Amino-substituted heterocycles for treating cancers with EGFR mutations

Abstract

To provide a new generation of receptor tyrosine kinase inhibitors that spare wild-type EGFR, penetrate the blood-brain barrier, and show specific activity against exon 20 insertions and / or drug-resistance mutations.SOLUTION: Disclosed are amino-substituted heteroaromatic compounds, for example 4-amino-quinazolines, pharmaceutically acceptable salts of the compounds, and pharmaceutical compositions thereof. Also disclosed are methods of treating or preventing cancer using the amino-substituted heteroaromatic compounds, pharmaceutically acceptable salts of the compounds, and pharmaceutical compositions thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application is a continuation of U.S. Provisional Patent Application No. 63 / 174,177, filed April 13, 2021. No. 63 / 239,089 filed August 31, 2021; No. 63 / 239,089 filed September 1, 2021 No. 63 / 242,837, filed on December 22, 2021; The present application claims priority to application No. 63 / 292,605, the contents of which are incorporated herein by reference. and is incorporated herein by reference. [Background technology]

[0002] Receptor tyrosine kinases (RTKs) transmit proliferation signals and other cell signals through their kinase activity. RTKs are cell surface proteins that transmit external signals to cells. Regulates many important biological processes, including cellular homeostasis. Abnormalities in the nucleus can lead to uncontrolled cell proliferation, which ultimately leads to Causes cancer.

[0003] Human epidermal growth factor receptor (HER) family proteins were first identified and are associated with cancer. HER is also known as ErbB, a name that is associated with The HER family is derived from the erythroblastosis oncogene B, a virus homologue. Contains three members: EGFR / HER1 / ErbB1, HER2 / ErbB2, HER 3 / ErbB3, and HER4 / ErbB4. They have an extracellular domain that binds to ligands. They share a highly related structure containing a membrane domain, a single transmembrane domain, and an intracellular kinase domain. EGFR (e.g., EGF and TGF-α) and HER3 / HER4 (e.g., Although several ligands for neuregulins have been identified, the ligand for HER2 is unknown. Upon activation, HER receptors form homo- or heterodimers and bind to mitochondria. ATP-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K) ), and catalyze downstream signaling via other pathways.

[0004] Dysregulation of EGFR is a hallmark of many cancers. Cancer cells express overexpressed, missense EGFR is hyperactivated by a variety of mechanisms, including mutations, insertions, and deletions. EGFR is involved in the progression of many solid tumors, including non-small cell lung cancer (NSCLC), breast cancer, and glioblastoma. , frequently overexpressed in prostate cancer, colorectal cancer, head and neck cancer, and many other solid tumors EGFR variant 3 (EGFR variant 2) with a large deletion of exons 2 to 7 I) is found in approximately 30% of glioblastomas. Various activating mutations in EGFR causes approximately 30% of NSCLC, with a higher prevalence in adenocarcinoma histology, non-smokers These activating mutations are associated with genotypes in older people, Asians, and women. L858R in exon 19), short deletions in exon 19 (mainly E746_A750del ), a short insertion in exon 20, and other more unusual variants not explicitly mentioned herein. Mutations further classified as L858R, E746_A750del, and exon 20 insertion account for approximately 35-40%, 40-45%, and 60% of all EGFR-mutant NSCLC cases, respectively. It accounts for 5-10% of the total.

[0005] HER2 dysregulation is also a well-documented cause of cancer. HER2 overexpression is associated with breast cancer. It is found in 15-25% of cases and is one of the major molecular subtypes of breast cancer. It is also found in ovarian, gastric, esophageal, endometrial, and lung cancers. Mutations are found in approximately 2% of NSCLC patients, but unlike EGFR, they are rarely expressed Limited to Son20 insertions (mainly A775_G776insYVMA).

[0006] Known drugs used to treat oncogenic EGFR or HER2 include: These have major drawbacks, including one or more of the following: toxicity due to wild-type EGFR inhibition, central nervous system Restricted activity in the central nervous system (CNS), as well as exon 20 insertions and drug resistance mutations EGFR is a critical epithelial regulator in the adult gastrointestinal lining and skin. Therefore, inhibition of non-mutated EGFR is thought to cause adverse reactions such as diarrhea and rash. These are considered to be general safety signals for many existing EGFR inhibitors. Up to 60% of patients with EGFR-mutant NSCLC and most patients with HER2-mutant NSCLC Up to 45% of patients develop brain metastases during the course of their disease. Therefore, CNS activity is a key factor in future therapeutic development. Among the major types of EGFR and HER2 mutations, exon 20 insertions are The number of patients receiving FDA-approved targeted therapy for these indications remains unmet. For these reasons, we have developed a method to preserve wild-type EGFR and penetrate the blood-brain barrier. and new generation of ribozymes that show specific activity against exon 20 insertions and / or drug resistance mutations. The development of inhibitors is necessary. Summary of the Invention

