CC-90009;

[0214] Protein cereblon regulators such as iverdomi / DNA-binding protein Ikaros inhibitors / zinc finger-binding protein Aiolos inhibitors;

[0215] Retinoid X receptor modulators such as alitretinoin and bexarotene (oral formulation);

[0216] RIP-1 kinase inhibitors such as GSK-3145095;

[0217] Selective estrogen receptor degraders such as AZD9833;

[0218] SUMO inhibitors such as TAK-981;

[0219] Thrombopoietin receptor agonists such as eltrombopag;

[0220] Thyroid hormone receptor agonists such as levothyroxine sodium;

[0221] TNF agonists such as Tasonelmin;

[0222] Tyrosine phosphatase substrate 1 inhibitors such as CC-95251;

[0223] HER2 inhibitors such as neratinib and tucatinib (ONT-380);

[0224] EGFR / ErbB2 / Ephb4 inhibitors such as tesevatinib;

[0225] EGFR / HER2 inhibitors such as TAK-788;

[0226] EGFR family tyrosine kinase receptor inhibitors such as DZD-9008;

[0227] Anti-ERBB antibodies such as CDX-3379, HLX-02, and cerivanthumb;

[0228] EGFR / ErbB-2 inhibitors such as baritinib;

[0229] Mutation-selective EGFR inhibitors such as PF-06747775, EGF816 (nazartinib), ASP8273, ACEA-0010, and BI-1482694;

[0230] epha2 inhibitors such as MM-310;

[0231] RAF kinase / VEGFR inhibitors such as RAF-265;

[0232] Polycomb protein (EED) inhibitors such as MAK683;

[0233] DHFR inhibitors such as pralatrexate / folate transporter 1 modulators / folate receptor antagonists;

[0234] DHFR / GAR transferformylase / thymidiylate synthase / transferase inhibitors such as pemetrexedni sodium;

[0235] p38 MAP kinase inhibitors such as larimetinib;

[0236] PRMT inhibitors such as MS203, PF-06939999, GSK3368715, and GSK3326595;

[0237] Sphingosine kinase 2 (SK2) inhibitors such as opaganib;

[0238] Omaberoxolone (RTA-408) and other nuclear erythrocyte-related factor distimulants;

[0239] Tropomyosin receptor kinase (TRK) inhibitors such as LOXO-195 and ONO-7579;

[0240] Mucin 1 inhibitors such as GO-203-2C;

[0241] MARCKS protein inhibitors such as BIO-11006;

[0242] Folic acid antagonists such as alpha-thixoline;

[0243] Galectin-3 inhibitors such as GR-MD-02;

[0244] Phosphorylated P68 inhibitors such as RX-5902;

[0245] CD95 / TNF modulators such as ofranergene obadenovec;

[0246] PI3K / Akt / mTOR inhibitors such as ABTL-0812;

[0247] Pan-PIM kinase inhibitors such as INCB-053914;

[0248] IL-12 gene stimulating factors such as EGEN-001 and tavoquinogenterceplasmid;

[0249] Heat shock protein HSP90 inhibitors such as TAS-116 and PEN-866;

[0250] VEGF / HGF antagonists such as MP-0250;

[0251] VEGF ligand inhibitors such as bevacizumab biosimilars;

[0252] VEGF receptor antagonists / VEGF ligand inhibitors such as ramucirumab;

[0253] VEGF-1 / VEGF-2 / VEGF-3 receptor antagonists; such as fluquintinib;

[0254] VEGF-1 / VEGF-2 receptor modulators such as HLA-A2402 / HLA-A0201 restriction epitope peptide vaccines;

[0255] Placental growth factor ligand inhibitors / VEGF-A ligand inhibitors such as aflibercept;

[0256] SYK tyrosine kinase / JAK tyrosine kinase inhibitors such as ASN-002;

[0257] Trk tyrosine kinase receptor inhibitors such as larotrectinib sulfate;

[0258] JK3 / JAK1 / TBK1 kinase inhibitors such as CS-12912;

[0259] IL-24 antagonists such as AD-IL24;

[0260] NLRP3 (NACHT LRR PYD domain protein 3) modulators such as BMS-986299;

[0261] RIG-I agonists such as the RGT-100;

[0262] Erolynizin-stimulating factors such as topsalicin;

[0263] P-glycoprotein 1 inhibitors such as HM-30181A;

[0264] CSF-1 antagonists such as the ARRY-382 and BLZ-945;

[0265] CCR8 inhibitors such as I-309, SB-649701, HG-1013, and RAP-310;

[0266] Anti-mesoserin antibodies such as SEL-403;

[0267] Thymidine kinase stimulants such as Agratimagembesadenobec;

[0268] Polo-like kinase 1 inhibitors such as PCM-075;

[0269] NAE inhibitors such as pevonesistat (MLN-4924) and TAS-4464; multi-pathway regulators such as abadomide (CC-122);

[0270] Amyloid protein-binding protein-1 inhibitors / ubiquitin ligase modulators such as pevonesistat;

[0271] FoxM1 inhibitors such as thiostreptopton;

[0272] UBA1 inhibitors such as TAK-243;

[0273] Src tyrosine kinase inhibitors such as VAL-201;

[0274] VDAC / HK inhibitors such as VDA-1102;

[0275] BRAF / PI3K inhibitors such as ASN-003;

[0276] Elf4a inhibitors such as rohinitib and eFT226;

[0277] TP53 gene stimulators such as ad-p53;

[0278] Retinoic acid receptor agonists such as tretinoin;

[0279] Retinoic acid receptor alpha (RARα) inhibitors such as SY-1425;

[0280] SIRT3 inhibitors such as YC8-02;

[0281] Oraptest pegol (NOX-A12) and other stromal cell-derived factor 1 ligand inhibitors;

[0282] IL-4 receptor modulators such as MDNA-55;

[0283] Arginase I stimulating factors such as pegdyraliginase;

[0284] Irinotecan hydrochloride and topoisomerase I inhibitors such as Onivyde;

[0285] Topoisomerase I inhibitors / hypoxia-inducible factor-1-alpha inhibitors such as PEG-SN38 (filtecan pegol);

[0286] Hypoxia-inducible factor-1-alpha inhibitors such as PT-2977 and PT-2385;

[0287] CD122 agonists such as NKTR-214;

[0288] TLR7 / TLR8 agonists such as NKTR-262;

[0289] TLR7 agonists such as DS-0509, GS-9620, LHC-165, and TMX-101 (imiquimod);

[0290] p53 tumor suppressor protein-stimulating factors such as kebetrin;

[0291] Mdm4 / Mdm2 p53 binding protein inhibitors such as ALRN-6924;

[0292] Kinesin spindle protein (KSP) inhibitors such as filanesib (ARRY-520);

[0293] CD80-fc fusion protein inhibitors such as FPT-155;

[0294] Menin and mixed-phenotype leukemia (MLL) inhibitors such as KO-539;

[0295] Liver x receptor agonists such as RGX-104;

[0296] IL-10 agonists such as Peg-Irodekakin (AM-0010);

[0297] VEGFR / PDGFR inhibitors such as bororanib;

[0298] IRAK4 inhibitors such as CA-4948;

[0299] Anti-TLR-2 antibodies such as OPN-305;

[0300] Calmodulin regulators such as CBP-501;

[0301] Glucocorticoid receptor antagonists such as Relacorirant (CORT-125134);

[0302] Second mitochondrial-derived activator (SMAC) protein inhibitors of caspases such as BI-891065;

[0303] Lactoferrin regulators such as LTX-315;

[0304] KIT proto-oncogenes such as PLX-9486, receptor tyrosine kinase (KIT) inhibitors;

[0305] Platelet-derived growth factor receptor alpha (PDGFRA) / KIT proto-oncogenes, receptor tyrosine kinase (KIT) variant-specific antagonists / inhibitors, such as BLU-285 and DCC-2618;

[0306] Exportin 1 inhibitors such as ertanexol;

[0307] CHST15 gene inhibitors such as STNM-01;

[0308] RAS inhibitors such as NEO-100;

[0309] Somatostatin receptor antagonists such as OPS-201;

[0310] CEBPA gene stimulators such as MTL-501;

[0311] DKK3 gene regulators such as MTG-201;

[0312] Chemokine (CXCR1 / CXCR2) inhibitors such as SX-682;

[0313] p70s6k inhibitors such as MSC2363318A;

[0314] Methionine aminopeptidase 2 (MetAP2) inhibitors such as M8891 and APL-1202;

[0315] Arginine N-methyltransferase 5 inhibitors such as GSK-3326595;

[0316] CD71 modifiers such as CX-2029-ABBV-2029;

[0317] Anti-IL-8 (interleukin-8) antibodies such as HuMax-Inflam;

[0318] ATM (ataxia telangiectasia) inhibitors such as AZD0156 and AZD1390;

[0319] CHK1 inhibitors such as GDC-0575, LY2606368 (prexacertib), SRA737, and RG7741 (CHK1 / 2);

[0320] CXCR4 antagonists such as BL-8040, LY2510924, Tinxafor (TG-0054), X4P-002, X4P-001-IO, and Prelixafor;

[0321] EXH2 inhibitors such as GSK2816126;

[0322] KDM1 inhibitors such as ORY-1001, IMG-7289, INCB-59872, and GSK-2879552;

[0323] CXCR2 antagonists such as AZD-5069;

[0324] GM-CSF antibodies such as lenzirumab;

[0325] DNA-dependent protein kinase inhibitors such as MSC2490484A (Nedicertib), VX-984, and AsiDNA (DT-01); protein kinase C (PKC) inhibitors such as LXS-196 and Sotrastaurin;

[0326] Selective estrogen receptor downregulators (SERDs) such as fulvestrant (Faslodex®), RG6046, RG6047, RG6171, elastrant (RAD-1901), SAR439859, and AZD9496;

[0327] Selective estrogen receptor covalent antagonists (SERCAs), such as H3B-6545;

[0328] Selective androgen receptor modulators (SARMs) such as GTX-024 and darolutamide;

[0329] Transforming growth factor-β (TGF-β) kinase antagonists such as garnicertib and LY3200882; TGF-β inhibitors described in International Publication No. 2019 / 103203;

[0330] TGF beta receptor 1 inhibitors such as PF-06952229;

[0331] Anti-transforming growth factor-β (TGF-β) antibodies such as ABBV-151, LY3022859, NIS793, and XOMA089;

[0332] ABT-165 (DLL4 / VEGF), MM-141 (IGF-1 / ErbB3), MM-111 (Erb2 / Erb3), JNJ-64052781 (CD19 / CD3) , PRS-343(CD-137 / HER2), AFM26(BCMA / CD16A), JNJ-61186372(EGFR / cMET), AMG-211(CEA / CD3) RG7802 (CEA / CD3), ERY-974 (CD3 / GPC3), vancizumab (angiopoietin / VEGF), PF-06671008 (cadherin / CD3), AFM-13 (CD16 / CD30), APVO436 (CD123 / CD3), flotetuzumab (CD123 / CD3), REGN-1979 (CD20 / CD3), MCLA -117(CD3 / CLEC12A), MCLA-128(HER2 / HER3), JNJ-0819, JNJ-7564(CD3 / heme), AMG-757(DLL3-CD3), MGD-013(PD-1 / LAG-3), FS-118(LAG-3 / PD-L1), MGD-019(PD-1 / CTLA-4), KN-046(PD-1 / CTLA-4), MEDI-5752(CTLA-4 / PD-1), RO-7121661(PD-1 / TIM-3), XmAb-20717(PD-1 / CTLA -4), AK-104 (CTLA-4 / PD-1), AMG-330 (CD33 / CD3), AMG-420 (BCMA / CD3), BI-836880 (VEFG / ANG2), JNJ-63709178 (CD123 / CD3), MGD-007 (CD 3 / gpA33), MGD-009(CD3 / B7H3), AGEN1223, IMCgp100(CD3 / gp100), AGEN-1423, ATOR-1015(CTLA-4 / OX40), LY-3415244(TIM3 / PDL1), INHI BRX-105 (4-1BB / PDL1), Falicimab (VEGF-A / ANG-2), FAP-4-IBBL (4-1BB / FAP), XmAb-13676 (CD3 / CD20), TAK-252 (PD-1 / OX40L), TG-1801 (CD19 / CD47), XmAb-18087 (SSTR2 / CD3), Katsumakisomab (CD3 / EpCAM), SAR-156597 (IL4 / IL13), EMB-01 (EGFR / cMET), REGN-4018 (MUC16 / CD3), REGN- Bispecific antibodies such as 1979 (CD20 / CD3), RG-7828 (CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), nabisikizumab (DLL4 / VEGF), GRB-1302 (CD3 / Erbb2), vanucizumab (VEGF-A / ANG-2), GRB-1342 (CD38 / CD3), GEM-333 (CD3 / CD33), IMM-0306 (CD47 / CD20), RG6076, and MEDI5752 (PD-1 / CTLA-4);

[0333] Antidelta-like protein ligand 3 (DDL3) antibodies such as lovalpituzumab tecilin;

[0334] Anti-clastin antibodies such as AB-16B5;

[0335] Anti-ephrin-A4 (EFNA4) antibodies such as PF-06647263;

[0336] Anti-RANKL antibodies such as denosumab;

[0337] Anti-mesoserin antibodies such as BMS-986148 and anti-MSLN-MMAE;

[0338] Antis of sodium phosphate cotransporter 2B (NaP2B), such as rifastuzumab;

[0339] Anti-c-Met antibodies such as ABBV-399;

[0340] Alpha-ketoglutarate dehydrogenase (KGDH) inhibitors such as CPI-613;

[0341] XPO1 inhibitors such as selinexol (KPT-330);

[0342] Isocitrate dehydrogenase 2 (IDH2) inhibitors such as enasidenib (AG-221);

[0343] IDH1 inhibitors such as AG-120, AG-881 (IDH1 and IDH2), IDH-305, and BAY-1436032;

[0344] IDH1 gene inhibitors such as ivosidenib;

[0345] Interleukin-3 receptor (IL-3R) modifiers such as SL-401;

[0346] Arginine deiminase-stimulating factors such as pegalgiminase (ADI-PEG-20);

[0347] Claudiximab and other claudin-18 inhibitors;

[0348] Beta-catenin inhibitors such as CWP-291;

[0349] Chemokine receptor 2 (CCR) inhibitors such as PF-04136309, CCX-872, and BMS-813160 (CCR2 / CCR5);

[0350] Thymimidylate synthase inhibitors such as ONX-0801;

[0351] ALK / ROS1 inhibitors such as lorlatinib;

[0352] Tankirase inhibitors such as G007-LK;

[0353] Mdm2 p53-binding protein inhibitors such as CMG-097 and HDM-201; and c-PIM inhibitors such as PIM447;

[0354] BRAF inhibitors such as dabrafenib, vemurafenib, encorafenib (LGX818), and PLX8394;

[0355] Sphingosine kinase-2 (SK2) inhibitors such as Yeliva® (ABC294640);

[0356] Cell cycle inhibitors such as selumetinib (MEK1 / 2) and sapacitabine;

[0357] Cell cycle / microtubule inhibitors such as eribulin mesylate;

[0358] AKT inhibitors such as MK-2206, ipatasertib, afrecertib, AZD5363, and ARQ-092, capivacertib, and trisirivine;

[0359] c-MET inhibitors such as AMG-337, savolitinib, tivantinib (ARQ-197), capmatinib, and tepotinib, ABT-700, AG213, AMG-208, JNJ-38877618 (OMO-1), meristinib, and HQP-8361;

[0360] c-Met / VEGFR inhibitors such as BMS-817378 and TAS-115;

[0361] c-Met / RON inhibitors such as BMS-777607;

[0362] BRAF / EGFR inhibitors such as BGB-283;

[0363] BCR / ABL inhibitors such as levastinib, aciminib, and ponatinib (ICLUSIG®);

[0364] MNK1 / MNK2 inhibitors such as eFT-508;

[0365] Cytochrome P450 11B2 / Cytochrome P450 17 / A, such as LAE-201 KT protein kinase inhibitors;

[0366] mTOR inhibitors such as TYME-88 / cytochrome P450 3A4 stimulating factors;

[0367] Cytochrome P450 3A4 stimulating factors such as mitotane;

[0368] Lysine-specific demethylase-1 (LSD1) inhibitors such as CC-90011;

[0369] Pan-RAF inhibitors such as LY3009120, LXH254, and TAK-580;

[0370] Raf / MEK inhibitors such as RG7304;

[0371] CSF1R / KIT and FLT3 inhibitors such as pexidartinib (PLX3397);

[0372] Flt3 tyrosine kinase / Kit tyrosine kinase inhibitors such as quizartinib dihydrochloride, and PDGF receptor antagonists;

[0373] Kinase inhibitors such as vandetanib;

[0374] E-selectin antagonists such as GMI-1271;

[0375] Differentiation-inducing factors such as tretinoin;

[0376] Epidermal growth factor receptor (EGFR) inhibitors such as osimertinib (AZD-9291) and cetuximab;

[0377] Topoisomerase inhibitors such as Adriamycin, Doxorubicin, Daunorubicin, Dactinomycin, DaunoXome, Caelyx, Eniposide, Epirubicin, Etoposide, Idarubicin, Irinotecan, Mitoxantrone, Pixantrone, Sobuzoxane, Topotecan, Irinotecan, MM-398 (Liposomal Irinotecan), Bosaroxine and GPX-150, Aldoxorubicin, AR-67, Marveleltinib, AST-2818, Abitinib (ACEA-0010), and Ilofluben (MGI-114);

[0378] Corticoids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, and prednisolone;

[0379] Growth factor signaling kinase inhibitors;

[0380] Nucleoside analogs such as DFP-10917;

[0381] Axl inhibitors such as BGB-324 (vemcentinib) and SLC-0211;

[0382] Inhibitors of bromodomain and extraterminal motif (BET) proteins (including ABBV-744, BRD2 (NCBI gene ID: 6046), BRD3 (NCBI gene ID: 8019), BRD4 (NCBI gene ID: 23476), and bromodomain testis-specific protein (BRDT; NCBI gene ID: 676)), e.g., INCB-054329, INCB057643, TEN-010, AZD-5153, ABT-767, BMS-986158, CC-90010, GSK525762 (molyblesiv), NHWD-870, ODM-207, GSK-2820151, GSK-1210151A , ZBC246, ZBC260, ZEN3694, FT-1101, RG-6146, CC-90010, CC-95775, Mibeblesib, BI-894999, PLX-2853, PLX-51107, CPI-0610, and GS-5829;

[0383] PARP inhibitors such as olaparib (MK7339), lucaparib, veliparib, talazoparib, ABT-767, BGB-290, fluzorepari (SHR-3162), niraparib (JNJ-64091742), and bendamustine hydrochloride;

[0384] PARP / tankylase inhibitors such as 2X-121(e-7499);

[0385] IMP-4297, SC-10914, IDX-1197, HWH-340, CK-102, and Simmiparib;

[0386] Proteasome inhibitors such as ixazomib (NINLARO®); carfilzomib (Kyprolis®), marizomib, and bortezomib;

[0387] Glutaminase inhibitors such as CB-839 (Teragrenasto) and bis-2-(5-phenylacetamido-1,3,4-thiadiazole-2-yl)ethyl sulfide (BPTES);

[0388] Mitochondrial complex I inhibitors such as metformin and pheneformin;

[0389] Peptide vaccines such as TG-01(RAS), GALE-301, GALE-302, Neripepimto-s, SurVaxM, DSP-7888, TPIV-200, PVX-410, VXL-100, DPX-E7, ISA-101, 6MHP, OSE-2101, Garimpepimto-S, SVN53-67 / M57-KLH, IMU-131, peptide subunit vaccine (acute lymphoblastic leukemia, University Children's Hospital Tuebingen); bacterial vector vaccines such as CRS-207 / GVAX and AXALIMODIN Phyllorisvac (ADXS11-001); nadofaragene Adenovirus vector vaccines such as firadenovec; autologous Gp96 vaccine; CVactm, tapuldencel-T, eltrapuldencel-T, SL-701, BSK01™, rocapuldencel-T (AGS-003), DCVAC, CVactm, tapuldencel-T, eltrapuldencel-T, SL-701, BSK01™, ADXS31-142, dendritic cell vaccines such as autologous dendritic cell vaccine (metastatic malignant melanoma, intradermal / intravenous, Universitatsklinikum Erlangen); tarimodine laherpalepvec, pexastimogene Oncolytic vaccines such as devacirepvec, GL-ONC1, MG1-MA3, parvovirus H-1, ProstAtak, enadenochucilev, MG1MA3, ASN-002 (TG-1042); therapeutic vaccines such as CVAC-301, CMP-001, CreaVax-BC, PF-06753512, VBI-1901, TG-4010, ProscaVax (trademark); tumor cell vaccines such as Vigil (registered trademark) (IND-14205), Oncoquest-L vaccine; attenuated recombinant serotype 1 poliovirus vaccines such as PVS-RIPO; Adagloxad simolenin; MEDI-0457; DPV-001 tumor-derived autophagosome-rich cancer vaccine; RNA vaccines such as CV-9209, LV-305; DNA vaccines such as MEDI-0457, MVI-816, INO-5401;Modified vaccinia virus Ankara vaccines expressing p53 such as MVA-p53; DPX-Survivac; BriaVax(trademark); GI-6301; GI-6207; GI-4000; IO-103; AGEN-2017, GEN-010, NeoVax, RG-6180, GEN-009, PGV-001(TLR-3A; Neoantigen peptide vaccines such as gonist, GRANITE-001, and NEO-PV-01; peptide vaccines targeting heat shock proteins such as PhosphoSynVax™; and NANT colorectal cancer vaccines containing Vitespen (HSPPC-96-C) and aldoxorubicin, autologous tumor cell vaccine + systemic CpG-B + IFN-alpha (cancer);

[0390] Anti-DLL4 (delta-like ligand 4) antibodies such as demcizumab;

[0391] STAT-3 inhibitors such as napabubacin (BBI-608);

[0392] ATPase p97 inhibitors such as CB-5083;

[0393] Smoothland (SMO) receptor inhibitors such as Odomzo® (sonidegib, formerly LDE-225), LEQ506, bismodegib (GDC-0449), BMS-833923, glassdegib (PF-04449913), LY2940680, and itraconazole;

[0394] Interferon alpha-2b, interferon alpha-2a biosimilar (Biogenomics), ropeg interferon alpha-2b (AOP-2014, P-1101, PEG IFN alpha-2b), multiferon (alpha-native, Viragen), interferon alpha-1b, roferon-A (camferon, Ro-25-3036), interferon alpha-2a biosimilar (Biosidus) (Inmutag, Inter 2A), interferon alpha-2b biosimilar (Biosidus-Bioferon, cytoferon, Ganapar, Beijing Kawin) Interferon alpha ligand modulators such as Technology-Cafelon, Alphaferon, PEGylated interferon alpha-1b, pegylated interferon alpha-2b biosimilar (Amega), recombinant human interferon alpha-1b, recombinant human interferon alpha-2a, recombinant human interferon alpha-2b, vertuzumab-IFN alpha-2b connjyuge-to, Dynavax (SD-101), and interferon alpha-n1 (Humoferon, SM-10500, Sumiferon);