[0007] In certain aspects, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, , in the formula, [ka] is a 3- to 10-membered heterocyclyl; [ka] is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, R 1 CN, C 1~5 Alkyl, C 1~5 Haloalkyl, C 2~5 Alkenyl, C 2~ 5-membered alkynyl, or 3- to 6-membered heterocyclyl, aryl, alkynyl, or heterocyclyl may be one or more R a is optionally replaced by occurrences of And, R a independently in each occurrence, halo, CN, N(R n1 )2, optionally substituted C1 ~5 Alkyl, -OC 1~5 Alkyl, -OC 1~5 Alkylene-OC 1~5 Al Kill, -CO2-C 1~5 Alkyl or optionally substituted 3- to 6-membered heterocyclyl or two R a taken together to form an optionally substituted alkenyl group And, Each R n1 are independently hydrogen or C 1~5 is alkyl, J is NR b and X 1 is CH or J is a bond and X 1 is N, Rb is hydrogen or an optionally substituted C 1~5 is alkyl, R 2 independently in each occurrence represents an optionally substituted C 1~5 is alkyl, or Two geminal R's 2 are taken together to form an oxo moiety, or Two non-geminal R 2 The occurrences of are grouped together and labeled C1-C4 (e.g., C1-C2) forming an alkylene bridge or R d and R 2 The appearance of taken together to form a 5- to 8-membered heterocyclic ring, n is 0 or an integer from 1 to 3 (inclusive) as valence permits; X 2 is -C=, -CH-, or N, U is for CR c or N, R c is hydrogen, halo, or optionally substituted C 1~5 is an alkoxy, V is CR d or N, R d is hydrogen, halo, optionally substituted C 1~5 Alkyl or optionally substituted C 1~5 Alkoxy or R d and R 2 The appearance of are bound together to form a 3- to 6-membered heterocyclic ring, W is N or CR e and R e is hydrogen, halo (e.g., fluoro), or cyano; Y 1 and Y 2 are independently CH, CR 4 , or N, where Y 1 and Y 2 At least one of the 4 and R 4 represents, independently in each occurrence, halo, optionally substituted C 1~5 Alkyl, or C replaced arbitrarily 1~5 is an alkoxy, m is 0 or an integer from 1 to 4 (inclusive) as valence permits; R 5 represents, independently in each occurrence, halo, optionally substituted C 1~5 Alkyl, or C replaced arbitrarily 1~5 is an alkoxy, p is 0 or an integer from 1 to 3 (inclusive) as far as valence allows, provides a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0008] In some embodiments of formula (I) (or subformulas thereof), V is N, or [ka] teeth, [ka] where: [ka] is a 5- or 6-membered heteroaryl, and Z 1 , Z 2 , Z 3 , and Z 4 are each unique It is C or N, [ka] Any atom in R can be 5 may be substituted by:

[0009] In one embodiment of formula (I) (or a subformula thereof), [ka] but, [ka] and [ka] but, [ka] and Y 1 and Y 2 However, each independently, CR 4 If Y 2 R in 4 teeth, C 1~5 is alkyl, and Y 1 R in 4 is a halo. In this state, Y 2 R in 4 is methyl. In one embodiment, Y 1 R in 4 Ha, Fu In one embodiment, Y 2 R in 4 is methyl, and Y 1 R in 4 is fluoro.

[0010] In one embodiment of formula (I) (or a subformula thereof), [ka] is a 6- to 10-membered bicyclic heterocyclyl or a 3- to 5- or 7- to 8-membered monocyclic heterocyclyl. It is cyclocyclyl.

[0011] In certain aspects, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, , in the formula, [ka] is a 4- to 7-membered heterocyclyl; R 1 teeth, [ka] and R a1 , R a2 , R a3 , and R a4 each independently represents hydrogen, halo, CN, N(R n 1 )2, optionally substituted C 1~5 Alkyl, optionally substituted -CH2O-C 1~5 a alkyl, optionally substituted -CH2O-(CH2) 1~2 -OC 1~5 Alkyl, any -CO2-C 1~5 Alkyl or optionally substituted 3- to 6-membered heterocycle Krill or R a1 and R a2 are linked together to form an alkenyl group And, Each R n1 are independently hydrogen or C 1~5 is alkyl, or R a1 and R a2 are linked together to form an alkenyl group, R 2 independently in each occurrence represents an optionally substituted C 1~5 is alkyl, or Two geminal R's 2 are taken together to form an oxo moiety, or Two non-geminal R 2 The occurrences of are grouped together and labeled C1-C4 (e.g., C1-C2) forming an alkylene bridge or R d and R 2 The appearance of taken together to form a 5- to 8-membered heterocyclic ring, n is 0 or an integer from 1 to 3 (inclusive) as valence permits; X 2 is -C=, -CH-, or N, U is for CR c or N, R c is hydrogen, halo, or optionally substituted C 1~5 is an alkoxy, V is CR d or N, R d is hydrogen, halo, optionally substituted C 1~5 Alkyl or optionally substituted C 1~5 Alkoxy or R d and R 2 The appearance of are bound together to form a 3- to 6-membered heterocyclic ring, W is N or CR e and R e is hydrogen, halo (e.g., fluoro), or cyano; R 6 , R 7 , R 8 , and R 9 are each independently hydrogen, halo, or an optionally substituted C1 ~5 Alkyl, or optionally substituted C 1~5 is an alkoxy, R 10 is hydrogen, halo, or optionally substituted C 1~5 is alkyl, Q 1 , Q 2 , Q 3, and Q 4 are each independently, NR f or CR g where , Q 1 , Q 2 , Q 3 , and Q 4 At least one of the g and R f represents, independently in each occurrence, hydrogen, optionally substituted C 1~5 Alkyl, or non Being, R g represents, independently in each occurrence, hydrogen, optionally substituted C 1~5 Alkyl, or non or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, Provide isomers.

[0012] In one embodiment of formula (II) (or a subformula thereof), [ka] but, [ka] and [ka] but, [ka] If R 8 is C 1~5 alkyl, and R 6 is a halo. In one embodiment, R 8 is methyl. In one embodiment, R 6 is fluoro. In embodiments, R 8 is methyl and R 6 is fluoro.

[0013] In certain embodiments, the compound of formula (II) has formula (III): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, , in the formula, R 11 , R 12 , R 13 , and R 14 are each independently hydrogen or an optionally substituted C 1~5 alkyl or R 11 , R 12 , R 13 , and R 14 Of the non Two geminal occurrences are grouped together to form a C1-C4 (e.g., C1-C2) alkylene The compound, or a pharmaceutically acceptable salt, stereoisomer, or or tautomers.