[0395] Interferon-gamma ligand modulators such as interferon-gamma (OH-6000, Ogamma100);

[0396] Tocilizumab, and IL-6 receptor modulators such as AS-101 (CB-06-02, IVX-Q-101);

[0397] Heat shock protein inhibitors / IL-6 receptor antagonists such as siltuximab;

[0398] Telomerase modulators such as teltomotide (GV-1001, HR-2802, Riavax) and imetelstat (GRN-163, JNJ-63935937);

[0399] DNA methyltransferase inhibitors such as temozolomide (CCRG-81045), decitabine, guadecitabine (S-110, SGI-110), KRX-0402, RX-3117, RRx-001, and azacitidine (CC-486);

[0400] DNA gyrase inhibitors such as pixantrone and sobuzoxane;

[0401] DNA gyrase inhibitors / topoisimerase II inhibitors such as amrubicin;

[0402] Bcl-2 family protein inhibitors such as ABT-263, venetoclax (ABT-199), ABT-737, RG7601, and AT-101;

[0403] Bcl-2 / Bcl-XL inhibitors such as Novitocrax;

[0404] Notch inhibitors such as LY3039478 (crenigamine), tarextumab (anti-Notch 2 / 3), and BMS-906024;

[0405] Anti-myostatin inhibitors such as landgrozumab;

[0406] Hyaluronidase-stimulating factors such as PEGPH-20;

[0407] Erbb2 tyrosine kinase receptor inhibitors / hyaluronidase stimulants such as Herceptin Hylecta;

[0408] Wnt pathway inhibitors such as SM-04755, PRI-724, and WNT-974;

[0409] Gamma-secretase inhibitors such as PF-03084014, MK-0752, and RO-4929097;

[0410] Grb-2 (growth factor receptor-binding protein-2) inhibitors such as BP1001;

[0411] TRAIL pathway-inducing compounds such as ONC201 and ABBV-621;

[0412] Adhesion plaque kinase inhibitors such as VS-4718, defactinib, and GSK2256098;

[0413] Hedgehog inhibitors such as salidegib, sonodegib (LDE225), and glassegib;

[0414] Alicertib (MLN-8237), and aurora kinase inhibitors such as AZD-2811, AMG-900, valacertib, and ENMD-2076;

[0415] HSPB1 regulators such as brivudine and apatorcene (heat shock protein 27, HSP27);

[0416] ATR inhibitors such as BAY-937, AZD6738, AZD6783, VX-803, VX-970 (belzocertib), and VX-970;

[0417] mTOR inhibitors such as sapoanicertib and vistucertib (AZD2014), ME-344, and sirolimus (oral nanoamorphous formulation, cancer);

[0418] mTOR / PI3K inhibitors such as gedatricib, GSK2141795, omiparisib, and RG6114;

[0419] Hsp90 inhibitors such as AUY922, Onarespib (AT13387), SNX-2112, and SNX5422;

[0420] DS-3032b, RG7775, AMG-232, HDM201, and Idazanuturi Mouse double microchromosome (mdm2) oncogene inhibitors such as RG7388;

[0421] CD137 agonists such as urelumab, utomirumab (PF-05082566), AGEN2373, and ADG-106;

[0422] STING agonists such as ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, and GSK3745417;

[0423] FGFR inhibitors such as FGF-401, INCB-054828, BAY-1163877, AZD4547, JNJ-42756493, LY2874455, and Debio-1347;

[0424] Fatty acid synthase (FASN) inhibitors such as TVB-2640;

[0425] Antigen CD19 inhibitors such as MOR208, MEDI-551, AFM-11, and inebilizumab;

[0426] CD44 binders such as A6;

[0427] Protein phosphatease 2A (PP2A) inhibitors such as LB-100;

[0428] CYP17 inhibitors such as ceviteronnel (VT-464), ASN-001, ODM-204, CFG920, and abiraterone acetate;

[0429] RXR agonists such as IRX4204;

[0430] Hedgehog / Smoothed (hh / Smo) antagonists such as Talladegib, Patidegib, and Bismodegib;

[0431] Complement C3 regulators such as Imprime PGG;

[0432] IL-15 agonists such as ALT-803, NKTR-255, and hetIL-15;

[0433] EZH2 (zeste homolog 2 enhancer) inhibitors such as tazemetostat, CPI-1205, GSK-2816126, and PF-06821497;

[0434] Oncolytic viruses such as pelareorep, CG-0070, MV-NIS therapy, HSV-1716, DS-1647, VCN-01, ONCOS-102, TBI-1401, tasadenoturev (DNX-2401), vocimagene amiretrorepvec, RP-1, CVA21, Celyvir, LOAd-703, OBP-301, and IMLYGIC®;

[0435] DOT1L (histone methyltransferase) inhibitors such as pranomethostat (EPZ-5676);

[0436] Cholera toxin, ricin, Pseudomonas exotoxin, Bordetella Toxins such as adenylate cyclase toxin, diphtheria toxin, and caspase activator pertussis;

[0437] DNA plasmids such as BC-819;

[0438] PLK inhibitors such as volasertib (PLK1), which target PLK1, 2, and 3;

[0439] WEE1 inhibitors such as AZD-1775 (adavocertib); Rho kinase (ROCK) inhibitors such as AT13148 and KD025;

[0440] - ERK inhibitors such as GDC-0994, LY3214996, and MK-8353;

[0441] Apoptotic protein (IAP) inhibitors such as ASTX660, debio-1143, virinapant, APG-1387, and LCL-161;

[0442] RNA polymerase inhibitors such as lurubinectedin (PM-1183) and CX-5461;

[0443] Tubulin inhibitors such as PM-184, BAL-101553 (lisabambrin), and OXI-4503, fluolapacin (AC-0001), prinabulin, and vinflunin;

[0444] Toll-like receptor 4 (TL4) agonists such as G100, GSK1795091, and PEPA-10;

[0445] Elongation factor 1-alpha-2 inhibitors such as pristicepsin;

[0446] Denilokin difuticotox and other elongation factor 2 inhibitors / interleukin-2 ligands / NAD ADP ribosyltransferase stimulators;

[0447] CD95 inhibitors such as APG-101, APO-010, and Asnercept;

[0448] WT1 inhibitors such as DSP-7888;

[0449] Splicing factor 3B subunit 1 (SF3B1) inhibitors such as H3B-8800;

[0450] Retinoid Z receptor γ (RORγ) agonists such as LYC-55716; and

[0451] Microbiome modifiers such as SER-401, EDP-1503, and MRx-0518.

[0452] In some embodiments, the compounds described herein are administered concurrently with one or more additional therapeutic agents, including the following inhibitors or antagonists: protein tyrosine phosphatase, non-receptor type (PTPN11 or SHP2; NCBI gene ID: 5781); myelocyte leukemia sequence 1 (MCL1) apoptosis regulator (NCBI gene ID: 4170); mitogen-activated protein kinase kinase kinase 1 (MAP4K1) (also known as hematopoietic progenitor kinase 1 (HPK1), NCBI gene ID: 11184); diacylglycerol kinase alpha (DGKA, DAGK, DAGK1, or DGK-alpha; NCBI gene ID: 1606); 5'-nucleotidase ecto (NT5E or CD73; NCBI gene ID: 4907); ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1 or CD39; NCBI gene ID: 593); tran Forming growth factor β1 (TGFB1 or TGFβ; NCBI gene ID: 7040); heme oxygenase 1 (HMOX1, HO-1, or HO1; NCBI gene ID: 3162); heme oxygenase 2 (HMOX2, HO-2, or HO2; NCBI gene ID: 3163); vascular endothelial growth factor A (VEGFA or VEGF; NCBI gene ID: 7422); erb-b2 receptor tyrosine kinase 2 (ERBB2, HER2, HER2 / neu, or CD340; NCBI gene ID: 2064), epidermal growth factor receptor (EGFR, E RBB, ERBB1, or HER1; NCBI gene ID: 1956); ALK receptor tyrosine kinase (ALK, CD246; NCBI gene ID: 238); poly(ADP-ribose) polymerase 1 (PARP1; NCBI gene ID: 142); poly(ADP-ribose) polymerase 2 (PARP2; NCBI gene ID: 10038); TCDD-inducible poly(ADP-ribose) polymerase (TIPARP, PARP7; NCBI gene ID: 25976); cyclin-dependent kinase 4 (CDK4; NCBI gene ID: 1019); cy Clin-dependent kinase 6 (CDK6; NCBI gene ID: 1021); TNF receptor superfamily member 14 (TNFRSF14, HVEM, CD270; NCBI gene ID: 8764); T cell immune receptor with Ig and ITIM domains (TIGIT; NCBI gene ID: 201633); X-linked apoptosis inhibitors (XIAP, BIRC4, IAP-3; NCBI gene ID: 331); baculovirus IAP repeat-containing 2 (BIRC2, cIAP1; NCBI gene ID: 329); baculovirus IAP repeat-containing 3 (BIRC3, cIAP2; NCBI gene ID: 330); 5 containing baculovirus IAP repeats (BIRC5, viable; NCBI gene ID: 332); 2 CC motif chemokine receptors (CCR2, CD192; NCBI gene ID: 729230); 5 CC motif chemokine receptors (CCR5, CD195; NCBI gene ID: 1234); 8 CC motif chemokine receptors (CCR8, CDw198; NCBI gene ID: 1237); 2 CXC motif chemokine receptors (CXCR2, CD182; NCBI gene ID: 3579);CXC-motif chemokine receptor 3 (CXCR3, CD182, CD183; NCBI gene ID: 2833); CXC-motif chemokine receptor 4 (CXCR4, CD184; NCBI gene ID: 7852); arginase (ARG1 (NCBI gene ID: 383), ARG2 (NCBI gene ID: 384)); carbonic anhydrase (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), 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), Prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCB I 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) and / or soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI gene ID: 2053); secreted phospholipase A2 (e.g., PLA2G1B (NCBI gene ID: 5319) PLA2G7 (NCBI gene ID: 7941), PLA2G3 (NCBI gene ID: 50487), PLA2G2A (NCBI gene ID: 5320); PLA2G4A (NCBI gene ID: 5321); PLA2G12A (NCBI gene ID: 81579); PLA2G12B (NCBI gene ID: 84647); PLA2G10 (NCBI gene ID: 8399); PLA2G5 (NCBI gene ID: 5322); PLA2G2D (NCBI gene ID: 26279); PLA2G15 (NCBI gene ID: 23659));Indoleamine-2,3-dioxyge; Inhibitors of indoleamine-2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620); indoleamine-2,3-dioxygenase 2 (IDO2; NCBI gene ID: 169355); hypoxia-inducible factor 1 subunit α (HIF1A; NCBI gene ID: 3091); angiopoietin 1 (ANGPT1; NCBI gene ID: 284); endothelial TEK tyrosine kinase (TIE-2, TEK, CD202B; NCBI gene ID: 7010); Janus kinase 1 (JAK1; NCBI gene ID: 3716); catenin β1 (CTNNB1; NCBI gene ID: 1499); histone deacetylase 9 (HDAC9; NCBI gene ID: 9734), and / or 5'-3' exoribonuclease 1 (XRN1; NCBI gene ID: 54464). Immune checkpoint modifiers

[0453] In various embodiments, the compounds described herein are combined 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 actively modulate T cell or NK cell activation and prevent immune evasion of cancer cells in the tumor environment. Activation or stimulation of stimulating immune checkpoints can enhance the effects of immune checkpoint inhibitors in cancer treatment. In various embodiments, immune checkpoint proteins or receptors modulate T cell responses (for example, as outlined in Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In various embodiments, immune checkpoint proteins or receptors modulate the NK cell response (as outlined, e.g., Davis, et al., Semin Immunol. (2017) 31:64-75, and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688).

[0454] Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane domain and immunoglobulin domain-containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily members 11 (IGSF11, VSIG3); natural killer cytotoxic receptor ligand 3 (NCR3LG1, B7H6); HERV-H LTR-related 2 (HHLA2, B7H7); 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); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-related (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-related protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); PVR-related immunoglobulin domain-containing (PVRIG, CD112R); possessing Ig and ITIM domains T cell immune receptor (TIGIT); T cell immunoglobulin and mucin domain-containing 4 (TIMD4; TIM4); Hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); Galectin 9 (LGALS9); Lymphocyte activation 3 (LAG3, CD223); Signal transduction lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150); Lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member Bar 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid initial transcript 1E (RAET1E; ULBP4); retinoic acid initial transcript 1G (RAET1G; ULBP5); retinoic acid initial transcript 1L (RAET1L; ULBP6); lymphocyte activation 3 (CD22 3); Killer cell immunoglobulin-like receptor (KIR); Killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); Killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); Killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C); Killer cell lectin-like receptor C3 (KLRC3, NKG2E); Killer cell lectin-like receptor C4 (KLRC4, NKG2F); Killer cell immunoglobulin-like receptor Cellular receptor, two Ig domains, and a long cytoplasmic terminal 1 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and a long cytoplasmic terminal 2 (KIR2DL2); killer cell immunoglobulin-like receptor, two Ig domains, and a long cytoplasmic terminal 3 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains, and a long cytoplasmic terminal 1 (KIR3DL1); and killer cell lectin-like receptor D1 (KLRD1).

[0455] In various embodiments, the compounds described herein are combined with one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. Examples of T cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, 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 receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-associated immunoglobulins Epidemic globulin domain-containing receptors (PVRIG, CD112R); T cell immune receptors with Ig and ITIM domains (TIGIT); Lymphocyte activation receptor 3 (LAG3, CD223); Hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); Galectin 9 (LGALS9); Killer cell immunoglobulin-like receptor (KIR); Killer cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic terminal 1 (KIR2DL1); Killer cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic terminal 2 (KIR2DL2); Killer cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic terminal 3 (KIR2DL3); and Killer cell immunoglobulin-like receptor with three Ig domains and a long cytoplasmic terminal 1 (KIR3DL1). In various embodiments, the compounds described herein are combined 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 (B. 7-1) CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4); and poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, for example, Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0456] In various embodiments, the agents described herein are combined with one or more agonists or activators of one or more T cell-stimulating immune checkpoint proteins or receptors. Examples of NK cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, the following: killer cell immunoglobulin-like receptor with three Ig domains and a long cytoplasmic terminal 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic terminal 1 (KIR2DL1); killer cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic terminal 2 (KIR2DL2); killer cell immunoglobulin-like receptor with two Ig domains and a long cytoplasmic terminal 3 (KIR2DL3); killer cell immunoglobulin-like receptor with three Ig domains and a long cytoplasmic terminal 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin-like receptor D1 (KLRD1, CD94). In various embodiments, the compounds described herein are combined with one or more agonists or activators of one or more NK cell-stimulating immune checkpoint proteins or receptors. Examples of NK cell-stimulating immune checkpoint proteins or receptors include, but are not limited to, CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7), as described in claim 306. For example, Davis See 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.

[0457] In various embodiments, the compounds described herein are combined with inhibitors of CD47 (IAP, MER6, OA3; NCBI gene ID: 961). Examples of CD47 inhibitors include, but are not limited to, anti-CD47 mAbs (Vx-1004), anti-human CD47 mAbs (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibody (Hu5F9-G4), NI-1701, NI-1801, RCT-1938, and TTI-621.

[0458] In some embodiments, one or more immune checkpoint inhibitors include protein-based (e.g., antibody or fragment thereof, or antibody mimetic) inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, one or more immune checkpoint inhibitors include small organic molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4.

[0459] Examples of CTLA4 inhibitors that can be administered concurrently include ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, and AGEN-2. 041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, BPI-002, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI Examples include, but are not limited to, -5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

[0460] Anti-CTLA-4 (cytotoxic T lymphocyte protein 4) antibodies such as tremelimumab, ipilimumab (BMS-734016), AGEN-1884, BMS-986218, AGEN1181, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, and BA-3071;

[0461] CTLA-4 (cytotoxic T lymphocyte protein 4) inhibitors such as BPI-002; TLR-3 agonists / interferon inducers such as poly-ICLC (NSC-301463);

[0462] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors / antibodies that can be administered concurrently include, but are not limited to, pembrolizumab, nivolumab, semiprimab, pizilizumab, AMG-404, AMP-224, MEDI0680 (AMP-514), spruarizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislerizumab), GEN-1046 (PD-L1 / 4-1BB), GLS-010 (WBP-3055) ), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001 (Tripalimab), JNJ-63723283, Genolizumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (Camrelizumab), Sym-021, ABBV-181, PD1~PIK, BAT-1306 (MSB0010718C), CX-072, CBT-502, TSR-042 (Dostalimab), MSB-231 1. JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (Scintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD -013(PD-1 / LAG-3), FS-118(LAG-3 / PD-L1), MGD-019(PD-1 / CTLA4), KN-046(PD-1 / CTLA4), MEDI-5752(CTLA4 / PD-1), RO-7121661(PD-1 / TIM-3), XmAb -20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), M7824 (PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1),RG7769 (PD-1 / TIM3), and INBRX-105 (4-1BB / PDL1), RG-7446 (Tecentriq, atezolizumab), ABBV-181, nivolumab (OPDIVO®, BMS-936558, MDX-1106), pembrolizumab (KEYTRUDA®, MK-3477, SCH-900475, lambrolizumab, CAS registry numbers 1374853-91~4), pyridylizumab, PF-06801591, BGB-A317 (Te Disrelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), CS-1003, HLX-10, MGA-012, BI-754091, REGN-2810 (semiprimab), AGEN-2034, JS-001 (tripalimab), JNJ-63723283, Genolizumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181, AK, Antiprogrammed cell death ligands 1 (anti-PD-L1), such as -105, PD1~PIK, BAT-1306, and BMS-936559, atezolizumab (MPDL3280A), durvalumab (MEDI-4736), avelumab, CK-301 (MSB0010718C), MEDI-0680, CX-072, CBT-502, PDR-001 (spartalizumab), PDR001 + Tafinla r(registered trademark)+Mekinist(registered trademark), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001(WBP-3155, KN-035, IBI-308(sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015(IMC-001), BCD-135, FAZ-053, TQB-2450, and MDX1105-01;

[0463] PD-L1 / VISTA antagonists such as CA-170;

[0464] PD-1 / PD-L1 inhibitors such as INCB086550, GS-4224, and GS-4416;

[0465] PD-L1 / EGFR inhibitors such as GNS-1480 (lazertinib);

[0466] PD-1 / CTLA-4 inhibitors such as PF-06936308;

[0467] PD-L1 / PD-L2 vaccines such as O-120+IO-103;

[0468] Anti-PVRIG antibodies such as COM-701;

[0469] Anti-TIGIT antibodies such as BMS-986207, RG-6058, and AGEN-1307;

[0470] Anti-TIM-3 antibodies such as TSR-022, LY-3321367, MBG-453, and INCAGN-2390;

[0471] Anti-LAG-3 (lymphocyte activation) antibodies such as relatrimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385, and TSR-033;

[0472] Monoclonal antibodies for the anti-killer cell immunoglobulin-like receptor (KIR3DL1); KIR; NCBI gene ID: 3811), such as lirirumab (IPH-2102) and IPH-4102;

[0473] Anti-NKG2a antibodies such as monalizumab;

[0474] Anti-VISTA antibodies such as HMBD-002;

[0475] Anti-CD27 antibodies such as valrirumab (CDX-1127);

[0476] Anti-CD70 antibodies such as AMG-172;

[0477] Anti-CD20 antibodies such as obinutuzumab, IGN-002, and PF-05280586;

[0478] Anti-ICOS antibodies such as JTX-2011 and GSK3359609;

[0479] ICOS agonists such as ICOS-L.COMP (Gariepy, J. et al. 106th Annual Meet Am Assoc Immunologists (AAI) (May 9-13, San Diego) 2019, Abst 71.5). Agonists or activators of members of the TNF receptor superfamily (TNFRSF).

[0480] In various embodiments, the compounds described herein include one or more members of the TNF receptor superfamily (TNFRSF), such as TNFRSF1A (NCBI gene ID: 7132), TNFRSF1B (NCBI gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI gene ID: 7293), TNFRSF5 (CD40; NCBI gene ID: 958), TNFRSF6 (FAS, NCBI gene ID: 355), and TNFRSF7 (CD2 7. 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), TNF RSF10D (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 (NG) It is combined with one or more agonists from among FR (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).

[0481] Examples of anti-TNFRSF4 (OX40) antibodies that may be administered concurrently include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tavorixizumab), 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.

[0482] Exemplary anti-TNFRSF5 (CD40) antibodies that may be administered concurrently include, but are not limited to, RG7876, SEA-CD40, APX-005M, ABBV-428, and ABBV-927.

[0483] In some embodiments, the anti-TNFRSF7 (CD27) antibody varylumab (CDX-1127) is administered concurrently.

[0484] Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that may be administered concurrently include, but are not limited to, urelumab, utomirumab (PF-05082566), AGEN2373, and ADG-106.

[0485] In some embodiments, the anti-TNFRSF17 (BCMA) antibody GSK-285791 Drug 6 is administered simultaneously.

[0486] Examples of anti-TNFRSF18(GITR) antibodies that may be co-administered include, but are not limited to, 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, co-targeted TNFRSF4(OX40), and TNFRSF18(GITR) are co-administered. Such antibodies are described, for example, in International Publication Nos. 2017096179 and 2018089628.

[0487] Examples of anti-TRAILR1, anti-TRAILR2, anti-TRAILR3, and anti-TRAILR4 antibodies that can be administered concurrently include, but are not limited to, ABBV-621.

[0488] Examples of bispecific antibodies targeting TNFRSF family members that can be administered concurrently include, but are not limited to, PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), AFM-13 (CD16 / CD30), REGN-1979 (CD20 / CD3), AMG-420 (BCMA / CD3), INHIBRX-105 (4-1BB / PDL1), FAP-4-IBBL (4-1BB / FAP), XmAb-13676 (CD3 / CD20), RG-7828 (CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), and IMM-0306 (CD47 / CD20), as well as AMG-424 (CD38 / CD3). Adenosine production and signal transduction

[0489] Adenosine receptor signaling pathways include A1R, A2AR, A2BR, A3R, CD73, CD39, and CD26.

[0490] Anti-CD73 antibodies include MEDI-9447 (oleculumab), CPX-006, IPH-53, BMS-986179, and NZV-930.

[0491] CD73 inhibitors include AB-680, PSB-12379, PSB-12441, PSB-12425, and CB-708.

[0492] PBF-1662 is an example of a CD39 / CD73 inhibitor.

[0493] TTX-030 is an example of an anti-CD39 antibody.

[0494] Examples of adenosine A2A receptor antagonists include CPI-444, AZD-4635, preradianant, and PBF-509.

[0495] Examples of adenosine deaminase inhibitors include pentostatin and cladrivir. Bi-Specific T-Cell Engager

[0496] In various embodiments, the compounds described herein are bispecific T cell inducers. T-cell engager) (e.g., without Fc) or anti-CD3 bispecific antibody (e.g., It is combined with (which has Fc). Examples of anti-CD3 bispecific antibodies, or BiTEs, that can be administered simultaneously include AMG-160 (PSMA / CD3) and AMG-212 (PS MA / CD3), AMG-330(CD33 / CD3), AMG-420(BCMA / CD3), AMG-427(FLT3 / CD3), AMG-562(CD19 / CD3), AMG-596(EGFRvIII / CD3), AM G-673 (CD33 / CD3), AMG-701 (BCMA / CD3), AMG-757 (DLL3 / CD3), JNJ-64052781 (CD19 / CD3), AMG-211 (CEA / CD3), BLINCYTO (registered trademark) )(CD19 / CD3), RG7802(CEA / CD3), ERY-974(CD3 / GPC3), huGD2-BsAb(CD3 / GD2), PF-06671008(cadherin / CD3), APVO436(CD123 / CD3), ERY974, flotetuzumab(CD123 / CD3), GEM333(CD3 / CD33), GEMoab(CD3 / PSCA), REGN-1979(CD20 / CD3), REGN-5678(PSMA / CD28), MCLA-117 (CD3 / CLEC12A), JNJ-0819, JNJ-7564 (CD3 / Heme), JNJ-63709178 (CD123 / CD3), MGD-007 (CD3 / gpA33), MGD-009 (CD3 / B7H3), IMCgp100 (CD3 / gp100), XmAb-14045 (CD123 / CD3), XmAb-13676 (CD3 / CD20), XmAb-18087 (SSTR2 / CD3), Katsumakisomab (CD3 / EpC Examples include AM), REGN-4018 (MUC16 / CD3), RG6026, RG6076, RG6194, RG-7828 (CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), GRB-1302 (CD3 / Erbb2), GRB-1342 (CD38 / CD3), GEM-333 (CD3 / CD33), PF-06863135 (BCMA / CD3), and SAR440234 (CD3 / CDw123). The anti-CD3 binding bispecificity molecule may or may not have Fc as needed.Exemplary bispecific T cell inducers that can be administered concurrently target CD3 and tumor-associated antigens described herein (e.g., CD19 (e.g., blinatumomab); CD33 (e.g., AMG330); CEA (e.g., MEDI-565); receptor tyrosine kinase-like orphan receptor 1 (ROR1)) (Gohilet al. Oncoimmunology. (2017) May 17;6(7):e1326437); PD-L1 (Horn et al. Oncotarget. 2017 Aug 3;8(35):57964-57980); and EGFRvIII (Yang et al. Cancer Lett. 2017 Sep 10;403:224-230). Dual- and triple-specific natural killer (NK) cell-inducing factors

[0497] In various embodiments, the compounds described herein are combined with bispecific NK cell inducers (BiKE) or trispecific NK cell engagers (TriKE) (e.g., without Fc), or bispecific antibodies against NK cell activating receptors (e.g., 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 (mediating 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). Examples of co-administered anti-CD16 bispecific antibodies, BiKEs, or TriKEs include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). The anti-CD16-binding bispecific molecule may or may not have an Fc, as required. The example co-administered bispecific NK cell inducers target CD16 and one or more tumor-associated antigens described herein (e.g., CD19, CD20, CD22, CD30, CD33, CD123, EGFR, EpCAM, ganglioside GD2, HER2 / neu, HLA class II, and FOLR1). For BiKEs and TriKEs, see, for example, Felices et al., Methods Mol Biol. (2016) 1441:333. See -346;Fang, et al., Semin Immunol. (2017) 31:37-54. MCL1 apoptosis regulator, BCL2 family member (MCL1) inhibitor

[0498] In various embodiments, the compounds described herein are combined with MCL1 apoptosis regulators and inhibitors of BCL2 family members (MCL1, TM; EAT; MCL1L; MCL1S; MCL1; BCL2L3; MCL1-ES; bcl2-L-3; MCL1 / EAT; NCBI gene ID: 4170). Examples of MCL1 inhibitors include AMG-176, AMG-397, S-64315, and AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, as well as those described in International Publication Nos. 2018183418, 2016033486, and 2017147410. SHP2 inhibitors

[0499] In various embodiments, the compounds described herein are combined 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, SAR442720, and those described in International Publication Nos. 2018172984 and 2017211303. Hematopoietic progenitor cell kinase 1 (HPK1) inhibitors

[0500] In various embodiments, the compounds described herein are combined with inhibitors of mitogen-activated protein 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. 2018183956, 2018183964, 2018167147, 2018183964, 2016205942, 2018049214, 2018049200, 2018049191, 2018102366, 2018049152, and 2016090300. Apoptosis signal-regulated kinase (ASK) inhibitors

[0501] In various embodiments, the compounds described herein are combined 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 include, but are not limited to, those described in International Publication Nos. 2011 / 008709 (Gilead Sciences) and 2013 / 112741 (Gilead Sciences). Bruton's tyrosine kinase (BTK) inhibitors

[0502] In various embodiments, the compounds described herein are combined 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), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebralutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, Examples include, but are not limited to, TAS-5315, Calquence + AZD6738, and Calquence + danvatirsen. Cyclin-dependent kinase (CDK) inhibitors

[0503] In various embodiments, the compounds described herein include: 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 combined with inhibitors 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), and 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, but are not limited to, abemaciclib, arbocidicib (HMR-1275, flavopyridol), AT-7519, dinaciclib, ibrance, FLX-925, LEE001, palbociclib, ribociclib, rigosertib, selinexol, UCN-01, SY1365, CT-7001, SY-1365, G1T38, milciclib, trilaciclib, PF-06873600, AZD4573, and TG-02. Discoidine domain receptor (DDR) inhibitors

[0504] In various embodiments, the compounds described 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, but are not limited to, dasatinib, and those disclosed in 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). Histone deacetylase (HDAC) inhibitors

[0505] In various embodiments, the compounds described herein are combined with inhibitors of histone deacetylases, such as histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; gene ID: 9734). Examples of HDAC inhibitors include, but are not limited to, abexinostat, ACY-241, AR-42, BEBT-908, bellinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, gibinostat, mosetinostat, panobinostat, prasinostat, xinostat (JNJ-26481585), resminostat, licorinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamstine, remetinostat, entinostat, romidepsin, and tusidinostat. Indreamine-pyrrole-2,3-dioxygenase (IDO1) inhibitor;

[0506] In various embodiments, the compounds described herein are indoleamine 2,3-dioxy It is used in combination with an inhibitor of genase 1 (IDO1, NCBI gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919 vaccines, PF-06840003, pyranonaphthoquinone derivative (SN-35837), resminostat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916. Janus kinase (JAK) inhibitors

[0507] In various embodiments, the compounds described herein are combined 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, but are not limited to, AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), restaurtinib, momerotinib (CYT0387), NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019. Matrix metalloproteinase (MMP) inhibitors

[0508] In various embodiments, the compounds described 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 used in combination with inhibitors of MMP15 (NCBI gene ID: 4324), MMP16 (NCBI gene ID: 4325), MMP17 (NCBI gene ID: 4326), MMP19 (NCBI gene ID: 4327), MMP20 (NCBI gene ID: 9313), MMP21 (NCBI gene ID: 118856), MMP24 (NCBI gene ID: 10893), MMP25 (NCBI gene ID: 64386), MMP26 (NCBI gene ID: 56547), MMP27 (NCBI gene ID: 64066), and / or MMP28 (NCBI gene ID: 79148). Examples of MMP9 inhibitors include, but are not limited to, marimastat (BB-2516), cipestat (Ro 32-3555), GS-5745 (andecaliximab), and those described in International Publication No. 2012 / 027721 (Gilead Biologics). RAS and RAS pathway inhibitors

[0509] In various embodiments, the compounds described herein include the KRAS 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 oncogene, GTPase (NRAS; also known as NS6;CMNS;NCMS;ALPS4;N-ras;NRAS1;NCBI gene ID:4893); HRas oncogene, GTPase (HRAS; also known as CTLO;KRAS;HAMSV;HRAS1;KRAS2;RASH1;RASK2;Ki-Ras;p21ras;C- It is combined with an inhibitor of H-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 (e.g., transcription inhibitor) level or the polypeptide (e.g., GTPase enzyme inhibitor) level. In some embodiments, the inhibitor targets one or more proteins in the Ras pathway, for example, inhibiting one or more of EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT, and mTOR. Examples of K-Ras inhibitors that can be administered concurrently include ARS-1620(G12C), SML-8-73-1(G12C), compound 3144(G12D), Kobe0065 / 2602(RasGTP), RT11, MRTX-849(G12C), and K-Ras(G12D) selective inhibitory peptides, including KRpep-2(Ac-RRRRCPLYISYDPVCRRRR-NH2)(SEQ ID NO: 108) and KRpep-2d(Ac-RRRRCPLYISYDPVCRRRR-NH2)(SEQ ID NO: 109). Examples of KRAS mRNA inhibitors include anti-KRAS U1 adapter, AZD-4785, siG12D-LODER(trademark), and siG12D exosome. Exemplary MEK inhibitors that may be administered concurrently include binimetinib, cobimetinib, PD-0325901, pimacertib, RG-7304, selumetinib, trametinib, and those described below and herein. An example of an AKT inhibitor that may be administered concurrently is RG7440. Exemplary Raf dimer inhibitors that may be administered concurrently with BGB-283, HM-95573, LXH-254, LY-3009120, RG7304, and TAK-580. Exemplary ERK inhibitors that may be administered concurrently are LTT-462, LY-3214996, MK-8353, labocertinib, and urixertinib. An example of a Ras GTPase inhibitor that may be administered concurrently is lyzigocertib.Examples of PI3K inhibitors that may be administered concurrently include idelalisib (Zydelig®), alpelisib, buparlisib, pitilisib, and those described below and herein. Examples of PI3K / mTOR inhibitors that may be administered concurrently include dactricib, omiparisib, and boxalisib. In certain embodiments, Ras-driven cancers with CDKN2A mutations (e.g., NSCLC) may be inhibited by concurrent 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. For example, see Booth, et al., Cancer Biol Ther. 2018 Feb 1;19(2):132-137.

[0510] K-Ras GTPase inhibitors: Examples of KRAS inhibitors include AMG-510, MRTX-849, COTI-219, MRTX-1257, ARS-3248, ARS-853, and WDB-178. Mitogen-activated protein kinase (MEK) inhibitors

[0511] In various embodiments, the compounds described herein are combined with inhibitors of mitogen-activated protein kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI gene ID: 5609). Examples of MEK inhibitors include antroquinonol, binimetinib, CK-127, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib + trametinib, PD-0325901, pimacertib, LTT462, AS703988, CC-90003, refametinib, TAK-733, CI-1040, and RG7421. Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0512] In various embodiments, the compounds described 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-α, p110-α; NCBI gene ID: 5290); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit β (PIK3CB, P110BETA, PI3 It is combined with inhibitors of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit γ (PIK3CG, PI3CG, PI3K, PI3Kγ, PIK3, p110γ, p120-PI3K; gene ID: 5494); and / or inhibitors of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit δ (PIK3CD, APDS, IMD14, P110DELTA, PI3K, p110D; NCBI gene ID: 5293). In some embodiments, the PI3K inhibitor is a pan-PI3K inhibitor.Examples of PI3K inhibitors include ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY10824391, BEZ235, buparisib (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. 2005 / 113556 (ICOS), International Publication No. 2013 / 052699 (Gilead Examples include, but are not limited to, the compounds described in Calistoga, Gilead Calistoga (No. 2013 / 116562), Gilead Calistoga (No. 2014 / 100765), Gilead Calistoga (No. 2014 / 100767), and Gilead Sciences (No. 2014 / 201409). Spleen tyrosine kinase (SYK) inhibitors

[0513] In various embodiments, the compounds described herein are combined with inhibitors of spleen-associated tyrosine kinase (SYK, p72-Syk, gene ID: 6850). Examples of SYK inhibitors include, but are not limited to, 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), and those described in U.S. Patent No. 8,450,321 (Gilead Connecticut) and U.S. Patent Application Publication No. 2015 / 0175616. Toll-like receptor (TLR) agonist

[0514] In various embodiments, the compounds described herein are 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), TLR It is combined with agonists of TLR8 (NCBI gene ID: 51311), TLR9 (NCBI gene ID: 54106), and / or TLR10 (NCBI gene ID: 81793).Examples of TLR7 agonists that may be administered concurrently include DS-0509, GS-9620, 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, and U.S. Patent Application Publication No. 20100143301 (Gilead Sciences), U.S. Patent Application Publication No. 20110098248 (Gilead Sciences), and U.S. Patent Application Publication No. 20090047249 (Gilead Sciences). (Sciences), U.S. Patent Publication No. 20140045849 (Janssen), U.S. Patent Publication No. 20140073642 (Janssen), International Publication No. 2014056953 (Janssen), International Publication No. 2014076221 (Janssen), International Publication No. 2014128189 (Janssen), U.S. Patent Publication No. 20140350031 (Janssen), International Publication No. 2014 / 023813 (Janssen), U.S. Patent Publication No. 20080234251 (Array Biopharma), U.S. Patent Publication No. 20080306050 (Array Biopharma), U.S. Patent Publication No. 20100029585 (Ventirx Examples of compounds disclosed in U.S. Patent Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Publication No. 20140275167 (Novira Therapeutics), and U.S. Patent Publication No. 20130251673 (Novira Therapeutics) include, but are not limited to, those disclosed in U.S. Patent Publication No.The TLR7 / TLR8 agonist that can be administered concurrently is NKTR-262. Examples of concurrently administered TLR8 agonists 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), U.S. Patent Application Publication No. 201400736. 42 (Janssen), International Publication No. 2014 / 056953 (Janssen), International Publication No. 2014 / 076221 (Janssen), International Publication No. 2014 / 128189 (Janssen), US Patent Application Publication No. 20140350031 (Janssen), International Publication No. 2014 / 023813 (Janssen), US Patent Application Publication No. 20080234251 (Array Array Biopharma, U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Examples of TLR9 agonists that may be co-administered include, but are not limited to, those disclosed in (Therapeutics) and U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics). Examples of TLR3 agonists include, but are not limited to, agatrimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod (MGN-1703), CYT-003, CYT-003-QbG10, and PUL-042. - Toll-like receptor 8 (TLR8) inhibitors: Examples of TLR8 inhibitors include, but are not limited to, E-6887, IMO-8400, IMO-9200, and VTX-763. - Toll-like receptor 8 (TLR8) agonists: Examples of TLR8 agonists include, but are not limited to, MCT-465, motlimod, GS-9688, and VTX-1463. - Toll-like receptor 9 (TLR9) inhibitors: Examples of TLR9 inhibitors include, but are not limited to, AST-008, IMO-2055, IMO-2125, lephyrimod, ritenimod, MGN-1601, and PUL-042.

[0515] Examples of TLR7 / TLR8 agonists include NKTR-262, IMO-4200, MEDI-9197 (tellatrimod), and reciquimod.

[0516] Examples of TLR7 agonists include DS-0509, GS-9620, LHC-165, and TMX-101 (imiquimod).

[0517] Examples of STING agonists include ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, and SR-8291.

[0518] In certain embodiments, the compounds described herein are combined with TLR agonists. Examples of TLR agonists include, but are not limited to, refitorimod, chilsotrimod, lintatrimod, DSP-0509, AL-034, G-100, covitrimod, AST-008, motrimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, and tellatrimod.

[0519] In some embodiments, the therapeutic agent is a small organic compound. In some embodiments, the therapeutic agent is a Toll-like receptor (TLR) agonist or activator, or an interferon gene stimulator (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic diAMP.

[0520] In some embodiments, the compounds described herein are combined with RIG-I modifiers such as RGT-100, or NOD2 modifiers such as SB-9200 and IR-103.

[0521] In certain embodiments, the compounds described herein are combined with interleukin agonists such as IL-2, IL-7, IL-15, IL-10, and IL-12, and examples of IL-2 agonists include proleukins (aldesleukins, IL-2); pegylated IL-2 (e.g., NKTR-214); and modified variants of IL-2 (e.g., THOR-707). Examples of IL-15 agonists include ALT-803, NKTR-255, and hetIL-15, interleukin-15 / Fc fusion protein, AM-0015, and NIZ-985.

[0522] In certain embodiments, the compounds described herein are combined with an Flt3 agonist. Indreamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors

[0523] In various embodiments, the compounds described herein are combined with inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1, NCBI gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919 vaccine, PF-06840003, pyranonaphthoquinone derivative (SN-35837), resminostat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

[0524] In some embodiments, the therapeutic agent is a small organic compound. In some embodiments, the therapeutic agent is a Toll-like receptor (TLR) agonist or activator, or an interferon gene stimulator (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic diAMP.

[0525] In some embodiments, the compounds described herein are combined with RIG-I modifiers such as RGT-100, or NOD2 modifiers such as SB-9200 and IR-103. Tyrosine kinase inhibitors (TKIs)

[0526] In various embodiments, the compounds described herein are combined with tyrosine kinase inhibitors (TKIs). TKIs may target epidermal growth factor receptor (EGFR) as well as receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include axitinib, afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bustinib, brigatinib, cabozantinib, cejiranib, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391 (Src), lapatinib, and restaurtinib. Examples include, but are not limited to, lenvatinib, midostaurin, nintedanib, ODM-203, olmutinib, osimertinib (AZD-9291), pazopanib, ponatinib, poziotinib, quizartinib, radotinib, rosiletinib, sulfatinib (HMPL-012), sunitinib, famitinib, L-malate (MAC-4), tiboanib, TH-4000, tiboanib, and MEDI-575 (anti-PDGFR antibody), TAK-659, and cabozantinib. Chemotherapy agents

[0527] In various embodiments, the compounds described herein are combined with chemotherapeutic agents or antineoplastic agents.

[0528] As used herein, the terms “chemotherapy agent” or “chemotherapy drug” (or “chemotherapy” when referring to treatment with a chemotherapy agent) mean to encompass any non-proteinogenic (e.g., non-peptidogenic) chemical compound useful in the treatment of cancer. Examples of chemotherapy agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and biposulfan; aziridines such as 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, particularly cryptophycin. Toficin 1 and Cryptophycin 8; Dorastatin; Duocalmycin, including synthetic analogs KW-2189 and CBI-TMI; Erythebin; 5-Azacitidine; Pancratistatin; Sarcodictiin; Spongestatin; Chlorambucil, Chlornafadin, Cyclophosphamide, Gluphosphamide, Evophosphamide, Bendamustine, Estramustine, Ifosfamide, Mechloretamine, Mechloretamine Oxide Hydrochloride, Melphalan, Novembitin, Fenesterine, Prednimustine, Trophosphamide, and Nitrosoureas such as Carmustine, Chlorozotocin, Foremustine, Lomustine, Nimustine, and Ranimustine;Endiine antibiotics (e.g., calcifemycin, especially calicheamicin γII and calicheamicin phiI1), dinemycin including dinemycin A, bisphosphonates such as clodronate, esperamycin, neocardinostatin chromophores and related chromoprotein enediine antibiotic chromophores, acrasinomycin, actinomycin, anthramycin, azaserin, bleomycin, kactinomycin, carabicin, carminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, detrubicin 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, merceromycin, mitomycin such as mitomycin C, mycophenolic acid, nogaramycin, olibomycin, peplomycin, porphyromycin, puromycin, keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinosuci Antibiotics such as iodine and zolubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as demopterin, methotrexate, pteropterin, and trimethrexate; purine analogs such as cladribine, pentostatin, fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and phloxuridine, carsterone, propio Androgens such as dromostanolone phosphate, epithiostanol, mepithiostan, and testotrachtone; anti-adrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as phloric acid; radiotherapy agents such as radium-223 and 177-Lu-PSMA-617; trichothecenes, especially T-2 toxin, beraclin A, loridine A, and anguidin; taxoids such as paclitaxel (TAXOL®), Abraxane, docetaxel (TAXOTERE®), cabazitaxel, BIND-014, and tesetaxel;Platinum analogs such as cisplatin and carboplatin, NC-6004 nanoplatin; acegraton; aldofsphamide glycosides; aminolevulinic acid; enyluracil; amsacrin; hestrabucil; bisanthren; edatrexate; defofamine; demecolsin; diazicone; elformutin; eriptinium acetate; epotilon; etogluside; gallium nitrate; hydroxyurea; lentinan; leucovorin; ronidamine; maytansinoids such as maytansin and ansamitosin; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Fenamet; Pirarubicin; Rosoxantrone; Fluoropyrimidine; Folic acid; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; Polysaccharide-K (PSK); Lazoxane; Rhizoxin; Schizophyllan; Spirogermanium; Tenuazonic acid; Trabectedin, Triadiquan; 2,2',2''-Trichlorotriemylamine; Urethane Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitractol; Pipobroman; Gacitosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa; Chlorambucil; Gemcitabine (GEMZAR®); 6-Thiogunine; Mercaptopurine; Methotrexate; Vinblastine; Platinum; Etoposide (VP-16); Ifosfamide; Mito Xanthrone; bancristine; vinorelbine (NAVELBINE®); novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylornithine (DFMO); retinoids such as retinoic acid; capecitabine; NUC-1031; FOLFOX (folic acid, 5-fluorouracil, oxaliplatin); FOLFIRI (folic acid, 5-fluorouracil, irinotecan); 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, are examples, but are not limited thereto. Such drugs can be conjugated to an antibody or any target drug described herein to produce an antibody-drug conjugate (ADC) or a targeted drug conjugate. Anti-hormone drugs

[0529] Furthermore, the definition of "chemotherapeutic agents" also 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.

[0530] Examples of anti-estrogens and SERMs include, for example, tamoxifen (including NOLVADEX®), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxyfen, keoxyfen, LY117018, onapristone, and toremifene (FARESTON®).

[0531] 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®).

[0532] Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, and ODM-204.

[0533] An example of a progesterone receptor antagonist is onapristone. Anti-angiogenic agents

[0534] In various embodiments, the compounds described herein are combined 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, metalloproteinase- Tissue inhibitors of 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 (crupein), sulfated chitin derivatives (prepared from snow crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, matrix metabolism regulators including proline analogs such as L-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, d,I-3,4-dehydroproline, thiaproline, α,α'-dipyridyl, β-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, Examples of effective inhibitors include, but are not limited to, totrexate, mitoxantrone, heparin, interferon, 2-macroglobulin serum, metalloproteinase-3 chicken inhibitor (ChIMP-3), chymostatin, β-cyclodextrin tetradecasulfate, eponemycin, fumagiline, sodium aurantithiomalate, d-penicillamine, β-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 these angiogenic growth factors, such as β-FGF, α-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF / SF, and Ang-1 / Ang-2. Antifibrotic agents

[0535] In various embodiments, the compounds described herein are combined with antifibrotic agents. Antifibrotic agents that may be administered concomitantly include, but are not limited to, 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 compounds disclosed in U.S. Patent No. 4,997,854, relating to compounds that inhibit LOX for the treatment of various pathological fibrotic conditions, which are incorporated herein by reference. Further exemplary inhibitors are described in U.S. Patents 4,943,593, 5,021,456, 5,059,714, 5,120,764, and 5,182,297 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 No. 2004-0248871, which are incorporated herein by reference.

[0536] Exemplary antifibrotic agents also 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.