[0014] In certain aspects, the present disclosure provides a compound of formula (aI): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, , in the formula, [ka] is a 3- to 10-membered heterocyclyl; [ka] is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, R 1 CN, C 1~5 Alkyl, C 1~5 Haloalkyl, C 2~5 Alkenyl, C 2~ 5-membered alkynyl, or 3- to 6-membered heterocyclyl, aryl, alkynyl, or heterocyclyl may be one or more R a is optionally replaced by occurrences of And, R a independently in each occurrence, halo, CN, N(R n1 )2, optionally substituted C1 ~5 Alkyl, -OC 1~5 Alkyl, -OC 1~5 Alkylene-OC 1~5 Al Kill, -CO2-C 1~5 Alkyl or optionally substituted 3- to 6-membered heterocyclyl or two R a taken together to form an optionally substituted alkenyl group And, Each R n1 are independently hydrogen or C 1~5 is alkyl, J is NR b and X 1 is CH or J is a bond and X 1 is N, R b is hydrogen or an optionally substituted C 1~4 is alkyl, K is a bond, C=O, or SO2; R 2 independently in each occurrence represents an optionally substituted C 1~5 is alkyl, or Two geminal R's 2 are taken together to form an oxo moiety, or Two non-geminal R 2 The occurrences of are grouped together and labeled C1-C4 (e.g., C1-C2) forming an alkylene bridge or R d and R 2 The appearance of taken together to form a 5- to 8-membered heterocyclic ring, n is 0 or an integer from 1 to 3 (inclusive) as valence permits; X 2 is -C=, -CH-, or N, U is for CR c or N, R c is hydrogen, halo, or optionally substituted C 1~5 is an alkoxy, V is CR d or N, R d is hydrogen, halo, optionally substituted C 1~5 Alkyl or optionally substituted C 1~5 Alkoxy or R d and R 2 The appearance of are bound together to form a 3- to 6-membered heterocyclic ring, W is N or CR e and R e is hydrogen, halo (e.g., fluoro), or cyano; Y 1 and Y 2 are independently CH, CR 4 , or N, where Y 1 and Y 2 At least one of the 4 and R 4 represents, independently in each occurrence, halo, optionally substituted C 1~5 Alkyl, or C replaced arbitrarily 1~5 is an alkoxy, m is 0 or an integer from 1 to 4 (inclusive) as valence permits; R 5 represents, independently in each occurrence, halo, optionally substituted C 1~5 Alkyl, or C replaced arbitrarily 1~5 is an alkoxy, p is 0 or an integer from 1 to 3 (inclusive) as far as valence allows, provides a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0015] In some embodiments of formula (aI) (or subformulas thereof), K is C=O or V is N, or [ka] but [ka] where: [ka] is a 5- or 6-membered heteroaryl, and Z 1 , Z 2 , Z 3 , and Z 4 are each unique It is C or N, [ka] Any atom in R can be 5 provided that it may be substituted by:

[0016] In one embodiment of formula (aI) (or a subformula thereof), K is a bond. In one embodiment of formula (aI) (or a subformula thereof), K is C=O. In one embodiment of that subformula, K is SO2.

[0017] In certain aspects, the present disclosure provides a compound of formula (Ii): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, , During the ceremony, [ka] is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, R 1 is C 1~5 Alkyl, C 1~5 Haloalkyl, C 2~5 Alkenyl, C 2~5 Al quinyl, or 3- to 6-membered heterocyclyl, A cyclic or heterocyclyl group may be one or more R a is optionally replaced by occurrences of , R a independently in each occurrence, halo, CN, N(R n1 )2, optionally substituted C1 ~5 Alkyl, optionally substituted -OC 1~5 Alkyl, optionally substituted -O-C1 ~5 Alkylene-OC 1~5 Alkyl, optionally substituted -CO2-C 1~5 Alkyl or an optionally substituted 3- to 6-membered heterocyclyl; Each R n1 are independently hydrogen or C 1~5 is alkyl, J is NR b and X 1 is CH or J is a bond and X 1 is N, s is 0, 1, or 2; t is 1 or 2, R b is hydrogen or an optionally substituted C 1~5 is alkyl, R 2 independently in each occurrence represents an optionally substituted C 1~5 is alkyl, or Two geminal R's 2are taken together to form an oxo moiety, or Two non-geminal R 2 The occurrence of,summarized,C 1~4 Forming an alkylene bridge And, n is 0 or an integer from 1 to 3 (inclusive) as valence permits; U is for CR c or N, V is CR d or N, with the proviso that at least one of U and V is N; R c is hydrogen, halo, or optionally substituted C 1~5 is an alkoxy, R d is hydrogen, halo, optionally substituted C 1~5 Alkyl or optionally substituted C 1~5 Alkoxy or R d and R 2 The appearance of It is bound to form a 5-6 membered heterocyclic ring, W is N or CR e and R e is hydrogen, halo, or cyano; Y 1 and Y 2 are independently CH, CR 4 , or N, where Y 1 and Y 2 At least one of the 4 and R 4 represents, independently in each occurrence, halo, optionally substituted C 1~5 Alkyl, or C replaced arbitrarily 1~5 is an alkoxy, m is 0 or an integer from 1 to 4 (inclusive) as valence permits; R 5 represents, independently in each occurrence, halo, optionally substituted C1~5 Alkyl, or C replaced arbitrarily 1~5 is an alkoxy, p is 0 or an integer from 1 to 3 (inclusive) as far as valence allows, provides a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0018] In certain embodiments, the compound of formula (Ii) has the formula (Iia): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0019] In certain embodiments, the compound of formula (Ii) has the formula (Ii-a0): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0020] In certain embodiments, the compound of formula (Ii) has the formula (Ii-a1): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, , During the ceremony, R 6 , R 7 , R 8 , and R 9 are each independently hydrogen, halo, or an optionally substituted C1 ~5 Alkyl, or optionally substituted C 1~5 is an alkoxy, R 10 is hydrogen, halo, or optionally substituted C 1~5 is alkyl, Q 1 , Q2 , Q 3 , and Q 4 are each independently NR as far as valence allows. f or CR g where Q 1 , Q 2 , Q 3 , and Q 4 At least one of the g Yes the law of nature, R f represents, independently in each occurrence, hydrogen, optionally substituted C 1~5 Alkyl, or non Being, R g represents, independently in each occurrence, hydrogen, optionally substituted C 1~5 Alkyl, or non Being, R 11 , R 12 , R 13 , and R 14 are each independently hydrogen or an optionally substituted C 1~5 alkyl or R 11 , R 12 , R 13 , and R 14 2 of are joined together to form a C1-C4 alkylene bridge.