[0537] Other antifibrotic agents are copper chelating agents that penetrate or do not penetrate cells. Exemplary compounds include indirect inhibitors that block aldehyde derivatives derived from the oxidative deamination of lysyl and hydroxylysyl residues by lysyl oxidase. Examples include thiolamins, particularly D-penicillamine, and their analogues, e.g., 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)butanesulfate, 2-acetamidoethyl-2-acetamidoethanethio Examples include sulfurphanate and sodium-4-mercaptobutane sulfinate trihydrate. Anti-inflammatory drugs

[0538] In various embodiments, the compounds described herein are combined with anti-inflammatory agents. Examples of anti-inflammatory agents include arginase (ARG1 (NCBI gene ID: 383), ARG2 (NCBI gene ID: 384)), carbonic anhydrase (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), 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 Examples of inhibitors include, but are not limited to, one or more of the following: prostaglandin endoperoxide synthase 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 kinase 8 (MAP3K8, TPL2; NCBI gene ID: 1326). In some embodiments, the inhibitor is a biantibody, such as a biantibody of COX-2 / COX-1, COX-2 / SEH, COX-2 / CA, and COX-2 / 5-LOX.

[0539] Examples of prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI gene ID: 5742) inhibitors that can be administered concurrently include, but are not limited to, mofezolac, GLY-230, and TRK-700.

[0540] Examples of prostaglandin endoperoxide synthase 2 (PTGS2, COX-2; NCBI gene ID: 5743) inhibitors that can be administered concurrently include, but are not limited to, 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, macoxib, NS-398, pamicogrel, parecoxib, robenacoxib, rofecoxib, lutecarpine, chilmacoxib, and zaltoprofen. Examples of dual COX1 / COX2 inhibitors that can be administered concurrently include, but are not limited to, HP-5000, lornoxicam, ketrolactromethamine, bromfenac sodium, and ATB-346. Examples of dual COX-2 / carbonic anhydrase (CA) inhibitors that can be administered concurrently include, but are not limited to, polmacoxib and imurecoxib.

[0541] 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, 2007124589, 2010100249, 2010034796, 2010034797, 2012022793, 2012076673, and 201 No. 2076672, No. 2010034798, No. 2010034799, No. 2012022792, No. 2009103778, No. 2011048004, No. 2012087771, No. 20121 61965, 2013118071, 2013072825, 2014167444, 2009138376, 2011023812, 2012110860, 20131535 Examples of compounds include, but are not limited to, those described in No. 35, No. 2009130242, No. 2009146696, No. 2013186692, No. 2015059618, No. 2016069376, No. 2016069374, No. 2009117985, No. 2009064250, No. 2009064251, No. 2009082347, No. 2009117987, and No. 2008071173. Metformin has also been found to inhibit the COX2 / PGE2 / STAT3 axis and can be administered concurrently. For example, see Tong, et al., Cancer Lett. (2017) 389:23-32 and Liu, et al. Oncotarget. (2016) 7(19):282 35-46.

[0542] 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), CA9 (NCB) Examples of inhibitors for one or more of the following (I 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, but are not limited to, acetazolamide, metazolamide, dorzolamide, zonisamide, brinzolamide, and diclofenamide. Dual COX-2 / CA1 / CA2 inhibitors that can be administered concurrently include CG100649.

[0543] Examples of arachidonic acid 5-lipoxygenase (ALOX5, 5-LOX; NCBI gene ID: 240) inhibitors that can be administered concurrently include, but are not limited to, meclofenamate sodium and dilauton.

[0544] Examples of inhibitors of soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI gene ID: 2053) that can be administered concurrently include, but are not limited to, the compounds described in International Publication No. 2015148954. Examples of dual inhibitors of COX-2 / SEH that can be administered concurrently include the compounds described in International Publication No. 2012082647. Examples of dual inhibitors of SEH and fatty acid amide hydrolase (FAAH; NCBI gene ID: 2166) that can be administered concurrently include the compounds described in International Publication No. 2017160861.

[0545] Examples of mitogen-activated protein kinase kinase 8 inhibitors that can be administered concurrently (MAP3K8, tumor progression locus 2, TPL2; NCBI gene ID: 1326) include GS-4875, GS-5290, BHM-078, and, for example, International Publication Nos. 2006124944, 2006124692, 2014064215, 2018005435, Teliet al. J Enzyme Inhib Med Chem.(2012)27(4):558-70, Gangwallet al.Curr Top Med Chem.(2013)13(9):1015-35, Wuet al.Bioorg Med Chem Lett.(2009)19(13):3485-8, Kaila,et al.,Bioorg Med Chem.(2007)15(19):6425-42, and Hu, et al.Bioorg Me Examples include, but are not limited to, those listed in Chem Lett. (2011) 21(16):4758-61. Tumor oxygenation agent

[0546] In various embodiments, the compounds described herein are combined with agents that promote or increase tumor oxygenation or reoxygenation, or prevent or reduce tumor hypoxia. Exemplary agents that may be administered concomitantly include, for example, hypoxia-inducible factor 1α (HIF-1α) inhibitors such as PT-2977 and PT-2385; VEGF inhibitors such as bevacizumab, IMC-3C5, GNR-011, tanibirumab, LYN-00101, and ABT-165; and / or oxygen carrier proteins (e.g., heme nitric oxide and / or oxygen-binding proteins (HNOX)) such as OMX-302 and HNOX proteins described, for example, in International Publications 2007 / 137767, 2007 / 139791, 2014 / 107171, and 2016 / 149562. Immunotherapy agents

[0547] In various embodiments, the compounds described herein are combined with immunotherapeutic agents.Examples of immunotherapeutic agents that can be administered concurrently include avagovomab, ABP-980, adecatumumab, aftumumab, alemtuzumab, altumomab, amatsuximab, anatumomab, alsitunomab, bavituximab, vectumomab, bevacizumab, bevacizumab biosimilar, vibatuzumab, blinatumamab, brentuximab, cantuzumab, catumakisomab, CC49, cetuximab, sitatuzumab, xixtumumab, cribatuzumab, conatumumab, dacetuzumab, darotuzumab, daratuzumab, detumomab, dinutuximab, and dorodizuma. Duligotumab, dusigitumab, eclomeximab, elotuzumab, emibetuzumab, encituzumab, erzmakisomab, etalacizumab, falletuzumab, ficratuzumab, figitumumab, frambotuzumab, futuximab, ganituzumab, gemtuzumab, girentuzumab, glenbatumumab, ibritumomab, igobomab, imugatuzumab, indatuximab, inotumomab, intetumumab, ipilimumab (YERVOY®, MDX-010, BMS-734016, and MDX-101), iratumumab, labet Tuzumab, lexatumumab, lintuzumab, rorbotuzumab, lucatumumab, mapatuzumab, matsuzumab, milatuzumab, minretuzumab, mitumomab, mogamulizumab, moxetumomab, moxetumomab pasdotox, naptumomab, nalnatuzumab, nesitumumab, nimotuzumab, nofetumomab, OBI-833, obinutuzumab, okalatuzumab, ofatumumab, oraratuzumab, onarutuzumab, oporutuzumab, olegobomab, panitumumab, pulsatuzumab, pasdotox, patrizumab, pemtumomab, pertuzumab, pintumoma Examples of 3F8 include, but are not limited to, bu, pritumumab, lakotumumab, radretumumab, ramucirumab (Cyramza®), rilotumumab, rituximab, lobatumumab, samarizumab, saturumamab, sibrotuzumab, siltuximab, solitomab, simtuzumab, takatuzumab, tapritumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, trastuzumab biosimilar, tucotzumab, ubirituximab, bertuzumab, borsetuzumab, botumumab, zaltumumab, and 3F8.Rituximab can be used to treat slow chronic B-cell cancers, including marginal zone lymphoma, WM, CLL, and small lymphocytic lymphoma. The combination of rituximab and chemotherapy agents is particularly effective.

[0548] The exemplified therapeutic antibodies may be further labeled or combined with radioactive isotope particles such as indium-111, yttrium-90 (90Y cribatuzumab), or iodine-131.

[0549] In some embodiments, the immunotherapy agent is an antibody-drug conjugate (ADC). Exemplary ADCs that can be administered concurrently include drug-conjugated antibodies, fragments thereof, or Examples include, but are not limited to, antibody mimetics targeting proteins or antigens listed above and herein (e.g., Table B). Examples of ADCs that can be administered concurrently include gemtuzumab, brentuximab, trastuzumab, inotuzumab, granbatumumab, anetuzumab, milbetuximab, depatuxizumab, novalpituzumab, vadasutuximab, rabetuzumab, sactuzumab, rifastuzumab, indusatuzumab, polatuzumab, pinatuzumab, coltuximab, indatuximab, milatuzumab, lovalpituzumab, ABBV-011, ABBV-2029, ABBV-321, ABBV-647, MLN0264 (anti-GCC, guanylyl cyclase C), and T-DM1 (tratuzumab emtansine, Kadcycla).SYD985 (anti-HER2, duocalmycin), milatuzumab doxorubicin (hCD74-DOX), brentuximab vedotin (ADCETRIS®), DCDT2980S, verantamab fodotin (GSK2857916), polatuzumab vedotin (RG-7596), SGN-CD70A, SGN-CD19A, inotuzumab ozogamicin (CMC-544), lorbotuzumab meltansine, SAR3419, isacutuzumab govitecan, enfortumab vedotin (ASG-22ME), ASG-15ME, DS-8 201(Trastuzumab deluctecan), 225Ac-Lintuzumab, U3-1402, 177Lu-Tetrexatetan-Tetroma, Tisotumab vedotin, Anetumab lavtansine, CX-2009, SAR-566658, W-0101, ABBV-085, Gemtuzumab ozogamicin, ABT-414, Glenbatumumab vedotin (CDX-011), Labetuzumab govitecan (IMMU-130), Sactuzumab govitecan (IMMU-132), Rifasuzumab vedotin, (RG-7599), Miratuzumab-doxorubicin (IMMU -110), Indatuximab tancin (BT-062), Pinatuzumab vedotin (RG-7593), SGN-LIV1A, SGN-CD33A, SAR566658, MLN2704, SAR408701, Robalbuspizumab tecilin, ABBV-399, AGS-16C3F, ASG-22ME, AGS67E, AMG172, AMG595, AGS-15E, BAY1129980, BAY1187982, BAY94-934 (Anetumab tancin), GSK2857916, Humax-TF-ADC (Tisotumab vedotin) IMGN289, IMGN529, IMGN853 (milbetuximab soravtansine), LOP628, PCA062, MDX-1203, MEDI-547, PF-06263507, PF-06647020, PF-06647263, PF-06664178, PF-06688992, PF-06804103, RG7450, RG7458, RG7598, SAR566658, SGN-CD33A, DS-1602, and DS-7300, DS-6157, DS-6000, TAK-164, MEDI2228, MEDI7247;ABBV-399, AGS-16C3F, ASG-22ME, AGS67E, AMG172, AMG575, BAY1129980, BAY1187982, BAY94-93 43, GSK2857916, Humax-TF-ADC, IMGN289, IMGN529, IMGN853, LOP628, PCA062, MDX-1203(BMS936 Examples of ADCs that may be administered concurrently include, but are not limited to, 561), MEDI-547, PF-06263507, PF-06647020, PF-06647263, PF-06664178, RG7450, RG7458, RG7598, SAR566658, SGN-CD19A, SGN-CD33A, SGN-CD70A, SGN-LIV1A, and SYD985. ADCs that may be administered concurrently are described in e.g., Lambert, et al., Adv Ther (2017) 34:1015-1035 and de Goeij, Current Opinion in Immunology (2016) 40:14-23.

[0550] Examples of therapeutic agents (e.g., anticancer agents or antineoplastic agents) that can be conjugated to drug-conjugated antibodies, fragments thereof, or antibody mimetic include monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), calitiamycin, ansamitosine, maytansine, or their analogues (e.g., meltansine / m Examples of anticancer or antineoplastic agents include, but are not limited to, tansine (DM1), ravtansine / soravtansine (DM4), anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepines (PBD), DNA crosslinking agent SC-DR002 (D6.5), duocalmycin, microtubule inhibitors (MTIs) (e.g., taxanes, vinca alkaloids, epotilone), pyrrolobenzodiazepines (PBD) or their dimers, and duocalmycin (A, B1, B2, C1, C2, D, SA, CC-1065), as well as other anticancer or antineoplastic agents described herein. Cancer gene therapy and cell therapy

[0551] In various embodiments, the compounds described herein are combined with oncogenetherapy and cell therapy. Oncogenetherapy and cell therapy include: insertion of normal genes into cancer cells to replace mutated or modified genes; gene modifications to silence mutated genes; genetic approaches to directly kill cancer cells; injection of immune cells designed to replace a large portion of the patient's own immune system, or to activate the patient's own immune system (T cells or natural killer cells) to kill or detect and kill cancer cells, for example, to enhance the immune response against cancer cells; and genetic approaches to further alter the endogenous immune responsiveness to cancer by modifying cell activity. cell therapy

[0552] In various embodiments, the compounds described herein are combined with one or more cell therapies. Exemplary cell therapies include, but are not limited to, the co-administration of one or more populations of natural killer (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophage (MAC) cells, tumor-infiltrating lymphocytes (TILs), and / or dendritic cells (DCs). In some embodiments, the cell therapy involves the co-administration of T cell therapy, e.g., populations of α / βTCR T cells, γ / δTCR T cells, regulatory T (Treg) cells, and / or TRuC® T cells. In some embodiments, the cell therapy involves the co-administration of NK cell therapy, e.g., NK-92 cells. If necessary, the cell therapy may involve the co-administration of autologous, syngeneic, or homogeneous cells to the subject.

[0553] In some embodiments, cell therapy involves the co-administration of cells containing a chimeric antigen receptor (CAR). In such therapies, a population of immune effector cells is engineered to express a CAR, which contains a tumor antigen-binding domain. In T-cell therapy, the T-cell receptor (TCR) is genetically engineered to target tumor-derived peptides presented on the surface of tumor cells.

[0554] Regarding the structure of CAR, in some embodiments, CAR includes an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain. In some embodiments, the intracellular domain includes a primary signaling domain, a costimulatory domain, or both a primary signaling domain and a costimulatory domain. In some embodiments, the primary signaling domain includes the functional signaling domain of one or more proteins selected from the group consisting of CD3ζ, CD3γ, CD3δ, CD3ε, common FcRγ (FCERIG), FcRβ (FcεRlb), CD79a, CD79b, FcγRIIa, DAP10, and DAP12.

[0555] In some embodiments, the co-stimulatory domain is a ligand that specifically binds to CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, CD2, CD7, LIGHT, NKG2C, B7-H3, CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD19, CD4, CD8α, CD8β, IL2Rβ, IL2Rγ, IL7Rα, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, ITGAE, CD103, ITGAL, CD1A (NCBI gene ID: 909), CD1B (NCBI gene ID: 910), CD1C (NCBI gene ID: 911), CD1D (NCBI gene ID: 912), CD1E (NCBI gene ID: 913), ITGAM, ITGAX, ITGB1, CD29, ITGB2 (CD18, LFA-1), ITGB7, TNFR2, TRANCE / RANKL, DNAM1 (CD226) It contains one or more functional domains of proteins selected from the group consisting of SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, NKp44, NKp30, NKp46, and NKG2D.

[0556] In some embodiments, the transmembrane domain is the α, β, or ζ chain of the T cell receptor, CD28, CD3ε, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, ICOS (CD278), 4-1BB (CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD19, IL2Rβ, IL2Rγ, IL7R, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1A, CD1B, CD1C, CD1D, CD1E, IT It contains a transmembrane domain of a protein selected from the group consisting of GAE, CD103, ITGAL, ITGAM, ITGAX, ITGB1, CD29, ITGB2 (LFA-1, CD18), ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (TACTILE), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp46, NKG2D, and NKG2C.

[0557] In some embodiments, the TCR or CAR antigen-binding domain or immunotherapy agent described herein (e.g., a monospecific or multispecific antibody or its antigen-binding fragment, or an antibody mimetic) binds to tumor-associated antigens (TAAs). In some embodiments, tumor-associated antigens include CD19; CD123; CD22; CD30; CD171; CS-1 (also known as CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24); type C lectin-like molecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor variant III (EGFRvlll); ganglioside G2 (GD2); ganglioside GD3 (αNeuSAc(2-8)αNeuSAc(2-3)βDGaip(1-4)bDGIcp(1-1)Cer); ganglioside GM3 (αNeuSAc(2-3)βDGalp(1-4)βDGIcp(1-1)Cer); TNF receptor superfamily member 17 (TNFRSF17, BCMA); Tn antigen ((Tn Ag) or (GaINAcu-Ser / Thr); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (RORI); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit α-2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor α (IL-11Ra); prostate stem cell antigen (PSCA); proteaseserine 21 (testisin or PRSS21); vascular endothelial growth factor Receptor 2 (VEGFR2); Lewis (Y) antigen; CD24; Platelet-derived growth factor receptor β (PDGFR-β); Stage-specific embryonic antigen-4 (SSEA-4); CD20; Delta-like antigen 3 (DLL3); Folate receptor α; Receptor tyrosine protein kinase, ERBB2 (Her2 / neu); Mucin 1, cell surface binding (MUC1); Epidermal growth factor receptor (EGFR); Neuronal adhesion molecule (NCAM); Prostase; Prostatic acid phosphatase (PAP); Elongation factor 2 mutation (ELF2M); Ephrin B2; Fibroblast activity Protein α (FAP); insulin-like growth factor 1 receptor (IGF-I receptor); carbonic anhydrase IX (CAIX); proteasome (prosome, macropain) subunit, β-type, 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consisting of cleavage cluster region (BCR) and Abelson mouse leukemia virus oncogene homolog 1 (Abl) (bcr-abl); tyrosinase; ephrin-type A receptor 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecule (sLe); transglutaminase 5 (TGS5); high molecular weight melanoma-associated antigen (HMWMAA); o-acetyl-GD2 ganglioside (OAcGD2); folate receptor β; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-associated (TEM7R); six transmembrane epithelial antigens of prostate I (STEAP1); claudin 6 (CLDN6); thyroid-stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5, member D (GPRCSD); X chromosome open reading frame 6 1 (CXORF61); CD97; CD179a; Anaplastic lymphoma kinase (ALK); Polysialic acid; Placenta-specific type 1 (PLAC1); Hexasaccharide moiety of globoH glycoceramide (GloboH); Mammary gland differentiation antigen (NY-BR-1); Uloplakin 2 (UPK2); Hepatitis A virus cell receptor 1 (HAVCR1); Adrenergic receptor β3 (ADRB3); Panexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); Lymphocyte antigen 6 complex, locus K9 (LY6K); Olfactory receptor 51E2 (ORS IE2); TCRγ alternative leading frame protein (TARP); Wilms' tumor protein (WT1);Cancer / testicular antigen 1 (NY-ESO-1); cancer / testicular antigen 2 (LAGE-la); melanoma-associated antigen 1 (MAGE-A1); ETS translocation variant gene 6 located on chromosome 12p (ETV6-AML); sperm protein 17 (SPA17); X antigen family, member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer testicular antigen-1 (MADCT-1); melanoma cancer testicular antigen-2 (MADCT-2); Fos-associated antigen 1; tumor protein p53 (p53); p53 variant; prostein; sulbibin; telomerase; prostate cancer tumor antigen-1 (PCTA-1 or galectin 8), recognized by T cell 1. Melanoma antigen (MelanA or MARTI); rat sarcoma (Ras) variant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoint; melanoma apoptosis inhibitor (ML-IAP); ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired-box protein Pax-3 (PAX3); androgen receptor; cyclin B1; v-myc tri-myeloma virus oncogene neuroblastoma-derived homolog (MYCN); Ras homolog family member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P450 1B1 (CYP IBI); CCCTC binding factor (zinc finger protein)-like (sibling of BORIS or imprinting site regulator), squamous cell carcinoma antigen 3 (SART3) recognized by T cells; paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); kinase anchor protein 4 (AKAP-4); synovial sarcoma, X-cleavage 2 (SSX2); receptor for advanced glycation end products (RAGE-I); renal ubiquitous protein 1 (RUI); renal ubiquitous protein 2 (RU2); regmine; human papillomavirus E6 (HPV E6); human papillomavirus E7 (HPV E7); enteric carboxylesterase; heat shock protein 70-2 mutation (mut hsp70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIRI); Fc fragment of IgA receptor (FCAR or CD89);Leukocyte immunoglobulin-like receptor subfamily A member 2(; The group is selected from LILRA2); CD300 molecule-like family member f (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module lymphocyte antigen 75 (LY75) including mucin-like hormone receptor-like 2 (EMR2); glypican 3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin λ-like polypeptide 1 (IGLL1). In some embodiments, the target is an epitope of tumor-associated antigen presented to the MHC.

[0558] In some embodiments, the tumor antigens are CD150, 5T4, ActRIIA, B7, TNF receptor superfamily member 17 (TNFRSF17, BCMA), CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148, CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261, CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD4 6, CD5, CD52, CD53, CD54, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1, CSPG4, ED-B fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, combined HER1-HER2, combined HER2-HER3, HERV-K, HIV-1 envelope glycoprotein gp120, HIV-1 envelope glycoprotein gp41, HLA-DR, HM1.24, HMW-MAA, Her2, Her2 / neu, IGF-1R, IL-11Rα, IL-13R-α2, IL-2, IL-22R-α, IL-6, IL-6R, Ia, Ii, L1-CAM, L1 cell adhesion molecule, Lewis Y, Ll-CAM, MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligand, NKG2D ligand, NYESO-1, OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R1, TRAIL-R1(DR4), TRAIL-R2(DR5), VEGF, VEGFR2, WT-I, G protein-binding receptor, alpha-fetoprotein (AFP), angiogenic factor, exogenous alloconjugate molecule (ExoCBM), oncogene product, antifolate receptor, c-Met, fetal carcinogen (CEA) The following are selected: cyclin (D1), ephrin B2, epithelial tumor antigen, estrogen receptor, fetal acetylcholine e receptor, folate-binding protein, gp100, hepatitis B surface antigen, κ chain, κ light chain, kdr, λ chain, livin, melanoma-associated antigen, mesoserin, mouse double microchromosome 2 homolog (MDM2), mucin 16 (MUC16), variant p53, variant ras, necrotic antigen, fetal cancer antigen, ROR2, progesterone receptor, prostate-specific antigen, tEGFR, tenacin, P2-microglobulin, and Fc receptor-like 5 (FcRL5).

[0559] Examples of cell therapies include AMG-119, Algenpantucel-L, ALOFISEL®, Sipuleucel-T, (BPX-501) Ribogen Recurcel (US Patent No. 9089520, International Publication No. 2016100236), AU-105, ACTR-087, activated allogeneic natural killer cells CNDO-109-AANK, MG-4101, AU-101, BPX-601, FATE-NK100, LFU- 835 hematopoietic stem cells, Imirecrucell-T, Baltarucel-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema, FT-1050 treated bone marrow stem cell therapy, CD4CARNK-92 cells, CryoStim, AlloStim, lentiviral transducer huCART-mesocells, CART-22 cells, EGFRt / 19-28z / 4-1BBL CAR T cells, autologous 4H11-28z / fIL-12 / EFGRt T cells, CCR5-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL-12, IMA-101, I MA-201, CARMA-0508, TT-18, CMD-501, CMD-503, CMD-504, CMD-502, CMD-601, CMD-602, CSG-005LAAP T-cell therapy, PD-1 knockout T-cell therapy (esophageal cancer / NSCLC), anti-MUC1 Examples include, but are not limited to, CAR T-cell therapy (esophageal cancer / NSCLC), anti-MUC1 CAR T-cell therapy + PD-1 knockout T-cell therapy (esophageal cancer / NSCLC), and anti-KRAS G12D mTCR PBL.