[0021] In certain embodiments, the compound of formula (Ii-a1) has the following formula: [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0022] In certain embodiments, the compound of formula (Ii-a1) has the following formula: [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0023] In certain embodiments, the compound of formula (Ii-a1) has the following formula: [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0024] In certain embodiments, the compound of formula (Ii-a1) has the following formula: [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0025] In certain embodiments, the compound of formula (Ii-a1) has formula (Ii-a2): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0026] In certain embodiments, the present disclosure provides a method for administering to a patient a therapeutically effective amount of a compound described herein (e.g., Formula (I), (Ii) (Iia), (Ii-a1), (Ii-a2), (aI ), (II), or (III), or a compound of any of their sub-formulas; any of its pharmaceutically acceptable salts, stereoisomers, or tautomers, and For use in a subject in the treatment or prevention of cancer, comprising one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical formulation is a pharmaceutical composition suitable for administering the pharmaceutical The compound may be for use in the treatment or prevention of a condition or disease described in

[0027] An aspect of the present disclosure is a method of treating cancer, comprising administering an effective amount of a compound disclosed herein. (For example, Formula (I), (Ii), (Iia), (Ii-a1), (Ii-a2) ), (aI), (II), or (III), or a compound disclosed herein any of these embodiments) or the pharmaceutical compositions provided herein, the method, including administering to a mammal (e.g., a human subject) in need of cancer treatment. In certain embodiments, a method for treating a HER2-associated cancer comprises administering to a subject an effective amount of The compounds disclosed herein (e.g., compounds of formula (I), (Ii), (Iia), (I -i-a1), (Ii-a2), (aI), (II), or (III) or any of the embodiments thereof disclosed herein) or The pharmaceutical compositions provided herein are administered to a mammal in need of treatment for a HER2-associated cancer (e.g., Such methods are provided herein, comprising administering to a subject (a human subject) a compound comprising: In certain embodiments, a human subject is in need of such treatment. The subject has been identified or diagnosed with a HER2-associated cancer. In certain embodiments, the HER2-associated cancer is a cancer caused by a gene encoding the HER2 gene, HER2 kinase, or other The present invention relates to dysregulation of the expression, activity, or levels of any of these proteins. In embodiments, the HER2-associated cancer is characterized by HER2 overexpression and / or HER2 amplification, and and / or associated with HER2 mutation(s). In certain embodiments, the cancer is a solid tumor. In certain embodiments, HER2-associated cancers include, but are not limited to, , non-small cell lung cancer, breast cancer, ovarian cancer, brain cancer, biliary tract cancer, cervical cancer, gastric cancer, esophageal cancer, endometrial cancer, Glioblastoma, prostate cancer, skin cancer, esophageal tumor, colorectal cancer, bladder cancer, gastrointestinal cancer, gallbladder tumor, These include kidney cancer, liver cancer, prostate cancer, and head and neck cancer. In some embodiments, the HER2-associated cancer is non-small cell lung cancer. In some embodiments, the HER2-associated cancer is breast cancer. In certain embodiments, the HER2-associated cancer is brain cancer. In this condition, HER2 exon 20 mutations were selected from YVMA insertion, VC insertion, and GSP insertion. In certain embodiments, the HER2 exon 20 mutation is one or more selected from the group consisting of A7 75_G776insYVMA, P780_Y781insGSP, G776>VC, G 776>IC, G776>LC, G778_S779insCPG, G780_P781 dupGSP, Y772_A775dup, G778_P780dup, E770_A7 71insGIRD, G778_S779insLPS, M774_A775insAY VM, G778_S779insLPG, G778dup, G776delinsVC, M774delinsWLV, A775_G776insSVMA, and A775_G7 76insI. In certain embodiments, the HER2 exon The 20 mutations are A775_G776insYVMA, P780_Y781insGSP, G776>VC, G776>IC, G776>LC, G778_S779insCPG, and G780_P781dupGSP. In this state, HER2 exon 20 mutations are A775_G776insYVMA, P780_ Y781insGSP, G776>VC, G776>IC, G776>LC, and G77 8_S779insCPG.

[0028] In some embodiments, the method of treating or preventing cancer comprises administering to a patient a compound of Formula (I), (Ii), (Iii), (Iiii), (Iiv), (Iv), (Ivi), (Iv ... Iia), (Ii-a1), (Ii-a2), (aI), (II), (III ), or a compound of a sub-formula thereof, in combination with a second therapeutic agent (e.g., an immunomodulator or a platinum-containing compound). The administration may include administering the compound by co-administration with a compound (an analogue). [Brief explanation of the drawings]

[0029] [Figure 1] Certain exemplary compounds encompassed by the present invention are shown. [Figure 2] Certain exemplary compounds encompassed by the present invention are shown. [Figure 3] Certain exemplary compounds encompassed by the present invention are shown. [Figure 4] Certain exemplary compounds encompassed by the present invention are shown. [Figure 5] Certain exemplary compounds encompassed by the present invention are shown. [Figure 6] Certain exemplary compounds encompassed by the present invention are shown. [Figure 7] Certain exemplary compounds encompassed by the present invention are shown. [Figure 8] Certain exemplary compounds encompassed by the present invention are shown. [Figure 9] Certain exemplary compounds encompassed by the present invention are shown. [Figure 10] Certain exemplary compounds encompassed by the present invention are shown. [Figure 11] Certain exemplary compounds encompassed by the present invention are shown. [Figure 12] Certain exemplary compounds encompassed by the present invention are shown. [Figure 13]Certain exemplary compounds encompassed by the present invention are shown. [Figure 14] Certain exemplary compounds encompassed by the present invention are shown. [Figure 15] Certain exemplary compounds encompassed by the present invention are shown. [Figure 16] Certain exemplary compounds encompassed by the present invention are shown. [Figure 17] Certain exemplary compounds encompassed by the present invention are shown. DETAILED DESCRIPTION OF THE INVENTION

[0030] definition Unless otherwise defined, all technical and scientific terms used herein are The following references are incorporated herein by reference in their entirety:

[0004] Singleton et al. provide general definitions of many of the terms used in this document to those skilled in the art. al.,Dictionary of Microbiology and Mole cular Biology(2nd ed.1994), The Cambridge Dictionary of Science and Technology(Wa ed., 1988), The Glossary of Genetics, 5th Ed., R. Rieger et al.(eds.), Springer V erlag (1991), and Hale & Marham, The Harper C. Collins Dictionary of Biology (1991). When used, the following terms have the meanings given to them below unless otherwise specified: do.

[0031] In some embodiments, the chemical structures are disclosed along with the corresponding chemical names. , the meaning of the chemical structure takes precedence over the chemical name.

[0032] In this disclosure, "comprises," "comprising," "," "containing," and "having" are used in the United States Patent Law. "includes", "include" and "includes It can mean "consisting essentially of" or "consisting essentially of". "partially of" or "consists essential "(ly)" also has the meaning given to it in U.S. patent law, and such term shall not be construed as an open The invention is a product of a technology that is fundamental or novel to the things listed by the existence of other things than those listed. The existence of other than those listed is permitted as long as the characteristics are not substantially changed, but the implementation of prior art Form is excluded.

[0033] As used herein, unless otherwise stated or clear from the context, the term "Or" is understood to be inclusive. Unless otherwise specified or clear from the context, Unless otherwise specified, as used herein, the terms "a," "an," and "the" refer to the singular or It is understood that the plural is either plural or plural.

[0034] The term "acyl" is art-recognized and refers to a group having the general formula: hydrocarbyl C (O)-, preferably alkylC(O)-.

[0035] The term "acylamino" is art recognized and refers to a group substituted with an acyl group. It refers to an amino group which may be represented, for example, by the formula: hydrocarbylC(O)NH—.

[0036] The term "acyloxy" is art recognized and refers to a group having the general formula: It refers to a group represented by alkylC(O)O—, preferably alkylC(O)O—.

[0037] The term "alkoxy" refers to an alkyl group having an oxygen attached thereto, preferably a lower alkyl group. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert- butoxy, etc.

[0038] The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group, and has the general formula : alkyl-O-alkyl.

[0039] As used herein, the term "alkenyl" refers to an alkyl group containing at least one double bond. It refers to an aliphatic group and is intended to include both "unsubstituted alkenyl" and "substituted alkenyl". The latter has a substituent in place of a hydrogen on one or more carbons of the alkenyl group. Such substituents may be contained within or not contained within one or more double bonds. Furthermore, such substituents may be present on one or more carbon atoms that are not stable. Except where indicated, all of the contemplated alkyl groups are included below. Examples: For example, one or more alkyl, carbocyclyl, aryl, heterocyclyl, or hetero Substitution of alkenyl groups by aryl groups is contemplated.

[0040] An "alkyl" group or "alkane" is a straight- or branched-chain non-aromatic carbon atom that is fully saturated. Typically, a straight or branched chain alkyl group has 1 to about 2 carbon atoms, unless otherwise defined. Examples of straight and branched chain alkyl groups include alkyl groups having 0 to 10 carbon atoms, preferably 1 to about 10 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, and sec-butyl. C1, tert-butyl, pentyl, hexyl, pentyl, and octyl. A .about.C6 straight or branched chain alkyl group is also referred to as a "lower alkyl" group.

[0041] Additionally, the term "alkyl" (as used throughout the specification, examples, and claims) or "lower alkyl") encompasses both "unsubstituted alkyl" and "substituted alkyl." The latter is intended to have substituents in place of hydrogens on one or more carbons of the hydrocarbon backbone. Such substituents include, for example, halo, unless otherwise specified. halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, hydroxyl, methyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphine Contain, amino, amide, amidine, imine, cyano, nitro, azide, sulfhydryl alkyl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl phenyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. The moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For example, the substituents of a substituted alkyl include substituted and unsubstituted alkyl groups. and unsubstituted amino, azido, imino, amido, phosphoryl (phosphonate and phosphine) sulfonyl (including sulfates, sulfonamides, sulfamoyl, and sulfonates), and silyl groups, as well as ether, alkylthio, carboxylate, Bornyl (including ketones, aldehydes, carboxylates, and esters), -CF3 , -CN, etc. Exemplary substituted alkyls are described below. is an alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl group It may be further substituted with alkyl, -CF3, -CN, and the like.