[0560] Additional drugs to target tumors include, but are not limited to, the following:

[0561] Alpha-fetoproteins such as ET-1402 and AFP-TCR;

[0562] Anthracus toxin receptor 1, such as in anti-TEM8 CAR T cell therapy;

[0563] 17 members of the TNF receptor superfamily (TNFRSF17, BCMA), including bb-2121(ide-cel), bb-21217, JCARH125, UCART-BCMA, ET-140, KITE-585, MCM-998, LCAR-B38M, CART-BCMA, SEA-BCMA, BB212, UCART-BCMA, ET-140, P-BCMA-101, AUTO-2 (APRIL-CAR), and JNJ-68284528;

[0564] Anti-CLL-1 antibodies such as KITE-796;

[0565] Anti-PD-L1~CAR tank cell therapy such as KD-045;

[0566] Anti-CD45 antibodies such as 131I-BC8 (lomab-B); anti-HER3 antibodies such as LJM716 and GSK2849330;

[0567] Anti-CD52 antibodies such as alemtuzumab,

[0568] B7 homologs 6 such as CAR-NKp30 and CAR-B7H6;

[0569] TBI-1501, CTL-119 huCART-19 T cells, iso-cel, JCAR-015 (US Patent No. 7446190), JCAR-014, JCAR-017 (International Publication Nos. 2016196388, 2016033570, 2015157386), Axicaptagensilolucel (KTE-C19, Yescarta®), KTE-X19 (US Patent Nos. 7741465, 6319494), UCART-19, EBV-CTL, T tisagenlecleucel-T (CTL019), International Publication Nos. 2012079000, 2017049166, CD19CAR-CD28-CD3 zeta-EGFRt expressing T cells, CD19 / 4-1BBL armed CAR T-cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-zeta T cells, PCAR-019, MatchCART, DSCAR-01, IM19 CAR-T, TC-110, and other B lymphocyte antigens CD19; anti-CD19 CAR T-cell therapy (B-cell acute lymphoblastic leukemia, University of Malaysia); anti-CD19 CAR T-cell therapy (acute lymphoblastic leukemia / non-Hodgkin lymphoma, University Hospital Heidelberg), anti-CD19 CAR T-cell therapy (suppressed IL-6 expression, cancer, Shanghai Unicar-Therapy Bio-medicine Technology), and MB-CART2019.1 (CD19 / CD20);

[0570] B lymphocyte antigens such as ACTR707 and ATTCK-20;

[0571] CD19 / B lymphocyte antigen 22, such as TC-310;

[0572] UCART-22, JCAR-018, International Publication No. 2016090190, and other B lymphocyte antigen 22 cell adhesion;

[0573] NY-ESO-1 modifiers such as GSK-3377794, TBI-1301, and GSK3537142;

[0574] Carbonic anhydrases such as DC-Ad-GMCAIX;

[0575] CaspaCIDe DLI and caspase-9 suicide genes such as BPX-501;

[0576] CCR5 such as SB-728;

[0577] CDw123 such as MB-102 and UCART-123;

[0578] CD4 such as ICG-122;

[0579] CD33, such as CIK-CAR.CD33;

[0580] CD38 such as T-007, UCART-38,

[0581] CD40 ligands such as BPX-201 and MEDI5083;

[0582] CD56, such as allogeneic CD56-positive, CD3-negative natural killer cells (myeloid malignancies);

[0583] T-cell antigen CD7 modulators such as anti-CD7 CAR T-cell therapy (for CD7-positive hematological malignancies);

[0584] CEACAM protein 5 modulators such as MG7-CART;

[0585] Claudine 6, such as CSG-002;

[0586] EBV targets such as CMD-003;

[0587] Autologous 4H11-28z / fIL-12 / EFGRt T cells and other MUC16EGFR cells;

[0588] Endonucleases such as PGN-514 and PGN-201;

[0589] Epstein-Barr virus-specific T lymphocytes such as TT-10;

[0590] Erbb2, such as CST-102 and CIDeCAR;

[0591] Gangliosides (GD2), such as 4SCAR-GD2;

[0592] Folic acid hydrolase 1 (FOLH1, glutamate carboxypeptidase II, PSMA; NCBI gene ID: 2346), CIK-CAR.PSMA, CART-PSMA-TGFβRDN, P-PSMA-101, etc.

[0593] TT-16, GLYCAR, and other Glypican-3 (GPC3);

[0594] Hemoglobin such as PGN-236,

[0595] Anti-cMet RNA CAR T receptors and other hepatocyte growth factor receptors;

[0596] Topapillomavirus E7 protein, such as KITE-439;

[0597] Immunoglobulin γFc receptor III, such as ACTR087;

[0598] IL-12, such as DC-RTS-IL-12;

[0599] IL-12 agonists / mucin-16 such as JCAR-020;

[0600] IL-13 Alpha 2, such as MB-101;

[0601] IL-2 such as CST-101;

[0602] K-Ras GTPases such as anti-KRAS G12V mTCR cell therapy;

[0603] L1-L1CAM (CD171), a neuronal cell adhesion molecule such as JCAR-023;

[0604] Ad5f35-LMPd1~2-Latent membrane protein 1 / Latent membrane protein 2 in transduced autologous dendritic cells, etc.

[0605] MAGE-A10C796T MAGE-A10 TCR and other melanoma-associated antigens 10;

[0606] Melanoma-associated antigens 3 / 6 (MAGE A3 / A6), such as KITE-718;

[0607] Mesothelin such as CSG-MESO and TC-210;

[0608] NKG2D, such as NKR-2;

[0609] Ntrkr1 tyrosine kinase receptors such as JCAR-024;

[0610] PRAMET cell receptors such as BPX-701;

[0611] Roundabout homolog 1 9Robo1, such as ATCG-427);

[0612] PSMA-CAR T-cell therapy (lentiviral vector, castration-resistant prostate cancer, etc.)

[0613] T lymphocytes such as TT-12;

[0614] T lymphocyte stimulating factors such as ATL-001;

[0615] Tumor-infiltrating lymphocytes such as LN-144 and LN-145; and

[0616] Wilms tumor proteins such as JTCR-016, WT1-CTL, or ASP-7517. Gene Editor

[0617] In various embodiments, the compounds described herein are combined with gene editors. Exemplary gene editing systems that may be co-administered include, but are not limited to, CRISPR / Cas9 systems, zinc finger nuclease systems, TALEN systems, homing endonuclease systems (e.g., ARCUS), and homing meganuclease systems.

[0618] In various embodiments, the compounds described herein are combined with other drugs that do not have a specific target, such as human immunoglobulin (10% liquid formulation), Cuvitru (human immunoglobulin (20% solution), disodium levofolinate, IMSA-101, BMS-986288, IMUNO BGC Moreau RJ, R-OKY-034F, GP-2250, AR-23, calcium levofolinate, sodium porfimer, RG6160, ABBV-155, CC-99282, polyfeprosan 20 containing carmustine, Veregen, disodium gadoxetate, gadobutrol, gadoteric acid meglumine, gadoteridol, 99mTc-cestamibi, pomalidomide, pacibanil, and barrubicin. Exemplary combination therapy Lymphoma or leukemia combination therapy

[0619] Some chemotherapy agents are suitable for the treatment of lymphoma or leukemia. These include aldezleukin, arbocidib, amifostine trihydrate, aminocamptothecin, antineoplaston A10, antineoplaston AS2-1, antithymocyte globulin, arsenic trioxide, Bcl-2 family protein inhibitor ABT-263, beta-aretin, BMS-345541, bortezomib (VELCADE®, PS-341), briostatin 1, brusulfan, campas-1H, carboplatin, carfilzomib (Kyprolis®), carmustine, caspofungin acetate, CC-5103, chlorambucil, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), cisplatin, cladribine, clofarabine, curcumin, and CVP (Cyclophosphamide, vincristine, and prednisone), cyclophosphamide, cyclosporine, cytarabine, denileukin difutytox, dexamethasone, docetaxel, dorastatin 10, doxorubicin, doxorubicin hydrochloride, DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide), enzastaurin, epoetin alfa, etoposide, everolimus (RAD001), FCM (fludarabine, cyclophosphamide, and mitoxantrone), FCR (fludarabine, cyclophosphamide, and rituximab), fenretinide, filgrastim, flavopyridol, fludarabine, FR (fludarabine and rituximab), geldanamycin (17AAG), hyperCVAD (ultrafractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate and cytarabine), ICE (ifosfamide, carboplatin and etoposide), ifosfamide, irinotecan hydrochloride, interferon alpha-2b, ixabepyrone, lenalidomide (REVLIMID®, CC-5013), pomalidomide (POMALYST® / IMNOVID®), lymphokine-activated killer cells, MCP (mitoxa (Petoxantrone, chlorambucil, and prednisolone), melphalan, mesna, methotrexate, mitoxantrone hydrochloride, motexafingadolinium, mycophenolate mofetil, nelarabine, ovatocrax (GX15-070), oblimersen, octreotide acetate, omega-3 fatty acids, Omr-IgG-am (WNIG, Omrix), oxaliplatin, paclitaxel, palbociclib (PD0332991), pegfilgrastim, pegylated liposomal doxorubicin hydrochloride, perifosine, prednisolone Zolone, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alpha, recombinant interleukin-11, recombinant interleukin-12, rituximab, R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximab and FCM), R-ICE (rituximab and ICE), RMCP (rituximab and MCP), R-roscovitine (celiciclib, CYC202), salglamostim This includes sildenafil citrate, simvastatin, sirolimus, styrylsulfone, tacrolimus, tanespimycin, temsirolimus (CCl-779), thalidomide, allogeneic lymphocytes for therapeutic use, thiotepa, tipifarnib, vincristine, vincristine sulfate, vinorelbine tartrate, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), vemurafenib (Zelboraf®), and venetoclax (ABT-199).

[0620] One modified approach is radioimmunotherapy, in which monoclonal antibodies are combined with radioactive isotope particles such as indium-111, yttrium-90, and iodine-131. Examples of combination therapies include, but are not limited to, iodine-131 tositumomab (BEXXAR®), yttrium-90 ibritumomab tiuxetan (ZEVALIN®), and BEXXAR® with CHOP.

[0621] The above therapies may be supplemented or combined with stem cell transplantation or other treatments. Therapeutic procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, stem cell infusion, bone marrow resection with stem cell support, in vitro treated peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme technology, low-LET cobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiotherapy, and non-myelectomyable allogeneic hematopoietic stem cell transplantation. Combination therapy for non-Hodgkin lymphoma

[0622] Treatment for non-Hodgkin lymphoma (NHL), particularly B-cell origin lymphoma, includes the use of monoclonal antibodies, standard chemotherapy approaches (e.g., CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), FCM (fludarabine, cyclophosphamide, and mitoxantrone), MCP (mitoxantrone, chlorambucil, and prednisone), all of which optionally include rituximab®), radioimmunotherapy, and combinations thereof, especially the integration of antibody therapy and chemotherapy.

[0623] Examples of non-conjugate monoclonal antibodies for the treatment of NHL / B-cell cancer include rituximab, alemtuzumab, human or humanized anti-CD20 antibodies, lumiliximab, anti-TNF-associated apoptosis-inducing ligand (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN-40, and anti-CD74.

[0624] Examples of experimental antibody drugs used to treat NHL / B-cell cancer include ofatumumab, ha20, PRO131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, lumiliximab, apolizumab, milatuzumab, and bevacizumab.

[0625] Examples of standard chemotherapy regimens for NHL / B-cell cancer include CHOP, FCM, CVP, MCP, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), R-FCM, R-CVP, and R-MCP.

[0626] Examples of radioimmunotherapy for NHL / B-cell cancer include Yttrium 90 ibritum It contains butiuxetane (ZEVALIN®) and iodine-131 tositumomab (BEXXAR®). Combination therapy for mantle cell lymphoma

[0627] Treatment for mantle cell lymphoma (MCL) includes combination chemotherapy regimens such as CHOP, hyperCVAD, and FCM. These regimens can also be supplemented with the monoclonal antibody rituximab to form combination therapies such as R-CHOP, hyperCVAD-R, and R-FCM. Any of the above therapies can be combined with stem cell transplantation or ICE to treat MCL.

[0628] An alternative approach to treating MCL is immunotherapy. One immunotherapy uses monoclonal antibodies such as rituximab. Another uses cancer vaccines such as GTOP-99, which are based on the genetic structure of the individual patient's tumor.

[0629] A modified approach to treating MCL is radioimmunotherapy, in which monoclonal antibodies are combined with radioactive isotope particles such as iodine-131 tositumomab (BEXXAR®) and yttrium-90 ibritumomab tiuxetan (ZEVALIN®). In another example, BEXXAR® is used in serial therapy with CHOP.

[0630] Other approaches to treating MCL include autologous stem cell transplantation combined with high-dose chemotherapy, administration of proteasome inhibitors such as bortezomib (VELCADE® or PS-341), or administration of anti-angiogenic agents such as thalidomide, particularly in combination with rituximab.

[0631] Another treatment approach involves administering drugs that, in combination with other chemotherapeutic agents, induce the degradation of the Bcl-2 protein, thereby increasing the sensitivity of cancer cells to chemotherapy, such as oblimersen.

[0632] Further therapeutic approaches include the administration of mTOR inhibitors, which can lead to inhibition of cell proliferation and even cell death. Non-limiting examples include sirolimus, temsirolimus (TORISEL®, CCI-779), CC-115, CC-223, SF-1126, PQR-309 (vimiralisib), voxtalisib, GSK-2126458, and temsirolimus in combination with RITUXAN®, VELCADE®, or other chemotherapeutic agents.

[0633] Other recent therapies for MCL have been disclosed. Such examples include flavopyridol, palbociclib (PD0332991), R-roscovitine (celiciclib, CYC202), styrylsulfone, ovatocrax (GX15-070), TRAIL, anti-TRAIL death receptor DR4 and DR5 antibodies, temsirolimus (TORISEL®, CCl-779), everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide (REVLIMID®, CC-5013), and geldanamycin (17 AAG). Adjunctive therapy for Waldenström-type macroglobulinemia

[0634] Therapies used to treat Waldenström macroglobulinemia (WM) include aldesleukin, alemtuzumab, arbocidib, amifostine trihydrate, aminocamptothecin, antineoplaston A10, antineoplaston AS2-1, antithymocyte globulin, arsenic trioxide, autologous human tumor-derived HSPPC-96, Bcl-2 family protein inhibitor ABT-263, β-aretin, and bortezomib (VELCADE ( (Registered trademark), Briostatin 1, Busulfan, Campas-1H, Carboplatin, Carmustine, Caspofungin acetate, CC-5103, Cisplatin, Clofarabine, Cyclophosphamide, Cyclosporine, Cytarabine, Deniloquin difutitox, Dexamethasone, Docetaxel, Dorastatin 10, Doxorubicin hydrochloride, DT-PACE, Enzastaurin, Epoetin α, Epratuzumab (hLL2-anti-CD2) 2 Humanized antibodies), etoposide, everolimus, fenretinide, filgrastim, fludarabine, ibrutinib, ifosfamide, indium-111 monoclonal antibody MN-14, iodine-131 tositumomab, irinotecan hydrochloride, ixabepylone, lymphokine-activated killer cells, melphalan, mesna, methotrexate, mitoxantrone hydrochloride, monoclonal antibody CD19 (tisagenlecleucel-T, CAR (T-19, CTL-019, etc.), monoclonal antibody CD20, motexafingadolinium, mycophenolate mofetil, nelarabine, oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, pegfilgrastim, pegylated liposomal doxorubicin hydrochloride, pentostatin, perifosine, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interf This includes feron alfa, recombinant interleukin-11, recombinant interleukin-12, rituximab, salgramostim, sildenafil citrate (VIAGRA®), simvastatin, sirolimus, tacrolimus, tanespimycin, thalidomide, allogeneic lymphocytes for therapeutic use, thiotepa, tipifarnib, tositumomab, urocuplumab, vertuzumab, vincristine sulfate, vinorelbine tartrate, vorinostat, WT1 126-134 peptide vaccine, WT-1 analog peptide vaccine, yttrium-90 ibritumomab tiuxetan, yttrium-90 humanized epratuzumab, and any combination thereof.

[0635] Examples of treatments used for WM include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, stem cell infusion, stem cell-supported bone marrow resection, in vitro peripheral blood stem cell transplantation, umbilical cord blood transplantation, immunoenzyme therapy, low-LET cobalt-60 gamma-ray therapy, bleomycin, conventional surgery, radiotherapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation. Combination therapy for diffuse large B-cell lymphoma

[0636] Therapies used to treat diffuse large B-cell lymphoma (DLBCL) include cyclophosphamide, doxorubicin, vincristine, prednisone, anti-CD20 monoclonal antibodies, etoposide, bleomycin, many of the drugs listed for WM, as well as any combination of them, such as ICE and RICE. Combination therapy for chronic lymphocytic leukemia

[0637] Examples of drugs used to treat chronic lymphocytic leukemia (CLL) include combination chemotherapy and chemoimmunotherapy, including chlorambucil, cyclophosphamide, fludarabine, pentostatin, cladribine, doxorubicin, vincristine, prednisone, prednisolone, alemtuzumab, many of the drugs listed for WM, and common combination regimens such as CVP, R-CVP, ICE, R-ICE, FCR, and FR. Combination therapy for myelofibrosis

[0638] Myelofibrosis inhibitors include, but are not limited to, hedgehog inhibitors, histone deacetylase (HDAC) inhibitors, and tyrosine kinase inhibitors. Non-exclusive examples of hedgehog inhibitors are salidegib and bismodegib. Examples of HDAC inhibitors include, but are not limited to, prasinostat and panobinostat. Non-exclusive examples of tyrosine kinase inhibitors are restaurtinib, bustinib, imatinib, gilteritinib, radotinib, and cabozantinib. Combination therapy for hyperproliferative disorders

[0639] To treat hyperproliferative disorders, gemcitabine, nab-paclitaxel, and gemcitabine / nab-paclitaxel can be used in combination with JAK inhibitors and / or PI3Kδ inhibitors. Combination therapy for bladder cancer

[0640] Therapies used to treat bladder cancer include atezolizumab, carboplatin, cisplatin, docetaxel, doxorubicin, fluorouracil (5-FU), gemcitabine, idosphamide, interferon α-2b, methotrexate, mitomycin, nab-paclitaxel, paclitaxel, pemetrexed, thiotepa, vinblastine, and any combination thereof. Combination therapy for breast cancer

[0641] Therapies used to treat breast cancer include albumin-bound paclitaxel, anastrozole, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, epirubicin, everolimus, exemestane, fluorouracil, fulvestrant, gemcitabine, ixabépirone, lapatinib, letrozole, methotrexate, mitoxantrone, paclitaxel, pegylated liposomal doxorubicin, pertuzumab, tamoxifen, toremifene, trastuzumab, vinorelbine, and any combination thereof. Triple-negative breast cancer combination therapy

[0642] Therapies used to treat triple-negative breast cancer include cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, paclitaxel, and combinations thereof. Combination therapy for colorectal cancer

[0643] Therapies used to treat colorectal cancer include bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab, ziv-aflibercept, and any combination thereof. Combination therapy for castration-resistant prostate cancer

[0644] Therapies used to treat castration-resistant prostate cancer include abiraterone, cabazitaxel, docetaxel, enzalutamide, prednisone, ciplucel-T, and any combination thereof. Combination therapy for esophageal and gastroesophageal junction cancer

[0645] Therapies used to treat esophageal and gastroesophageal junction cancers include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof. Combination therapy for gastric cancer

[0646] Therapies used to treat gastric cancer include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combination thereof. Combination therapy for head and neck cancer

[0647] Drugs used to treat head and neck cancer include afatinib, bleomycin, and capesita. This includes vinorelbine, carboplatin, cetukimab, cisplatin, docetaxel, fluorouracil, gemcitabine, hydroxyurea, methotrexate, nivolumab, paclitaxel, pembrolizumab, vinorelbine, and any combination thereof. Combination therapy for hepatobiliary tract cancer

[0648] Therapies used to treat hepatobiliary tract cancer include capecitabine, cisplatin, fluoropyrimidine, 5-fluorouracil, gemecitabine, oxaliplatin, sorafenib, and any combination thereof. Combination therapy for hepatocellular carcinoma

[0649] Therapies used to treat hepatocellular carcinoma include capecitabine, doxorubicin, gemcitabine, sorafenib, and any combination thereof. Combination therapy for non-small cell lung cancer

[0650] Therapies used to treat non-small cell lung cancer (NSCLC) include afatinib, albumin-bound paclitaxel, alectinib, bevacizumab, bevacizumab biosimilar, cabozantinib, carboplatin, cisplatin, crizotinib, dabrafenib, docetaxel, erlotinib, etoposide, gemcitabine, nivolumab, paclitaxel, pembrolizumab, pemetrexed, ramucirumab, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine, vinorelbine, and any combination thereof. Combination therapy for small cell lung cancer

[0651] Therapies used to treat small cell lung cancer (SCLC) include bendamustime, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, gemcitabine, ipilimumab, irinotecan, nivolumab, paclitaxel, temozolomide, topotecan, vincristine, vinorelbine, and any combination thereof. Combination therapy for melanoma

[0652] Therapies used to treat melanoma cancer include albumin-bound paclitaxel, carboplatin, cisplatin, cobiemtinib, dabrafenib, daclavadin, IL-2, imatinib, interferon α-2b, ipilimumab, nitrosourea, nivolumab, paclitaxel, pembrolizumab, pyrimumab, temozolomide, trametinib, vemurafenib, vinblastine, and any combination thereof. Ovarian cancer combination therapy

[0653] Therapies used to treat ovarian cancer include 5-fluorouracil, albumin-bound paclitaxel, altretamine, anastrozole, bevacizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, exemestane, gemcitabine, ifosfamide, irinotecan, letrozole, leuprolide acetate, liposomal doxorubicin, megestrol acetate, melphalan, olaparib, oxaliplatin, paclitaxel, pazopanib, pemetrexed, tamoxifen, topotecan, vinorelbine, and any combination thereof. Combination therapy for pancreatic cancer

[0654] Therapies used to treat pancreatic cancer include 5-fluorouracil, albumin-bound paclitaxel, capecitabine, cisplatin, docetaxel, erlotinib, fluoropyrimidine, gemcitabine, irinotecan, leucovorin, oxaliplatin, paclitaxel, and any combination thereof. Combination therapy for renal cell carcinoma

[0655] Therapies used to treat renal cell carcinoma include axitinib, bevacizumab, cabozantinib, erlotinib, everolimus, levantinib, nivolumab, pazopanib, sorafenib, sunitinib, temsirolimus, and any combination thereof. Preparation of compounds

[0656] Some embodiments of this disclosure relate to processes and intermediates useful for preparing a target compound or a pharmaceutically acceptable salt thereof.

[0657] The compounds described herein can be purified by any chromatographic technique known in the art, such as high-performance liquid chromatography (HPLC), preparative thin-layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase, such as normal-phase, reverse-phase, and ionic resins, can be used. Most typically, the disclosed compounds are purified by silica gel and / or alumina chromatography.

[0658] During any step in the process for preparing the target compound, it may be necessary and / or desirable to protect the sensitive or reactive groups in any of the molecules involved. This is described in TWGreene and PGMWuts, "Protective Groups in Organic Synthesis," 4. th This can be achieved by conventional protecting groups, as described in standard studies such as Wiley, New York 2006. The protecting groups can be removed in a convenient subsequent step using methods known from the art. General synthesis scheme Scheme 1: Preparation of optically pure general intermediates GI-01A and GI-01B [ka]

[0659] The intermediates illustrated by formula GI-01-1 can be prepared using the procedure described in International Publication No. 2016033486, or by the procedure described in the following specific examples.

[0660] Step 1: Intermediate GI-01-2 can be prepared by dissolving intermediate GI-01-1 in a suitable solvent such as THF, DMF, or CH2Cl2, and treating it with a suitable organic base such as trimethylamine, diisopropylethylamine, or imidazole at a suitable temperature, preferably 0°C, and a suitable silylating agent such as TBDMSCl or TBDMSOTf.

[0661] Step 2: Intermediate GI-01-3 can be prepared as a mixture of stereoisomers by suspending Ph3PCl2 in a suitable solvent such as CH2Cl2 or 1,2-dichloroethane under an N2 atmosphere, adding a suitable organic base such as trimethylamine or diisopropylethylamine, then adding a solution of intermediate GI-01-2 in a suitable solvent such as CH2Cl2 or 1,2-dichloroethane, and subsequently bubbling with ammonia gas.

[0662] Step 3: Intermediate GI-01-5 can be prepared as a mixture of stereoisomers by dissolving intermediate GI-01-4 (prepared as described in the following examples) in a suitable solvent such as tetrahydrofuran under an N2 atmosphere, treating it with a suitable strong organic base such as n-butyllithium at a suitable temperature, preferably -40°C, and then adding intermediate GI-01-3 as a solution in a suitable solvent such as tetrahydrofuran.

[0663] Step 4: General intermediate GI-01A can be prepared in an optically pure form by dissolving intermediate GI-01-5 in a suitable solvent such as tetrahydrofuran and treating it with a suitable desilylation agent such as tetrabutylammonium fluoride. The resulting mixture of general intermediate GI-01A and intermediate GI-01-6 can be separated by any technique suitable for separating a mixture of stereoisomers, such as chiral HPLC or SFC.

[0664] Step 5: Intermediate GI-01-7 can be prepared in an optically pure form by dissolving intermediate GI-01-6 in a suitable solvent such as CH2Cl2, and then treating it with a trifluoroacetylating agent such as trifluoroacetic anhydride and an organic base such as triethylamine.

[0665] Step 6: General intermediate GI-01B can be prepared in an optically pure form by dissolving intermediate GI-01-7 in a suitable solvent such as CH2Cl2, and then treating it with a reagent to deprotect the chiral carbamate, preferably trifluoroacetic acid. Scheme 2: Preparation of optically pure general intermediate GI-02A

[0666] The intermediates exemplified by formulas GI-02-1 and GI-02-2 can be prepared in optically pure form by using the procedure described in International Publication No. 2016033486 or by the methods described in the following specific examples.

[0667] Step 1: Intermediate GI-02-3 can be prepared by dissolving the intermediate exemplified by formula GI-02-1 in a suitable solvent such as 1,2-dichloroethane, and treating it with intermediate GI-02-2, an acid such as acetic acid, and a hydrogenation reducing agent, preferably sodium triacetoxyborate. [ka] Scheme 3. A method for preparing the general intermediate GI-03 in an optically pure form. [ka]

[0668] Step 1: Intermediate GI-03-1 can be prepared by dissolving a mixture of general intermediates GI-01A and GI-02A in a suitable solvent such as CH2Cl2, and then treating it with an organic base, preferably 4-dimethylaminopyridine, and a coupling agent such as EDCI.

[0669] Step 2: General intermediate GI-03-2 can be prepared by dissolving intermediate GI-03-1 in a suitable solvent such as CH2Cl2, and then treating it with an acid, preferably trifluoroacetic acid reagent.

[0670] Step 3: Intermediate GI-03-3 can be prepared by dissolving intermediate GI-03-2 in a suitable solvent such as CH2Cl2, adding a suitable organic base such as triethylamine and a suitable acylation catalyst such as 4-dimethylaminopyridine, and then treating with an acylation agent, preferably di-tert-butyl dicarbonate.

[0671] Step 4: General intermediate GI-03 can be prepared by stirring intermediate GI-03-3 with a second-generation Hoveyda Grubbs catalyst in a suitable solvent such as CH2Cl2 or 1,2-dichloroethane at a high temperature, preferably 60°C. After concentrating the reaction mixture, the residue can be purified by preparative HPLC or silica gel column chromatography. Scheme 4. A method for preparing the general intermediate GI-03 in an optically pure form. [ka]

[0672] Step 1: Intermediate GI-03-1 can be prepared by dissolving a mixture of general intermediates GI-01A and GI-02A in a suitable solvent such as CH2Cl2, and then treating it with an organic base, preferably 4-dimethylaminopyridine, and a coupling agent such as EDCI.

[0673] Step 2: General intermediate GI-03-2 can be prepared by dissolving intermediate GI-03-1 in a suitable solvent such as CH2Cl2, and then treating it with an acid, preferably trifluoroacetic acid reagent.

[0674] Step 3: General intermediate GI-03 is prepared in a suitable solvent such as CH2Cl2 or 1,2-dichloroethane at a high temperature, preferably 60°C, and intermediate GI-03-2 is prepared using the second generation Hoveyda Grubbs method. The reaction mixture can be prepared by stirring with a catalyst. After concentrating the reaction mixture, the residue can be purified by preparative HPLC or silica gel column chromatography. Scheme 5. A method for preparing the general intermediate GI-03 in an optically pure form. [ka]

[0675] Step 1: Intermediate GI-03-4 can be prepared by dissolving a mixture of general intermediates GI-01B and GI-02A in a suitable solvent such as DCM, and then treating it with an organic base, preferably 4-dimethylaminopyridine, and a coupling agent such as EDCI.

[0676] Step 2: General intermediate GI-03-2 can be prepared by dissolving intermediate GI-03-4 in a suitable polar protic solvent such as methanol, and then treating it with a base, preferably potassium carbonate.

[0677] Step 3: General intermediate GI-03 can be prepared by stirring intermediate GI-03-2 with a second-generation Hoveyda Grubbs catalyst in a suitable solvent such as DCM or 1,2-dichloroethane at a high temperature, preferably 60°C. After concentrating the reaction mixture, the residue can be purified by preparative HPLC or silica gel column chromatography. Scheme 6. A method for preparing the general intermediate GI-03 in an optically pure form.

[0678] Step 1: Intermediate GI-03-5 can be prepared by dissolving general intermediate GI-02A in DCM or 1,2-dichloroethane. By adding a suitable acid chloride forming agent, such as thionyl chloride or oxanylate chloride, intermediate GI-03-5 can be produced that can be used immediately in the next step.

[0679] Step 2: Intermediate GI-03-6 can be prepared by dissolving intermediate GI-01-3 in a suitable polar solvent such as acetonitrile, adding pyridazine, and then dissolving intermediate GI-03-5 in a suitable polar solvent such as acetonitrile. [ka]

[0680] Step 3: Intermediate GI-03-7 can be prepared by dissolving intermediate GI-03-6 in a suitable solvent such as DCM, adding a suitable organic base such as triethylamine and a suitable acylation catalyst such as 4-dimethylaminopyridine, and then treating with an acylation agent, preferably di-tert-butyl dicarbonate.

[0681] Step 4: General intermediate GI-03 can be prepared by stirring intermediate GI-03-2 with a second-generation Hoveyda Grubbs catalyst in a suitable solvent such as CH2Cl2 or 1,2-dichloroethane at a high temperature, preferably 60°C. After concentrating the reaction mixture, the residue can be purified by preparative HPLC or silica gel column chromatography to separate the stereoisomers and provide both general intermediate GI-03 and the stereoisomer intermediate GI-03-8. Alternatively, the mixture of stereoisomers can be carried over to a subsequent step, after which the stereoisomers can be separated by preparative HPLC or silica gel column chromatography. Scheme 7.R 15 or R 16 A method for introducing a group to prepare an optically pure compound of formula (I). [ka]

[0682] Method A: Product GI-04 can be prepared by dissolving a mixture of general intermediate GI-03 and general carboxylic acid intermediate GI-04-1 in a suitable solvent such as DCM, and then treating it with an organic base, preferably 4-dimethylaminopyridine, and a coupling agent such as EDCI. After the reaction is complete, the reaction product can be concentrated and the residue can be purified by preparative HPLC or silica gel column chromatography.

[0683] Method B: Product GI-05 can be prepared by first treating the general intermediate GI-03 with a carbonylating reagent such as diphenyl carbonate and an acylation catalyst such as 4-dimethylaminopyridine in a suitable solvent such as dichloromethane overnight at a high temperature, preferably 40°C. Then, the amine intermediate GI-05-1 is added, followed by the addition of an organic base such as triethylamine, and the resulting reaction mixture is stirred at a high temperature, preferably 40°C. Once the reaction is complete, the mixture can be purified by an aqueous workup containing an aqueous acid solution, preferably 1N hydrochloric acid, followed by an aqueous base solution, preferably an aqueous sodium bicarbonate solution, and the resulting residue can be purified by preparative HPLC or silica gel column chromatography.

[0684] Method C: Product GI-06 can be prepared by mixing general intermediate GI-03 with heteroaryl chloride or heteroaryl fluoride intermediate GI-06-1 and a suitable base such as cesium carbonate or potassium carbonate in a suitable polar solvent such as N-methylpyrrolidone, N,N-dimethylformamide, or 1,4-dioxane at a high temperature of 80-150°C. After cooling, the mixture can be purified by preparative HPLC or silica gel column chromatography. Scheme 8. Modification of the macrocycle for preparing the optically pure compound of formula (I). [ka]

[0685] General intermediate GI-07 can be prepared by the method described above in Scheme 7 for products GI-04, GI-05, or GI-06, or by the specific method described in the following examples.

[0686] Step 1: Products GI-08A and GI-08B can be prepared by mixing the general intermediate GI-07 with an oxidizing agent, preferably selenium dioxide, in a suitable aprotic solvent such as 1,4-dioxane at a high temperature, preferably 100-120°C. The resulting residue can be purified by preparative HPLC or silica gel column chromatography to separate the stereoisomers and provide products GI-08A and GI-08B. Scheme 9. Modification of the macrocycle for preparing the optically pure compound of formula (I).

[0687] Intermediate GI-09-1 can be prepared by the method described for products GI-04, GI-05, and GI-06 in Scheme 7.

[0688] Step 1: Intermediate GI-09-2 can be prepared by treating intermediate GI-09-1 with an oxidizing agent such as des-martin periodinane in a suitable solvent such as dichloromethane. [ka]

[0689] Step 2: Products GI-09A and GI-09B can be prepared by first treating the carbonyl compound GI-09-3 with a strong base such as lithium diisopropylamide in a suitable aprotic solvent such as tetrahydrofuran at a suitable temperature, preferably -78°C, and then adding the intermediate GI-09-2. After workup, the resulting residue can be purified by preparative HPLC or silica gel column chromatography to separate the stereoisomers and provide products GI-09A and GI-09B. [Examples]

[0690] The exemplary chemicals of this disclosure are provided in the following specific examples. Those skilled in the art will understand that, in order to obtain the various compounds described herein, the starting materials may be suitably selected such that the ultimately desired substituents are supported through a reaction scheme with or without protection as necessary to obtain the desired product. Alternatively, it may be necessary or desirable to use, instead of the ultimately desired substituents, suitable groups that are supported through the reaction scheme and can be appropriately replaced with the desired substituents. Furthermore, those skilled in the art will understand that the transformations shown in the following schemes may be carried out in any order that is suitable for the functionality of the particular pendant groups.

[0691] The examples provided herein describe the synthesis of the compounds disclosed herein, as well as the intermediates used to prepare the compounds. It should be understood that the individual steps described herein can be combined. It should also be understood that separate batches of the compounds can be combined and carried over to the next synthesis step.

[0692] In the following description of embodiments, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to carry out specific embodiments of the disclosure. Other embodiments may be utilized, and logical and other modifications may be made without departing from the scope of the disclosure. Therefore, the following description is not intended to limit the scope of the disclosure. Intermediate A and Intermediate B [ka]

[0693] Step 1: To a stirred solution of (2R,3S)-3-methylhexa-5-ene-2-sulfonamide (International Publication No. 2016033486) (2.00 g, 11.28 mmol) in THF (16 mL), triethylamine (3.15 mL, 22.57 mmol) in an ice bath was slowly added, followed by TBDMSCl (2.13 g, 14.10 mmol) in THF (8 mL). The resulting mixture was stirred at room temperature for 2 days. The precipitate was filtered and washed with ether. The filtrate was concentrated and purified by silica gel column (siRNA / hexane = 1 / 4) to obtain A-1. 1 ¹H NMR (400MHz, chloroform-d) δ 5.76-5.67 (m,1H), 5.08-5.02 (m,2H), 3.95 (s,1H), 3.95-2.97 (m,1H), 2.44-2.41 (m,1H), 2.14-2.08 (m,1H), 2.02-1.96 (m,1H), 1.27 (d,J=8.0Hz,3H), 1.02 (d,J=8.0Hz,3H), 0.94 (m,9H), 0.27-0.26 (m,6H).

[0694] Step 2: Triethylamine (0.43 mL, 3.087 mmol) was added to a stirred suspension of Ph3PCl2 (754.33 mg, 2.264 mmol) in CH2Cl2 (4.0 mL) under an N2 atmosphere. The mixture was stirred at room temperature for 10 minutes, then cooled to 0°C, and a solution of A-1 (600.00 mg, 2.058 mmol) in DCM (4 mL) was added. The reaction mixture was stirred at 0°C for 1 hour. Ammonia gas was bubbled into the reaction mixture, the reaction vessel was sealed, and the mixture was stirred at 0°C for 2 hours. The resulting precipitate was filtered and washed with CH2Cl2. The filtrate was concentrated and purified by silica gel column (siRNA / hexane = 1 / 4) to obtain A-2. 1 ¹H NMR (400MHz, chloroform-d) δ 5.80-5.69 (m,1H), 5.08-5.02 (m,2H), 4.17 (w,2H), 3.06-2.98 (m,1H), 2.54-2.46 (m,1H), 2.11-1.95 (m,2H), 1.29-1.26 (m,3H), 1.01-0.98 (m,3H), 0.92-0.88 (m,9H), 0.13-0.11 (m,6H).

[0695] Step 3: A mixture of (1S)-1-(4-phenylphenyl)ethanol (8.7 g, 71.2 mmol) was dissolved in MeTHF (90 mL) and cooled to 0°C. Pyridine (7.1 mL) was added to this cold, stirred solution. Then, 4-nitro-phenyl-chloroformate was added. A solution of (14.4 g, 71.2 mmol) in MeTHF (60.0 mL) was added dropwise using a dropping funnel. After addition, the resulting mixture was removed from the cooling bath and stirred at ambient temperature for 2 hours. Additional (1S)-1-(4-phenylphenyl)ethanol (2.6 g, 21.3 mmol) and pyridine (1.0 mL) were added, and the reaction mixture was stirred overnight. The reaction mixture was then washed with 1N HCl (twice) and brine (twice), dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in DCM, mixed with silica gel, concentrated to dryness, and purified by normal-phase chromatography (silica gel, 0-20% siRNA / hexane). The desired fractions were combined and concentrated to obtain A-3. 1 ¹H NMR (400MHz, chloroform-d): δ 8.34-8.16 (m, 2H), 7.48-7.31 (m, 7H), 5.84 (q, J=6.6Hz, 1H), 1.70 (d, J=6.6Hz, 3H).

[0696] Step 4: A-2 (5.9 g, 20.1 mmol) was azeotropically mixed with anhydrous toluene (3 × 20 mL) and dissolved in anhydrous tetrahydrofuran (150 mL) under an argon atmosphere. This mixture was cooled to -50°C. A solution of 2.5 M n-BuLi in hexane (17.3 mL, 43.3 mmol) was added dropwise over 5 minutes. This mixture was stirred for 15 minutes. Simultaneously, A-3 (7.5 g, 26.2 mmol) was azeotropically mixed with toluene (3 × 20 mL). Under an argon atmosphere, the material was added to anhydrous tetrahydrofuran (60 mL). Using a cannula, the solution was added to the reactants over 5 minutes. After 15 minutes, the reactants were heated to 0°C (ice bath) and stirred for 1 hour. The reactants were quenched with 0°C water (75 mL). HCl (50 mL) was added to separate the phases, and the aqueous phase was extracted with HCl (2 × 50 mL). The combined organic phases were washed with saturated NaHCO3 (75 mL) and brine (75 mL). The organic phases were dried with sodium sulfate, and the solvent was removed under reduced pressure to obtain A-4.

[0697] Step 5: A solution of TBAF (1.0 M, 19.7 mL, 19.7 mmol) was added to a solution of A-4 (6.64 g, 15.1 mmol) in anhydrous THF at 0°C and stirred for 1 hour. The solvent was removed under reduced pressure, and the residue was diluted with water (80 mL) and SiO (80 mL). The phases were separated, and the aqueous phase was extracted with SiO (3 x 50 mL). The combined organic phases were washed with brine, dried over sodium sulfate, and concentrated. The residue was subjected to flash chromatography (0-65% SiO / hexane). The purified material was subjected to chiral SFC separation using a ChiralPak IC column with methanol as the cosolvent, yielding intermediate A as the first eluted diastereomer (provisionally assigned stereochemistry) and intermediate B as the second eluted diastereomer (provisionally assigned stereochemistry).

[0698] Intermediate A: 1H NMR (400MHz, chloroform-d) δ7.45-7.33(m,4H),7.33-7.30(m,1H),5.73(q,J=6.7 Hz,1H),5.48(dddd,J=16.4,10.1,8.2,6.0Hz,1H),5.06-4.93(m,2H),3.41(qd ,J=7.0,2.2Hz,1H),2.53-2.39(m,1H),2.07(dt,J=14.0,6.2Hz,1H),2.00-1. 86(m,1H),1.59(d,J=6.7Hz,3H),1.34(d,J=7.0Hz,3H),1.02(d,J=6.8Hz,3H).

[0699] Intermediate B: 1 H NMR (400MHz, chloroform-d) δ7.43-7.32(m,4H),7.33-7.29(m,1H),5.75(q,J=6.6 Hz,1H),5.71-5.62(m,1H),5.13-5.03(m,2H),3.38(qd,J=7.1,2.3Hz,1H),2. 47(dtd,J=8.9,6.9,2.2Hz,1H),2.11(dtt,J=13.1,6.5,1.4Hz,1H),2.07-1.9 6(m,1H),1.59(d,J=6.7Hz,3H),1.31(d,J=7.0Hz,3H),1.04(d,J=6.9Hz,3H). Intermediate C and Intermediate D [ka]

[0700] Intermediates C and D were synthesized in the same manner as intermediates A and B, starting with (S)-2-methylpenta-4-ene-1-sulfonamide (International Publication No. 2016033486).

[0701] Intermediate C, first eluted diastereomer (Rt=3.05 min on ChiralPakIC with 15% ethanol cosolvent, absolute stereochemistry provisionally assigned at the time of extraction): 1H NMR (400MHz, chloroform-d) δ7.43-7.33(m,4H),7.33-7.29(m,1H),5.74(q,J=6. 7Hz,1H),5.62(ddt,J=16.0,11.0,7.1Hz,1H),5.05(d,J=1.3Hz,1H),5.04-4. 99(m,1H),3.43(dd,J=14.4,4.5Hz,1H),3.06(dd,J=14.4,7.9Hz,1H),2.30- 2.20(m,1H),2.20-2.04(m,2H),1.59(d,J=6.7Hz,3H),1.14(d,J=6.7Hz,3H).

[0702] Intermediate D, the second eluted diastereomer (Rt=4.92 min on ChiralPakIC with 15% ethanol cosolvent, with provisional absolute stereochemistry assigned at the time of extraction): 1 H NMR (400MHz, chloroform-d) δ7.44-7.32(m,4H),7.32-7.30(m,1H),5.79-5.73(m,1H),5.73-5.66(m,1H),5.16-5.05(m,2H),3.38(dd,J=14.5 ,4.4Hz,1H),3.20(dd,J=14.4,7.7Hz,1H),2.27(dq,J=12.5,6.8Hz,1H),2.22-2.10(m,2H),1.59(d,J=6.7Hz,3H),1.14(d,J=6.7Hz,3H). Intermediate E and Intermediate F

[0703] Intermediates E and F were synthesized in the same manner as intermediates A and B, starting with (R)-hept-6-ene-3-sulfonamide (International Publication No. 2016033486). After step 4 of the synthesis sequence, the diastereomers were separated by silica gel column chromatography (ethyl acetate / hexane). [ka]

[0704] Intermediate E, second diastereomer eluted by silica gel column chromatography (absolute stereochemistry tentatively assigned at the time of extraction):1 H NMR(400MHz,chloroform-d)δ8.49(s,1H),7.24(d,J=2.1Hz,1H),7.17(d,J=5.2Hz,1H),7.13-7.05(m,2H),6 .93(d,J=8.2Hz,1H),4.78(s,2H),4.18-4.01(m,2H),3.62(q,J=7.4Hz,2H),3.50(d,J=14.2Hz,1H),3.4 0(dd,J=14.6,6.4Hz,1H),3.32(d,J=14.2Hz,1H),3.26(dd,J=14.6,6.4Hz,1H),2.89-2.75(m,1H),2.69(dq,J=1 4.0,6.8Hz,1H),2.15-2.03(m,2H),2.00-1.70(m,4H),1.61(ddd,J=13.5,9.6,3.7Hz,1H),1.44(t,J=7.4Hz,2H).

[0705] Intermediate E, the first eluted diastereomer after silica gel column chromatography (absolute stereochemistry tentatively assigned at the time of extraction): 1 ¹H NMR (400MHz, chloroform-d) δ 8.38 (s, 1H), 7.23 (d, J=2.1Hz, 1H), 7.18 (d, J=5.2Hz, 1H), 7.10 (d, J=5.3Hz, 1H), 7.06 (dd, J=8.2, 2.1Hz, 1H), 6.92 (d, J=8.2Hz, 1H), 4.21-4.01 (m, 2H), 4.02-3.86 (m ,2H),3.62(q,J=7.4Hz,1H),3.53-3.15(m,3H),2.87-2.74(m,1H),2.09(td,J=9.7,8.7,6.6Hz, 1H),1.97-1.72(m,3H),1.60(ddd,J=13.4,9.5,3.6Hz,1H),1.44(t,J=7.4Hz,3H),1.25(s,1H). Intermediate G and intermediate H [ka]

[0706] Intermediates G and H were synthesized in the same manner as intermediates A and B, starting with (S)-2-ethylpenta-4-ene-1-sulfonamide (International Publication No. 2016033486).