[0042] The term “C x~y " is an acyl, acyloxy, alkyl, alkenyl, alkynyl, or When used with a chemical moiety such as alkoxy, it refers to a group containing x to y carbons in the chain. For example, the term "C x~y "Alkyl" means a group containing x to y carbon atoms in the chain. Substituted or unsubstituted saturated hydrocarbon groups, including straight chain alkyl and branched chain alkyl groups, e.g. For example, haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. CO alkyl refers to hydrogen when the group is in a terminal position and hydrogen when it is in an internal position. The term "C 2~y alkenyl" and "C 2~y "Alkynyl" means any of the above alkyl groups. are similar in length and possible substitution to, but each has at least one double bond or refers to a substituted or unsubstituted unsaturated aliphatic group containing a triple bond.

[0043] As used herein, the term "alkylamino" refers to an amino group having at least one alkyl group. Refers to a substituted amino group.

[0044] As used herein, the term "alkylthio" refers to a thiol substituted with an alkyl group. It refers to a group that can be represented by the general formula: alkylS-.

[0045] As used herein, the term "alkynyl" refers to an alkyl group containing at least one triple bond. It refers to an aliphatic group and is intended to include both "unsubstituted alkynyl" and "substituted alkynyl". The latter is an alkynyl group having a substituent in place of a hydrogen atom on one or more carbon atoms of the alkynyl group. Such substituents may or may not be contained within one or more triple bonds. It may be present on one or more carbon atoms. Furthermore, such substituents may be present if they inhibit stability. Included are all of the contemplated alkyl groups as described above, except for: , one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl Substitution of alkynyl groups with alkyl groups is contemplated.

[0046] As used herein, the term "amide" refers to the group: [ka] In the formula, each R 30 independently represent hydrogen or a hydrocarbyl group, or 2 R's 30 are grouped together with the N atoms to which they are attached to form a ring structure with 4 to 8 It forms a heterocyclic ring with atoms.

[0047] The terms "amine" and "amino" are art-recognized and refer to unsubstituted and Both substituted amines, as well as their salts, e.g., [ka] wherein each R 31 are independently hydrogen or hydrocarbyl represents a methyl group, or two R 31 are grouped together with the N atoms to which they are attached. As used herein, the term "aromatic ring" refers to a heterocyclic ring having 4 to 8 atoms in the ring structure. The term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0048] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group. Refers to...

[0049] As used herein, the term "aryl" refers to a substituted or unsubstituted alkyl group in which each atom of the ring is carbon. The ring preferably has 5 to 7 members, more preferably 6 members. The term "aryl" refers to a ring in which two or more carbons are shared between two adjacent rings, At least one of the rings is aromatic, e.g., the other cyclic ring is a cycloalkyl , cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heteroaryl The term also encompasses polycyclic ring systems having more than one cyclic ring, which may be a cycloalkyl group. Examples include benzene, naphthalene, phenanthrene, phenol, and aniline. do.

[0050] The term "carbamate" is art recognized and refers to a group: [ka] In the formula, R 32 and R 33 are independently hydrogen or a hydrocarbyl group, e.g. , an alkyl group, or R 32 and R 33 is grouped together with the atom(s) in between. The ring structure is a heterocycle having 4 to 8 atoms.

[0051] As used herein, the terms "carbocycle" and "carbocyclic" refer to a ring in which each atom is carbon. The term carbocycle refers to both aromatic and non-aromatic carbocycles. Non-aromatic carbocycles include cycloalkane rings in which all carbon atoms are saturated, and and cycloalkene rings containing at least one double bond.

[0052] The term "carbocycle" includes 5- to 7-membered monocyclic rings and 8- to 12-membered bicyclic rings. Each ring in the carbocycle may be selected from saturated, unsaturated, and aromatic rings. It also includes bicyclic molecules in which one, two or more atoms are shared between the two rings. "Fused carbocycle" refers to a bicyclic carbocycle in which each ring shares two adjacent atoms with the other ring. Each ring of the fused carbocycle may be selected from saturated rings, unsaturated rings, and aromatic rings. In embodiments, the aromatic ring, e.g., phenyl, may be a saturated or unsaturated ring, e.g., cyclohexyl. It may be condensed with cyclohexane, cyclopentane, or cyclohexene, as long as valence permits. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocyclic. Exemplary "carbocycles" include cyclopentane, cyclohexane, bicyclo[2.2.1 ]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydro Naphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H- indene, and bicyclo[4.1.0]hept-3-ene. It may be substituted at any one or more positions that can have a hydrogen atom.

[0053] A "cycloalkyl" group is a cyclic hydrocarbon that is fully saturated. The cycloalkyl groups include monocyclic and bicyclic rings. Typically, monocyclic cycloalkyl groups are particularly Unless otherwise defined, alkyl groups have from 3 to about 10 carbon atoms, more typically from 3 to 8 carbon atoms. The second ring of the bicyclic cycloalkyl is selected from a saturated ring, an unsaturated ring, and an aromatic ring. Cycloalkyl can be a group in which one, two, or three or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic molecule in which each ring is bonded to the other ring. refers to bicyclic cycloalkyls sharing two adjacent atoms. The second ring may be selected from saturated, unsaturated, and aromatic rings. is a cyclic hydrocarbon containing one or more double bonds.

[0054] As used herein, the term "carbocyclylalkyl" refers to a carbocyclic group substituted with Refers to an alkyl group.

[0055] The term "carbonate" is art recognized and refers to the group: -OCO-R 34 where R 34 represents a hydrocarbyl group.

[0056] As used herein, the term "carboxy" refers to a group represented by the formula: -CO2H. Point.

[0057] As used herein, the term "ester" refers to the group: -C(O)OR 35 Here, So, R 35 represents a hydrocarbyl group.