[0707] Intermediate G, first eluted diastereomer (Rt=1.73 min on Chiralpak IC with 40% ethanol cosolvent, absolute stereochemistry provisionally assigned at the time of extraction): 1 H NMR(400MHz,DMSO-d6)δ7.35(d,J=3.6Hz,4H),7.31-7.23(m,3H),5.77-5.65(m,1H),5.61(q,J=6.6Hz,1H),5.11-5.00(m,2H),3.33(s,1H) ),3.31-3.19(m,2H),2.25-2.06(m,2H),1.97(p,J=6.1Hz,1H),1.42(d,J=6.6Hz,4H),1.39(dd,J=8.0,2.2Hz,2H),0.83(t,J=7.4Hz,3H).

[0708] Intermediate H, second eluted diastereomer (Rt=2.17 min on Chiralpak IC with 40% ethanol cosolvent, absolute stereochemistry provisionally assigned at the time of extraction): 1 H NMR(400MHz,DMSO-d6)δ7.33(d,J=3.9Hz,4H),7.31-7.22(m,3H),5.72-5.56(m,2H),5.06-4.90(m,2H),3.32(s,1 H),3.25(d,J=5.8Hz,2H),2.17-1.99(m,2H),1.94(hept,J=6.0Hz,1H),1.51-1.34(m,5H),0.83(t,J=7.4Hz,3H). Intermediate I Method 1. [ka]

[0709] Step 1: Hydrogenate (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxylic acid (International Publication No. 2016033486) (1.02 g, 2.18 mmol) in a solution of (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazepine-3,1'-naphthalene]-7-carboxylic acid (International Publication No. 2016033486) (1.02 g, 2.18 mmol) in THF (10 mL) that has been stirred at 0°C. Sodium (60% of mineral oil, 183.1 mg, 4.57 mmol) was added, followed by iodomethane (618.7 mg, 4.359 mmol). The resulting mixture was allowed to rise to room temperature and stirred for 5 hours. The reaction mixture was then poured into ice-cold H2O and extracted with CH2Cl2. The organic layer filtrate was concentrated and purified by silica gel column (Âxy / hexane = 2 / 3) to obtain I-1-1. LCMS-ESI+(m / z):C 28 H 32 ClNO4's [M+H] + Calculated value: 482.0; Measured value: 482.2.

[0710] Step 2: Sodium hydride (60% of mineral oil, 88.0 mg, 2.2 mmol), followed by iodomethane (312.3 mg, 2.2 mmol), was added to a stirred solution of I-1-1 (707.0 mg, 1.4 mmol) in DMF (8 mL) at 0°C. The resulting mixture was stirred overnight at room temperature. The reaction mixture was then poured into ice-cold H2O and extracted with DCM. The organic layer filtrate was concentrated and purified using a silica gel column (Â / hexane = 1 / 4) to obtain I-1-2. LCMS-ESI+(m / z):C 29 H 34 ClNO4's [M+H] + Calculated value: 496.0; Measured value: 496.2.

[0711] Step 3: I-1-2 (659.0 mg, 1.33 mmol) was stirred overnight in 2N NaOH aqueous solution (3 mL) and MeOH (8 mL) at 60°C. After cooling, the mixture was acidified with HCl and concentrated. The resulting solid was treated with CH2Cl2 and filtered. The filtrate was concentrated to obtain crude product I-1-3. This was used directly in the next step. LCMS-ESI+(m / z):C 28 H32 ClNO4's [M+H] + Calculated value: 482.2; Measured value: 482.1.

[0712] Step 4: To a stirred solution of intermediate I-1-3 (9.68 g, 20.1 mmol) in DCM (200 mL), intermediate C (6.17 g, 19.9 mmol), EDCI (7.62 g, 39.75 mmol), and DMAP (4.21 g, 34.46 mmol) were added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with DCM and washed with 1N HCl and brine. The organic phase was dried over MgSO4, filtered, and concentrated to obtain I-1-4. This was used without further purification.

[0713] Step 5: To a solution of intermediate I-1-4 (12.7 g, 16.4 mmol) in DCM (130 mL), TFA (25 mL) was added. The reaction mixture was stirred at room temperature. Once complete, the solvent was removed under vacuum. The residue was dissolved in DCM and washed with saturated NaHCO3 solution. The organic phase was separated, dried over MgSO4, filtered, and concentrated to obtain I-1-5. This was used without further purification.

[0714] Step 6: To a solution of intermediate I-1-5 (10 g, 15.97 mmol) in DCM, triethylamine (4.45 mL, 31.94 mmol), DMAP (500 mg, 4.09 mmol), and di-tert-butyl dicarbonate (5.23 g, 23.95 mmol) were added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was washed with 1N HCl (aqueous solution) and brine. The organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (0-100% siRNA / hexane) to obtain I-1-6.

[0715] Step 7: The solutions of I-1-6 (1 g, 1.38 mmol) and Hoveyda-Grubbs II (258.13 mg, 0.41 mmol) in 1,2-dichloroethane (400 mL) were degassed with argon. The reaction mixture was stirred overnight at 60°C. The reaction mixture was concentrated, and the residue was purified by column chromatography (silica gel, 0-70% toluene / hexane) to obtain intermediate I. 1 H NMR (400MHz, chloroform-d) δ7.76(d,J=8.5Hz,1H),7.43(dd,J=8.2,1.9Hz,1H),7.32(d,J=2.0Hz,1H),7.20(dd,J=8.5,2.3Hz,1H),7.10(d,J=2.3Hz,1H) ,6.93(d,J=8.2Hz,1H),6.27(ddd,J=15.1,7.9,5.2Hz,1H),5.99(s,2H),5. 56(dd,J=15.3,8.2Hz,1H),4.20(s,2H),4.06(t,J=11.4Hz,2H),3.92-3.82 (m,1H),3.82-3.69(m,2H),3.47(d,J=5.6Hz,2H),3.36(d,J=14.6Hz,1H),3 .28(s,3H),3.02(dd,J=15.0,11.0Hz,1H),2.80(dt,J=11.3,5.1Hz,2H),2. 63-2.53(m,1H),2.47-2.36(m,2H),2.26(dt,J=14.4,7.3Hz,2H),2.03-1.8 4(m,3H),1.84-1.57(m,4H),1.41(t,J=13.4Hz,1H),1.16(d,J=6.1Hz,3H). LCMS-ESI+(m / z):C 32 H 40 ClN3O4S's [M+H] + calculation Value: 598.2; Measured value: 598.1. Method 2. [ka]

[0716] Step 1: To a solution of intermediate D (1.1 g, 3.54 mmol) in DCM (50 mL) at 0°C, triethylamine (1.48 mL, 10.63 mmol) and trifluoroacetic anhydride (1 mL, 7.08 mmol) were added and the mixture was stirred for 30 minutes. The reaction mixture was quenched with brine, diluted with DCM, and washed with saturated NaHCO3 solution. The organic phase was separated, dried over MgSO4, filtered, and concentrated to obtain I-2-1. This was used without further purification.

[0717] Step 2: TFA (10 mL) was added to a solution of I-2-1 (1.4 g, 3.44 mmol) in DCM (30 mL). The reaction mixture was stirred at room temperature. After completion, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (0-50% siRNA / hexane) to obtain I-2-2.

[0718] Step 3: To a stirred solution of intermediate I-1-3 (1.5 g, 3.11 mmol) in DCM (200 mL), I-2-2 (790 mg, 3.06 mmol), EDCI (1.5 g, 7.78 mmol), and DMAP (760 mg, 6.22 mmol) were added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with DCM and washed with 1N HCl and brine. The organic phase was dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (0-100% siRNA / hexane) to obtain I-2-3.

[0719] Step 4: To the solution of I-2-3 (72 mg, 0.1 mmol) in DCE (10 mL), add TFA (0.02 mL, 0.2 mmol) and the second-generation Hoveyda-Grubs catalyst ( 12.46 mg (0.02 mmol) was added. The reaction mixture was degassed with argon and then stirred overnight at 60°C. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (0-100% Â / hexane) to obtain I-2-4.

[0720] Step 5: Potassium carbonate (129.4 mg, 0.94 mmol) was added to a solution of I-2-4 (130 mg, 0.19 mmol) in MeOH (10 mL) and H2O (2 mL). The reaction mixture was stirred overnight at 60°C. The reaction mixture was concentrated, dissolved in ethyl acetate, washed with water, and back-extracted with ethyl acetate. The organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (0-70% HCl / hexane) to obtain intermediate I. Method 3. [ka]

[0721] Step 1: A mixture of I-1-5 (2.14 g, 3.42 mmol), magnesium oxide (413 mg, 10.3 mmol), and second-generation Hoveyda-Grub catalyst (449 mg, 717 μmol) in 1,2-dichloroethane (485 mL) was heated to 80°C and stirred for 18.5 hours. The resulting mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The residue was dissolved in a mixture of ethyl acetate (50 mL) and toluene (100 mL). Silica gel (40 g) was added, and the resulting slurry was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-65% ethyl acetate in hexane) and re-purified by reverse-phase preparative HPLC (acetonitrile / 0.1% trifluoroacetic acid in water) to obtain intermediates I and I-3-1.

[0722] I-3-1: 1¹H NMR (400MHz, acetone-d6) δ 7.79 (d, J=8.5Hz, 1H), 7.39 (d, J=1.9Hz, 1H), 7.31 (dd, J=8.2, 1.9Hz, 1H), 7.24 (dd, J=8.5, 2.4Hz, 1H), 7.14 (d, J=2.3Hz, 1H), 7.07 (s, 1H), 6.89 (d, J=8.2Hz, 1H), 5.82 (td, J=9.8, 6.1Hz, 1H), 5.54-5.43 (m, 1H), 4.28-4.17 (m, 1H), 4.11 (d ,J=12.1Hz,1H),4.01(d,J=12.1Hz,1H),3.94(d,J=15.1Hz,1H),3.78(d,J=14.3Hz,1H),3.64(dd,J=14.3,3.4Hz,1H),3.49(d,J= 14.3Hz,1H), 3.40(dd,J=14.3,8.1Hz,1H),3.28(dd,J=15.2,10.7Hz,1H),3.23(s,3H),2.88-1.27(m,15H),1.17(d,J=6.9Hz,3H). LCMS-ESI+(m / z):C 32 H 40 ClN3O4S's [M+H] + Calculated value: 598.2; Measured value: 598.2. Intermediate J [ka]

[0723] Step 1: A solution of osmium tetroxide (260 mg, 0.026 mmol) was added to a mixture of I-1-1 (2.5 g, 5.19 mmol), N-methylmorpholine N-oxide (911 mg, 7.78 mmol), and DMAP (6 mg, 0.052 mmol) in tBuOH (2.4 mL), THF (0.8 mL), and water (0.8 mL). The resulting solution was heated at 45°C for 4 hours, then at 80°C for 4 hours, and then cooled to ambient temperature. Sodium sulfite and water were added, and the mixture was quenched by vigorously stirring for 20 minutes. The mixture was filtered through Celite, and the filter cake was washed with SiO2. The combined organic phase was dried over magnesium sulfate, filtered, and concentrated to obtain J-1. This was the crude product carried over to the next step.

[0724] Step 2: A solution of sodium periodate (3.33 g, 15.6 mmol) in water (33 mL) was added dropwise to J-1 (2.68 g, 5.19 mmol) in acetone (21 mL) at 0°C. The reaction mixture was then heated to ambient temperature and stirred for 120 minutes. The acetone was removed under reduced pressure, and the aqueous layer was extracted with phenylethylamine. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Intermediate J was obtained by purification by silica gel flash column chromatography (0-30% ethyl acetate in hexane). LCMS-ESI+:(m / z):C 26 H 28 ClNO4's [M+H] + Calculated value: 454.2; Measured value: 454.2. Intermediate K Method 1. [ka]

[0725] Intermediate K was synthesized in the same manner as intermediate I (Method 1 - Steps 4-7), using intermediate A instead of intermediate C. 1 ¹H NMR (400MHz, chloroform-d) δ 7.778 (d, J=8.5Hz, 1H), 7.45 (dd, J=8.3, 1.9Hz, 1H), 7.30 (d, J=2.0Hz, 1H), 7.20 (dd, J=8.5, 2.3Hz, 1H), 7.10 (d, J=2.4Hz, 1H), 6.93 (d, J=8.3Hz, 1H), 5.91 (dt, J=15.8, 5.8Hz, 1H), 5. 69(dd,J=15.8,6.8Hz,1H),4.18-3.95(m,2H),3.87(dd,J=14.9,3.4Hz,1H),3.73(s,5H),3.41-3.23(m, 4H),3.01(dd,J=15.0,10.9Hz,1H),2.89-2.72(m,2H),2.62(s,2H),2.46(s,1H),2.31-2.01(m,3H),1.9 9-1.64(m,6H),1.46(s,3H),1.11(d,J=6.9Hz,3H). LCMS-ESI+(m / z):C 33 H 42ClN3O4S's [M+H] + Calculated value: 612.26; Measured value: 612.06. Method 2.

[0726] Intermediate K was prepared from intermediate B in the same manner as intermediate I (Method 2). Intermediate L [ka]

[0727] Preparation of L-1: L-1 was prepared in the same manner as intermediate A, using penta-4-en-1-sulfonamide instead of (2R,3S)-3-methylhexa-5-en-2-sulfonamide, and performing step 5 at room temperature instead of 0°C. 1 H NMR (400MHz, chloroform-d) δ7.45-7.31(m,4H),5.83-5.59(m,2H),5.12-4.96(m,2H) ,3.35-3.21(m,2H),2.28-2.11(m,2H),2.01-1.87(m,2H),1.59(d,J=6.7Hz,3H).

[0728] Step 1: To a mixture of I-1-3 (215 mg, 0.45 mmol) in DCM (20 mL) at 0°C, EDCI (152 mg, 0.98 mmol), followed by DMAP (120 mg, 0.98 mmol), was added. After 5 minutes, a solution of L-1 (159 mg, 0.54 mmol) in DCM (3 mL) was added, and the resulting mixture was removed from the cooling bath and stirred overnight at room temperature. The reaction product was further diluted with DCM (30 mL), washed with 1N HCl (15 mL), saturated sodium bicarbonate (15 mL), and brine (15 mL), dried over sodium sulfate, filtered, concentrated, and the residue was subjected to normal-phase chromatography (silica gel column, 0-80%). The solution was purified using ethyl acetate / hexane to obtain L-2. LCMS-ESI+(m / z):[M+H] + Calculated value: 761.0, Measured value: 759.9. 1H NMR (400MHz, chloroform-d) δ7.67(d,J=8.5Hz,1H),7.50(s,1H),7.39-7.28(m,6H),7.16(dd,J=8.5,2.3Hz,1H),7.08(d,J=2.3Hz,1H),6.91(d,J=8.2Hz) ,1H),5.86(p,J=6.3Hz,1H),5.77-5.48(m,2H),5.21-5.08(m,2H),5.08-4 .96(m,2H),4.14-4.04(m,2H),3.81-3.71(m,2H),3.70-3.48(m,3H),3.39 -3.13(m,5H),2.84-2.69(m,2H),2.52(dd,J=10.7,7.4Hz,1H),2.16(dt,J=13.3,7.6Hz,3H),2.01-1.74(m,7H),1.70-1.39(m,7H).

[0729] Step 2: The solution of L-2 in DCE (10 mL) was sparged with nitrogen for 5 minutes, and then the second-generation Hoveyda-Grubs catalyst (7 mg, 0.011 mmol) was added. The newly formed mixture was degassed for a further 2 minutes, capped, and heated at 60°C for 16 hours. The reaction product was then cooled to room temperature, concentrated, and purified by normal-phase chromatography (silica gel, 0-5% DCM / MeOH (containing 2.0N NH3)) to obtain intermediate L as the first elution peak and L-3 as the second elution peak. Intermediate L: LCMS-ESI+(m / z):C 31 H 38 ClN3O4S's [M+H] + Calculated value: 584.2; Measured value: 583.4. L-3:LCMS-ESI+(m / z):C 40 H 46 ClN3O6S's [M+H] + Calculated value: 732.9; Measured value: 730.8.

[0730] Step 3: TFA (1.0 mL) was added to a solution of L-3 (15.8 mg, 0.022 mmol) in DCM (1.0 mL) at 0°C. The resulting mixture was stirred at 0°C for 2 minutes, then at room temperature for 1 hour. The reaction mixture was cooled back to 0°C and basicized to pH ~8 with 1N NaOH. The mixture was extracted with DCM (twice). The combined organic layers were washed with brine (once), dried over sodium sulfate, filtered, concentrated, and the residue was purified by flash column chromatography (silica gel, 0-100% Âxane) to obtain intermediate L. 1 ¹H NMR (400MHz, chloroform-d):δ 7.73 (d, J=8.6Hz, 1H), 7.44-7.39 (m, 1H), 7.33 (d, J=1.8Hz, 1H), 7.16 (dd, J=8.5, 2.3Hz, 1H), 7.06 (d, J=2.3Hz, 1H), 6.90 (d, J=8.2Hz, 1H), 6.04-5.93 (m, 1H), 5.73-5.61 ( m,1H),4.12-3.94(m,2H),3.88-3.68(m,2H),3.62-3.51(m,2H),3.40-3.17(m,6H),3.00(dd,J=15 .0,11.0Hz,1H),2.82-2.63(m,4H),2.47-2.20(m,4H),1.99-1.59(m,6H),1.37(t,J=13.1Hz,1H). LCMS-ESI+(m / z):C 31 H 38 ClN3O4S's [M+H] + Calculated value: 584.2, Measured value: 583.3. Intermediate M [ka]

[0731] Intermediate I (445 mg, 0.744 mmol) was dissolved in 1,4-dioxane (7 mL). Selenium dioxide (330 mg, 4 equivalents) was added all at once. The mixture was heated under reflux until LC-MS showed approximately 50% conversion to the corresponding allyl alcohol. The reaction mixture was then cooled to room temperature, and the residue was purified by Gilson reverse-phase preparative HPLC (containing 0.1% TFA, 40-90% MeCN / H2O) to obtain intermediate M as the main product.1 H NMR(400MHz,メタノール-d4)δ7.76(d,J=8.6Hz,1H),7.29(dd,J=8.2,1.9Hz,1H),7.18(dd,J=8.6, 2.3Hz,1H),7.11(d,J=2.4Hz,1H),7.07(d,J=1.9Hz,1H),6.84(d,J=8.2Hz,1H),6.25(dd,J=15 .3,6.1Hz,1H),5.76(dd,J=15.5,9.0Hz,1H),4.38(d,J=6.0Hz,1H),4.26(dd,J =15.0,6.1Hz,1H),4.09-4.00(m,2H),3.93-3.81(m,2H),3.65(d,J=14.1Hz,1H ),3.30(m,6H),3.10-3.03(m,1H),2.87-2.70(m,3H),2.57-2.30(m,2H),2.25- 2.09(m,2H),2.01-1.66(m,7H),1.43(t,J=12.7Hz,1H),1.21(d,J=6.9Hz,3H). LCMS-ESI+(m / z):C 32 H 40 ClN3O5Sの[M+H] + Calculated value: 614.3; measured value: 614.1. Intermediate N

change

[0732] Step 1: A 2.5 M solution of n-BuLi in hexane (0.179 L, 448.7 mmol) was added to a stirred solution of (1R,2S)-2-morpholino-1-phenyl-1-propanol (Chemistry Eur.J.2007, pp.2587) (99.1 g, 448.7 mmol) in toluene (0.39 L) at -15°C, and the mixture was stirred for 30 minutes. Next, a 0.28 M solution of divinyl zinc in 1:1 ethyl ether:THF (1.6 L, 448.7 mmol) was added, and the reaction mixture was stirred for 1 hour. ((1R,2R)-2-formylcyclobutyl)methyl acetate (International Publication No. 2016033486) (35 g, 224.3 mol) was added to toluene (0.39 L), and the reaction mixture was stirred for 2 hours. The reaction mixture was quenched with a 30% citric acid solution and diluted with ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column (10-20% ethyl acetate in petroleum ether) to obtain methyl ((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)acetate. 1 ¹H NMR (400MHz, chloroform-d) δ 5.88-5.67 (m,1H), 5.31-5.19 (m,1H), 5.19-5.06 (m,1H), 4.18-4.08 (m,1H), 4.07-3.91 (m,1H), 2.60-2.36 (m,1H), 2.15-2.09 (m,1H), 2.06 (s,3H), 2.04 (d,J=3.7Hz,1H), 1.99-1.91 (m,1H), 1.91-1.81 (m,1H), 1.72-1.56 (m,1H).

[0733] Step 2: Potassium carbonate (79 g, 570 mmol) was added to a stirred solution of ((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl acetate (35 g, 190 mmol) in MeOH (0.35 L), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was cooled to 0°C, water and ethyl acetate were added, and the mixture was stirred at room temperature for 20 minutes. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column (20-30% ethyl acetate in petroleum ether) to obtain (S)-1-((1R,2R)-2-(hydroxymethyl)cyclobutyl)propa-2-en-1-ol. 1 ¹H NMR (400MHz, chloroform-d) δ 5.75 (ddd, J=17.0, 10.4, 6.5Hz, 1H), 5.33-5.18 (m, 1H), 5.16-5.06 (m, 1H), 3.91 (dd, J=9.6, 6.5Hz, 1H), 3.69 (d, J=10.3Hz, 1H), 3.42 (t, J=10.3Hz, 1H), 2.94 (d, J=40.8Hz, 2H), 2.41-2.21 (m, 1H), 2.11-1.93 (m, 1H), 1.64-1.61 (m, 1H), 1.70-1.47 (m, 1H).

[0734] Step 3: Add tert-butyldiphenylchlorosilane (37g, 134mmol) to 0 (S)-1-((1R,2R)-2-(hydroxymethyl)cyclobutyl)propa-2-en-1-ol (19 g, 134 mmol) and imidazole (18 g, 267 mmol) in DCM (0.38 L), stirred at °C, were added dropwise, and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched with cold water and diluted with DCM. The organic layer was separated, and water was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified with silica gel (5-10% SiO in petroleum ether) to obtain (S)-1-((1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)propa-2-en-1-ol.

[0735] Step 4: Sodium hydride (60% in mineral oil, 11.6 g, 292 mmol) was added to a solution of (S)-1-((1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)propa-2-en-1-ol (37 g, 97.3 mmol) and methyl iodide (30.3 mL, 486 mmol) in THF (0.37 L), which had been stirred at 0°C. The reaction mixture was brought to room temperature and stirred for 4 hours. The reaction mixture was quenched with cold water and diluted with ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was diluted with 20% ethyl acetate in petroleum ether, passed through a silica gel plug, and concentrated under reduced pressure to obtain tert-butyl(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methoxy)diphenylsilane.

[0736] Step 5: A 1.0 M solution of TBAF in THF (141 mL, 141 mmol) was added to a stirred solution of tert-butyl(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methoxy)diphenylsilane (37 g, 94 mmol) in THF (0.37 L) at 0°C. The reaction mixture was allowed to rise to room temperature and stirred for 4 hours. The reaction mixture was cooled to 0°C, diluted with water and ethyl acetate, allowed to rise to room temperature, and stirred for 20 minutes. The organic layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column (5-10% ethyl acetate in petroleum ether) to obtain intermediate N. 1 H NMR(400MHz,DMSO-d6)δ5.62-5.49(m,1H),5.24-5.19(m,1H),5.18(d,J=0.9Hz,1H),4.25(dd,J=5.9,4.7Hz,1H),3.45(t,J=7.7Hz,1H),3. 38(m,1H),3.34-3.25(m,1H),3.17(s,3H),2.28-2.15(m,1H),2.13-1 .97(m,1H),1.85-1.74(m,1H),1.74-1.64(m,1H),1.64-1.52(m,2H). Intermediate O [ka]

[0737] Step 1: To a solution of methyl(3S)-6'-chlorospiro[4,5-dihydro-2H-1,5-benzoxazepine-3,1'-tetralin]-7-carboxylate (5.03 g, 14.06 mmol) in DMF (9 mL), DMAP (1.89 g, 15.46 mmol) and triethylamine (14 mL, 0.1 mol) were added. Then, trifluoroacetic anhydride (10 mL, 71.94 mmol) was slowly added at room temperature. The reaction mixture was stirred overnight at 50°C. The reaction mixture was cooled to room temperature, and triethylamine (4 mL, 0.03 mol) and trifluoroacetic anhydride (4 mL, 0.03 mol) were added. The reaction mixture was stirred overnight at 50°C. The reaction mixture was diluted with ethylamine, washed with water, and back-extracted with ethylamine. The combined organic phases were washed with 1N HCl solution and saturated NaHCO3 solution, dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (0-20% toluene / hexane) to obtain O-1. 1 ¹H NMR (400MHz, chloroform-d)δ 8.09 (dd, J=8.4, 2.1Hz, 1H), 7.99 (s, 1H), 7.27 (s, 1H), 7.19 (d, J=2.2Hz, 1H), 7.15-7.07 (m, 1H), 7.00 (d, J=8.3Hz, 1H), 4.91 (d, J=13.8Hz, 1H), 4.26 (d, J=12.4Hz, 1H), 3.96 (s, 3H), 3.83 (d, J=12.4Hz, 1H), 3.23 (d, J=13.8Hz, 1H),2.94-2.75(m,2H),2.07(s,1H),2.00(d,J=12.0Hz,2H),1.91-1.78(m,1H).

[0738] Step 2: To a solution of O-1 (1.8 g, 3.97 mmol) in benzene (50 mL), t-butyl hydroperoxide (70%, 2.72 mL, 19.83 mmol) and pyridinium dichromate (4.47 g, 11.9 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour. To this mixture, t-butyl hydroperoxide (70%, 3.81 mL, 0.03 mol) and pyridinium dichromate (4.48 g, 0.01 mol) were added. The reaction mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture and stirred at room temperature for 0.5 hours. The layers were separated, and the organic phase was washed with 10% Na2SO3 solution, 1% Na2S2O3 solution, and brine. The organic phase was dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (0-30% RINKAN / hexane) to obtain O-2. 1 H NMR(400MHz,chloroform-d)δ8.17-8.07(m,2H),8.02(s,1H),7.52(dd,J=8.4,2.4Hz,1H),7.31(s,1H),5.04(d,J=13.9Hz,1H),4.39(d,J=12.5Hz,1H) ,4.03(d,J=12.3Hz,1H),3.96(s,3H),3.33(d,J=13.9Hz,1H),3.05(q,J= 8.0,6.9Hz,1H),2.80(dt,J=18.0,6.0Hz,1H),2.32(s,1H),1.56(s,2H).

[0739] Step 3: Lithium bis(trimethylsilyl)amide (1.0 M THF, 20.39 mL) was added to a solution of O-2 (7.95 g, 16.99 mmol) in THF (60 mL) at -78 °C and stirred for 30 minutes. A solution of phenyltrifluimide (6.37 g, 17.84 mmol) in THF (25 mL) was added dropwise, the reaction mixture was heated to 0 °C and stirred for 2.5 hours, then quenched with H2O. The reaction mixture was then partitioned between toluene and H2O. The aqueous layer was collected and extracted with toluene. The combined organic layers were then washed with brine, dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (0-100% toluene in hexane) to obtain O-3.

[0740] Step 4: A solution of O-3 (10.08 g, 16.8 mmol) in DMF (100 mL) was sparged with argon for 15 minutes. Triethylsilane (2.8 mL, 17.5 mmol) and dichloro-1,1-bis(diphenylphosphino)ferrocenepalladium(II)dichloromethane (0.26 g, 0.35 mmol) were added. The resulting mixture was further sparged for 10 minutes and heated at 65°C for 4 hours. The reaction mixture was cooled to room temperature and partitioned between phosphate and H2O. The organic layer was washed with brine, dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (0-30% phosphate in hexane) to obtain O-4.

[0741] Step 5: A 500 mL two-necked flask was attached to a dropping funnel, dried under vacuum, refilled with argon, then CH2Cl2 (24 mL) was added and cooled to 0°C. A solution of diethylzinc (1 M hexane, 5 equivalents, 85 mmol, 85 mL) was added, followed by CH2Cl2 (10 mL), and the dropping funnel was rinsed. A solution of TFA (4.9 equivalents, 83.2 mmol, 6.4 mL) in CH2Cl2 (12 mL) was added dropwise over 30 minutes, followed by CH2Cl2 (5 mL). The reaction mixture was stirred for a further 20 minutes, and a solution of diiodomethane (5 equivalents, 84.9 mmol, 6.8 mL) in CH2Cl2 (12 mL) was added dropwise over 20 minutes, followed by CH2Cl2 (5 mL). The reaction mixture was stirred for a further 20 minutes, and a solution of O-4 (1 equivalent, 17.0 mmol, 7.67 g) in CH2Cl2 (12 mL) was added dropwise over 20 minutes, followed by the addition of CH2Cl2 (5 mL). The reaction mixture was then slowly heated from 0°C to room temperature and stirred for 62 hours. The mixture was quenched with saturated ammonium chloride and extracted in CH2Cl2. The combined organic layer was then partially saturated with sodium bicarbonate aqueous solution. The mixture is then washed with semi-saturated brine, dried with sodium sulfate, filtered, concentrated, and used to obtain the diastereomer. 1 A 1.4:1 mixture was obtained using 1H NMR. Purification by silica gel chromatography (0-30% toluene in hexane) yielded diastereomer O-5 as a lower polarity peak. 1H NMR (400MHz, methanol-d4) δ8.10-8.02(m,2H),7.44(d,J=2.2Hz,1H),7.29(d,J=8.3Hz,1H),7.18-7.0 8(m,2H),4.69(dd,J=13.4,2.4Hz,1H),4.61(dd,J=12.3,2.4Hz,1H),3.92(s,3H),3.72(d,J=13.4H z,1H),3.51(d,J=12.1Hz,1H),2.81(dd,J=14.3,8.4Hz,1H),2.02(td,J=8.8,4.8Hz,1H),1.52(dt, J=8.4,5.5Hz,1H),1.39(dd,J=14.2,6.0Hz,1H),1.28(td,J=8.5,4.3Hz,1H),0.37(q,J=4.6Hz,1H).

[0742] Step 6: A solution of O-5 (2.59 g, 5.56 mmol) in anhydrous MeOH (56 mL) in a 100 mL Schlenk flask dried in an oven was treated with sodium methoxide (1.5 g, 27.8 mmol) under argon, sealed, and stirred at 65°C for 15 hours. The reaction mixture was cooled to room temperature, quenched with water, and extracted with toluene. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain O-6. LCMS-ESI+(m / z):C 21 H 20 ClNO3's [M+H] + Calculated value: 370.1; Measured value: 370.2.

[0743] Step 7: Dess-Martin periodinane (238 mg, 0.56 mmol) was added to a mixture of intermediate N (67.3 mg, 0.43 mmol) in DCM (2.9 mL) that had been stirred at 0°C. The resulting mixture was removed from the cooling bath and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, diluted with DCM (20.0 mL), quenched with a 1:1 mixture of 1N sodium thiosulfate and saturated sodium bicarbonate (10.0 mL), and vigorously stirred for 15 minutes. The layers were separated, and the aqueous layer was extracted with DCM (10.0 mL). The combined organic layers were washed with brine (10.0 mL), dried over sodium sulfate, filtered, and concentrated to obtain O-7.

[0744] Step 8: The solutions of intermediate O-6 (1.0 g, 2.7 mmol) and crude product O-7 (1.5 equivalents, 4.06 mmol) in DCE (11 mL) and acetic acid (0.55 mL) were stirred at room temperature for 30 minutes. The reaction mixture was then cooled to 0°C, treated with STAB (860 mg, 4.06 mmol), divided into 5 parts over 60 minutes, then warmed to room temperature and stirred overnight. The reaction mixture was quenched with water and extracted three times with RINKAN (5 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (0-50% RINKAN in hexane) to obtain O-8. LCMS-ESI+(m / z):C 30 H 34 ClNO4's [M+H] + Calculated value: 508.2; Measured value: 508.3.

[0745] Step 9: The solution of intermediate O-8 (1.27 g, 2.5 mmol) in 5 / 1 / 1 THF / MeOH / water (total 25 mL) was treated with lithium hydroxide (599 mg, 25 mmol) and heated overnight at 60°C. The reaction mixture was quenched with 1N HCl and extracted three times with CH2Cl2. The combined organic layers were washed with semi-saturated brine, dried over sodium sulfate, filtered, and concentrated to obtain the desired product O-9. LCMS-ESI+(m / z):C 29 H 32 ClNO4's [M+H] + Calculated value: 494.2; Measured value: 494.2.

[0746] Synthesis of intermediate O: Intermediate O was synthesized using O-9 and intermediate C in the same manner as intermediate I (Method 1, steps 4-7). LCMS-ESI+(m / z):C 33 H 40 ClN3O4S's [M+H] + Calculated value: 610.2; Measured value: 610.1. Intermediate P [ka]

[0747] Intermediate P was synthesized in the same manner as intermediate I (Method 1, Steps 4-7), using L-1 instead of intermediate C and O-9 instead of I-1-3. Intermediate Q

[0748] Step 1: Ethyl (4-chlorophenyl) acetate (5.0 g, 25.17 mmol) was dissolved in CCl4 (100 mL). Azobicisobutyronitrile (124.0 mg, 0.755 mmol) and N-bromosuccinimide (5375.9 mg, 30.20 mmol) were added to the solution at room temperature. The mixture was heated at 80°C for 15 hours. After cooling to room temperature, the resulting suspension was filtered through Celite (3 g). The filtrate was washed with brine (30 mL x 2) and dried over Na2SO4. The solvent was removed under reduced pressure, and Q-1 was obtained without further purification. 1 H NMR (400MHz, acetone-d6) δ7.65(dd,J=8.6,1.9Hz,2H),7.53-7.38(m,2H),5.70(d,J=1.5Hz,1H),4.33-4.14(m,2H),1.35-1.13(m,3H).

[0749] Step 2: Thioglycolic acid (2.55 g, 27.69 mmol) was dissolved in DMF (30 mL). DIPEA (6.51 g, 27.69 mmol) and Q-1 (7.0 g, 25.17 mmol) were added to this solution at 0°C. The mixture was stirred at 0°C for 2 hours. HCl (2 mL), brine (30 mL), and siRNA (100 mL) were added to the solution. The layers were separated, the organic layer was washed with brine (30 mL), dried over Na2SO4, concentrated, and the residue was purified by silica gel column chromatography (10%~50%~67% THF / hexane) to obtain Q-2. 1 H NMR (400MHz, acetone-d6) δ7.57-7.48(m,2H),7.46-7.39(m,2H),4.96(s,1H),4.31 -4.10(m,2H),3.38(d,J=15.3Hz,1H),3.20(d,J=15.3Hz,1H),1.31-1.13(m,3H). [ka]

[0750] Step 3: Q-2 (568.4 mg, 1.969 mmol) was dissolved in DCM (4 mL) and DMF (0.1 mL). To the solution, a solution of oxalyl chloride (299.8 mg, 2.36 mol) in DCM (1 mL) was added at room temperature, and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure. DCM (20 mL) was added to the residue, and the solvent was removed. DCM (5 mL) and AlC3 (577.4 mg, 4.33 mmol) were added to the residue at room temperature, and the mixture was stirred for 1 hour. Water (30 mL) and siRNA (100 mL) were added to the reaction mixture. The two-phase solution was filtered through Celite (3 g). The organic layer was washed with brine (30 mL), dried over Na2SO4, concentrated, and the residue was purified by silica gel column chromatography (10%~25% siRNA / hexane) to obtain Q-3. 1 H NMR (400MHz, acetone-d6) δ7.97(d,J=2.4Hz,1H),7.62(dd,J=8.2,2.4Hz,1H),7.48(d,J=8.2Hz,1H),4.80(s ,1H),4.23(q,J=7.1Hz,2H),4.13(d,J=16.7Hz,1H),3.42(dd,J=16.7,1.2Hz,1H),1.26(t,J=7.1Hz,3H).

[0751] Step 4: The solution of Q-3 (5.06 g, 18.69 mmol) in EtOH (18 mL) and THF (9 mL) was cooled to -40°C, and NaBH4 (1.06 g, 28.04 mmol) was added. After 45 minutes, the reaction mixture was allowed to cool to 0°C. After 15 minutes, the reaction mixture was quenched with water and brine and extracted with SiO2. The organic layer was washed with brine and dried over Na2SO4. Q-4 was obtained as a mixture of stereoisomers by filtration and removal of the solvent.

[0752] Step 5: InCl3 (6.20 g, 28.04 mmol) was added to a solution of Q-4 (5.59 g, 18.69 mmol) in DCE (200 mL). The mixture was heated at 80°C for 2 hours. The mixture was cooled to 0°C, water was added, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. Q-5 was obtained by purification by silica gel column chromatography (4%~13% toluene / hexane).

[0753] Step 6: Et3SiH (20 mL, 125 mmol) was added to a solution of Q-5 (3.20 g, 12.56 mmol) in TFA (100 mL). The mixture was heated at 70°C for 2 hours. The mixture w...

Claims

1. Formula (II): 【Chemistry 1】 Compounds of [in the formula, Z １ CR １ａ And; Z ２ CR ２ａ R ２ｂ Selected from S and O; Here, each R １ａ , R ２ａ , and R ２ｂ It is selected independently of hydrogen and halo; Here, R １６ is a 3- to 12-membered heterocyclyl or a 5- to 12-membered heteroaryl; where R １６ is optionally substituted with 1 to 5 R Ａ ; R ２ is hydrogen, halo, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, and -C １～４ Alkylene-OC １～６ Selected from alkyl groups; R ３ is hydrogen, halo, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C ３～１０ Cycloalkyl, 3-12 membered heterocyclyl, and -C １～４ Selected from alkylene-O-5 to 10-membered heteroaryls; where R ３ Each C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C ３～１０ Cycloalkyl, 3-12 membered heterocyclyl, and -C １～４ Alkylene-O-5 to 10-membered heteroaryls are halos and C １～６ Alkyl, C １～６ Haloalkyl and C １～６ Optionally substituted with 1 to 4 groups independently selected from the alkoxyl; Each R ４ and R ５ is hydrogen, halo, hydroxyl, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl, -NR ａａ R ｂｂ , -NHC(O)-C １～６ Alkyl, -C(O)NH-C １～６ Alkyl, -O-C ２～６ Alkinyl, -OC(O)-C １～６ Alkyl, -O-(CH ２ CH ２ O) ｎ -C １～６ Alkyl, C ３～１０ Cycloalkyl, 3-12 membered heterocyclyl, -O-C ３～１０ Cycloalkyl, -O-3 to 12-membered heterocyclyl, -O-C １～４ Alkylene-C ３～１０ Cycloalkyl, 5-10 membered heteroaryl, -O-C １～４ Alkylene-3 to 12-membered heterocyclyl, -O-5 to 10-membered heteroaryl, and -O-C １～４ Independently selected from alkylene-5 to 10-membered heteroaryls; Here, R ４ and R ５ Each C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Haloalkyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl, -NHC(O)-C １～６ Alkyl, -C(O)NH-C １～６ Alkyl, -O-C ２～６ Alkinyl, -OC(O)-C １～６ Alkyl, -O-(CH ２ CH ２ O) ｎ -C １～６ Alkyl, C ３～１０ Cycloalkyl, 3-12 membered heterocyclyl, -O-C ３～１０ Cycloalkyl, -O-3 to 12-membered heterocyclyl, -O-C １～４ Alkylene-C ３～１０ Cycloalkyl, 5-10 membered heteroaryl, -O-C １～４ Alkylene-3 to 12-membered heterocyclyl, -O-5 to 10-membered heteroaryl, and -O-C １～４ Alkylene-5 to 10-membered heteroaryls are halo, hydroxyl, oxo, and C. １～６ Alkyl, C １～６ Alkoxyl, C １～６ Haloalkoxyl, -NR ａａ R ｂｂ , C ３～１０ Optionally substituted with 1 to 4 groups independently selected from cycloalkyl and 3- to 12-membered heterocyclines; Each R ６ and R ７ is independently selected from hydrogen, halo, hydroxyl, C １～６ alkyl, C １～６ alkoxyl, C １～６ haloalkyl, and C １～６ haloalkoxyl; R ８ is selected from hydrogen, halo, hydroxyl, oxo, C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ alkoxyl, -O-C ２～６ alkenyl, -O-C ２～６ alkynyl, C ３～１０ cycloalkyl, 3- to 12-membered heterocyclyl, C ６～１０ aryl, 5- to 10-membered heteroaryl, -O-C ３～１０ cycloalkyl, -O-3- to 12-membered heterocyclyl, -O-C ６～１０ aryl, -O-5- to 10-membered heteroaryl, -O-C １～４ alkylene-C ３～１０ cycloalkyl, -O-C １～４ alkylene-3- to 12-membered heterocyclyl, -O-C １～４ alkylene-C ６～１０ aryl, and -O-C １～４ alkylene-5- to 10-membered heteroaryl; R ９ It is absent when R 8 is an oxo, or is hydrogen, halo, hydroxyl, or C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkoxyl, -O-C ２～６ Alkenyl, -O-C ２～６ Alkinyl, C ３～１０ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１０ Aryl, 5-10 member heteroaryl, -O-C ３～１０ Cycloalkyl, -O-3 to 12-membered heterocyclyl, -O-C ６～１０ Aryl, -O-5 to 10-membered heteroaryl, -O-C １～４ Alkylene-C ３～１０ Cycloalkyl, -O-C １～４ Alkilen-3 to 12-membered heterocyclyl, -O-C １～４ Alkylene-C ６～１０ Aryl, and -O-C １～４ Selected from alkylene-5 to 10-membered heteroaryls; Here, R ８ and R ９ Each C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkoxyl, -O-C ２～６ Alkenyl, -O-C ２～６ Alkinyl, C ３～１０ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１０ Aryl, 5-10 member heteroaryl, -O-C ３～１０ Cycloalkyl, -O-3 to 12-membered heterocyclyl, -O-C ６～１０ Aryl, -O-5 to 10-membered heteroaryl, -O-C １～４ Alkylene-C ３～１０ Cycloalkyl, -O-C １～４ Alkilen-3 to 12-membered heterocyclyl, -O-C １～４ Alkylene-C ６～１０ Aryl, and -O-C １～４ Alkylene-5 to 10-membered heteroaryls have 1 to 5 R Ａ It is independently and arbitrarily substituted; R １０ It is a halo; Each R １１ , R １２ , R １３ , and R １４ is hydrogen; Each R Ａ is halo, hydroxyl, oxo, -CN, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkoxyl, C １～６ Haloalkyl, C １～６ Haloalkoxyl, -C １～４ Alkylene-OC １～４ Alkyl, C ３～１０ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１０ Aryl, 5-10 membered heteroaryl, and -NR ａａ R ｂｂ Selected independently of; Here, R Ａ Each C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkoxyl, C １～６ Haloalkyl, C １～６ Haloalkoxyl, -C １～４ Alkylene-OC １～４ Alkyl, C ３～１０ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１０ Aryl, 5-10 member heteroaryls are halo, hydroxyl, -CN, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Haloalkyl, C １～６ Haloalkoxyl, C ３～１０ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１０ Aryl, 5-10 membered heteroaryl, and -NR ａａ R ｂｂ It is independently replaced by 1 to 3 elements independently selected from; Each R ａａ and R ｂｂ is hydrogen, C １～６ Alkyl, C ３～１０ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１０ Aryl, 5-10 member heteroaryl, -C １～６ Alkylene-C ３～１０ Cycloalkyl, -C １～６ Alkilen-3 to 12-membered heterocyclyl, -C １～６ Alkylene-C ６～１０ Aryl, and -C １～６ Independently selected from alkylene-5 to 10-membered heteroaryls; Here, R ａａ and R ｂｂ Each C １～６ Alkyl, C ３～１０ Cycloalkyl, 3-12 membered heterocyclyl, C ６～１０ Aryl, 5-10 member heteroaryl, -C １～６ Alkylene-C ３～１０ Cycloalkyl, -C １～６ Alkilen-3 to 12-membered heterocyclyl, -C １～６ Alkylene-C ６～１０ Aryl, and -C １～６ Alkylene-5 to 10-membered heteroaryls are halos, C １～６ Alkyl, -CN, C １～６ Alkoxyl, and C １～６ They are independently and optionally substituted with 1 to 4 groups independently selected from the haloalkyl group; Here, the 3- to 12-membered heterocyclil is nitrogen, sulfur, phosphorus, -N(O)-, -S(O)-, and S(O) ２ - A monocyclic or polycyclic ring having 1 to 4 heteroatoms independently selected from; and the polycyclic ring may be condensed, bridged, or spiro; and Here, the 5-10 membered heteroaryl is an aromatic group having a monocyclic or polycyclic ring; here, the 5-10 membered heteroaryl is nitrogen, oxygen, sulfur, -N(O)-, -S(O)-, and -S(O) ２ A compound containing 1 to 4 heteroatoms independently selected from the above, or a pharmaceutically acceptable salt thereof.

2. R １６ but, 【Chemistry 2-1】 【Chemistry 2-2】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

3. R ４ However, hydrogen, hydroxyl, F, -CH ３ ien-CH ２ CH ３ ien-CH ２ CH ２ CH ３ , -OCH ３ , -OCH ２ CH ３ , -OCH ２ CH ２ CH ３ , 【Transformation 3】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

4. R ５ However, hydrogen, hydroxyl, and -OCH ３ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

5. Each R ８ and R ９ OH, F, -CH ３ , 【Chemistry 5-1】 【Chemistry 5-2】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, independently selected from the above.

6. R ８ but, 【Transformation 6】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. below: 【Chemistry 7-1】 【Chemistry 7-2】 【Transformation 7-3】 【Chemistry 7-4】 【Transformation 7-5】 【Transformation 7-6】 【Transformation 7-7】 [Transformation 7-8] 【Transformation 7-9】 A compound selected from, or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

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