[0058] As used herein, the term "ether" refers to a group that is connected through an oxygen to another hydrocarbyl group. Thus, an ether substituent on a hydrocarbyl group is a hydroxyl group. The ether may be symmetrical or asymmetrical. Examples of ethers include: Examples include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include "alkyl" rings, which can be represented by the general formula: alkyl-O-alkyl. The term "alkoxyalkyl" includes "alkoxyalkyl" groups.

[0059] As used herein, the terms "halo" and "halogen" mean halogen and chloro. Includes bromo, fluoro, bromo, and iodo.

[0060] As used herein, the terms "hetaralkyl" and "heteralkyl" are used interchangeably. "Heteroaralkyl" refers to an alkyl substituted with a hetaryl group. Refers to the base. As used herein, the term "heteroalkyl" refers to any group in which any two heteroatoms are adjacent. refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom that is not cyclic.

[0061] The terms "heteroaryl" and "hetaryl" refer to groups having at least one ring structure. At least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or A substituted or unsubstituted aromatic monocyclic structure containing two heteroatoms, preferably a 5- to 7-membered ring More preferably, it includes a 5- or 6-membered ring. The terms "heteroaryl" and "hetaryl" has two or more carbon atoms shared by two adjacent rings, and at least one of the rings Heteroaromatic rings, the other cyclic rings being cycloalkyl, cycloalkenyl, cyclo two of which may be alkynyl, aryl, heteroaryl, and / or heterocyclyl; Polycyclic ring systems having the above cyclic rings are also included. Examples of heteroaryl groups include pyrrolidone, phenyl ... furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrazole Examples include lysine, pyrazine, pyridazine, and pyrimidine.

[0062] As used herein, the term "heteroatom" refers to any element other than carbon or hydrogen. The term "heteroatom" refers to an atom. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0063] The terms "heterocyclyl," "heterocycle," and "heterocyclic" refer to a heterocyclic ring structure having at least one heteroatoms, preferably 1 to 4 heteroatoms, more preferably 1 or 2 a substituted or unsubstituted non-aromatic ring structure containing a heteroatom, preferably a 3- to 10-membered ring, more preferably Preferably, it refers to a 3- to 7-membered ring. The terms "heterocyclyl" and "heterocyclic" refer to one or more carbon is shared by two adjacent rings, and at least one of the rings is heterocyclic. For example, the other cyclic ring may be a cycloalkyl, cycloalkenyl, cycloalkynyl, two or more cyclic groups, which may be aryl, heteroaryl, and / or heterocyclyl; Polycyclic ring systems having rings, e.g., bicyclic systems (e.g., fused or spiro bicyclic heterocycles) The terms "heterocyclyl" and "heterocyclic" refer to substituted or unsubstituted moieties. In some embodiments, heterocyclyl also includes at least one unsaturated non-aromatic ring structure. It is a 3- to 10-membered monocyclic or bicyclic ring system with at least one double bond. In embodiments, heterocyclyl is a 3- to 10-membered monocyclic or is a bicyclic ring system. In some embodiments, the heterocyclyl has at least one bicyclic ring. In some embodiments, the heterocyclyl is a 6-membered heterocyclyl ring having a bond. A 6-membered heterocyclyl ring having only one double bond. The heterocyclyl group may be: For example, piperidine, piperazine, pyrrolidine, morpholine, lactone, lactam, tetrahydrofuran Hydrofuran, 1,4-diazabicyclo[2.2.2]octane (DABCO), tetrahydrofuran Hydroquinoline and the like.

[0064] As used herein, the term "heterocyclylalkyl" refers to a heterocyclic group substituted with a heterocyclic group. It refers to an alkyl group.

[0065] As used herein, the term "hydrocarbyl" refers to a group containing an ═O or ═S substituent. They are bonded through carbon atoms that do not have a carbon-hydrogen bond, and usually have at least one carbon-hydrogen bond and a It refers to a group having a carbon skeleton, which may optionally contain heteroatoms. In terms of specific examples, methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are preferred. The group is considered hydrocarbyl, but does not include acetyl (=O substituent on the connecting carbon atom). Substituents such as hydroxyl (having hydroxyl groups) and ethoxy (linked through an oxygen rather than a carbon) are Hydrocarbyl groups include, but are not limited to: Aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl and combinations thereof.

[0066] As used herein, the term "hydroxyalkyl" refers to a group substituted with a hydroxy group. Refers to an alkyl group.

[0067] Chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or When used with alkoxy, the term "lower" refers to 10 or fewer alkyl groups in the substituent, preferably 10 or fewer alkyl groups. is intended to include groups in which six or fewer non-hydrogen atoms are present. For example, it refers to an alkyl group containing 10 or less, preferably 6 or less, carbon atoms. In certain embodiments, acyl, acyloxy, alkyl, aryl, aryloxy ... Alkenyl, alkynyl, or alkoxy substituents are preferred if they are, for example, hydroxyalkyl. aryl and aralkyl (where, for example, atoms in the aryl group are not carbon atoms in the alkyl substituent) appearing alone or in other substituents in the description of the atom (not counted when counting atoms) and lower acyl, lower acyloxy, lower acyloxy, and lower acyloxy, respectively. The alkyl group is lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy.

[0068] The terms "polycyclyl," "polycycle," and "polycyclic" refer to a ring structure in which two or more atoms are bonded to two adjacent rings. Two or more rings that are shared by a ring, for example, the rings are "fused rings" (e.g., cyclopentadiene cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or or heterocyclyl). Each ring of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains 3 to 10, preferably 5 to 7, atoms in the ring. nothing.

[0069] The term "silyl" refers to a silicon moiety having three hydrocarbyl moieties attached thereto.

[0070] The term "substituted" refers to a moiety having a substituent in place of a hydrogen on one or more carbons of the backbone. "Substituted" or "substituted with" refers to such substitution as applied to the substituted atom and the substituent. The substitution is in accordance with the allowed valences of the group and does not result in a stable compound, e.g., spontaneous rearrangement, This may include the implicit condition that a stable compound is produced that does not undergo transformation by cyclization, elimination, etc. It will be understood that, as used herein, the term "substituted" means any permissible group in an organic compound. In a broad aspect, the permissible substituents include, but are not limited to, alkyl, aryl, arylsulfonic acid ... , acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and The permissible substituents include one or more aromatic and non-aromatic substituents for appropriate organic compounds. For purposes of this disclosure, the term "nitrogen" refers to a group of atoms, such as nitrogen. The heteroatom may be any of the hydrogen substituents and / or alkyl groups described herein that satisfy the valence of the heteroatom. The radicals may have any permissible substituents of organic compounds, including those described herein. Any substituents present, such as halogen, hydroxyl, carbonyl (e.g., xyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphatidyl Sulfate, phosphonate, phosphinate, amino, amide, amidine, imine, cyano No, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfonyl sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic The substituents may themselves be substituted, where appropriate. It will be understood by those skilled in the art that unless specifically stated as "unsubstituted," It is understood that references to chemical moieties in the specification encompass substituted variants. For example, reference to an "aryl" group or moiety connotes both substituted and unsubstituted variants. implicitly contains.

[0071] The term "sulfate" is art recognized and refers to the group: -OSO3H, or a pharmaceutically acceptable salt thereof.

[0072] The term "sulfonamide" is art recognized and refers to a compound having the general formula: [ka] wherein each R 36 and R 37 are independently hydrogen or hydrochloride carbyl, e.g., alkyl, or R 36 and R 37 is the atom (multiple atoms) between them. Together with the aryl group (which can be used), they form a heterocycle with 4 to 8 atoms in the ring structure.

[0073] The term "sulfoxide" is art recognized and refers to the group: -S(O)-R 38 where R 38 represents a hydrocarbyl.

[0074] The term "sulfonate" is art recognized and refers to the group: -SO3H or refers to a pharmaceutically acceptable salt thereof.

[0075] The term "sulfone" is art recognized and refers to the group: -S(O)-R 3 9 where R 39 represents a hydrocarbyl.

[0076] As used herein, the term "thioalkyl" refers to an alkyl substituted with a thiol group. Refers to the base.

[0077] As used herein, the term "thioester" refers to the group: -C(O)SR 40 or- SC(O)R 40 where R 40 represents a hydrocarbyl.

[0078] As used herein, the term "thioether" refers to a thioether in which an oxygen is replaced with a sulfur. It corresponds to ether.

[0079] The term "urea" is art recognized and has the general formula: [ka] wherein R 41 and R 42 are independently hydrogen or hydrocarbyl, For example, it represents alkyl, or R41 Any occurrence of R 42 and the atoms in between (several) together form a heterocycle with 4 to 8 atoms in the ring structure .

[0080] The term "protecting group" refers to a group that, when attached to a reactive functional group in a molecule, masks the reactivity of that functional group. Protecting groups are groups of atoms that block, reduce, or prevent the activity of a compound. Protecting groups are usually chosen as desired during synthesis. Examples of protecting groups are described in Greene and Wuts, Protective Groups. ive Groups in Organic Chemistry,3 rd Ed., 1999, John Wiley & Sons, NY and Harrison e Compendium of Synthetic Organic Me thods,Vols.1-8,1971-1996,John Wiley & So Representative nitrogen protecting groups include, but are not limited to: Formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (" CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TM 2-trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted trimethylsilyl Lithium, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FM OC), nitroveratryloxycarbonyl (NVOC), etc. Suitable hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is acyl those that are esterified or alkylated, e.g., benzyl and trityl ethers , as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers ethers (e.g., TMS or TIPS groups), glycol ethers, e.g., ethylene glycol Cholesterol and propylene glycol derivatives, and allyl ethers.

[0081] In certain embodiments, the compounds of the present disclosure may be racemates. In embodiments, the compounds of the present disclosure may be enriched in one enantiomer. For example, The compounds have an ee of greater than about 30%, about 40%, about 50%, about 60%, about 70% ee, about 80% ee, about 90% ee, or even about 95% ee, or In certain embodiments, compounds of the present disclosure may have two or more ee's. In certain such embodiments, compounds of the present disclosure may have one or more diastereocenters. For example, compounds of the present disclosure may be enriched in an isomer with a de of greater than about 30%, a de of about 40%, or % de, about 50% de, about 60% de, about 70% de, about 80% de, about 90 % de, or even about 95% de, or even higher de.

[0082] In certain embodiments, the therapeutic formulation is a compound represented by the formula (e.g., Formula (I) or (II) or ( III) can be enriched to provide predominantly one enantiomer of the compound. Thiomer-enriched mixtures are preferred, e.g., at least about 60 mole percent. or at least about 75, about 90, about 95, or even about 99 mole percent of one In certain embodiments, the compound may be enriched in one enantiomer. The compound is substantially free of the other enantiomer, where substantially free does not mean that the compound is free of the other enantiomer. The subject substance may be, for example, in a composition or mixture of compounds, in relation to the amount of the other enantiomer. In comparison, less than about 10%, or less than about 5%, or less than about 4%, or less than about 3%, or or less than about 2%, or less than about 1%. For example, a composition or compound The mixture was prepared by mixing about 98 grams of the first enantiomer and about 2 grams of the second enantiomer. When the methyl group contains about 98 mole percent of the first enantiomer and only about 2% of the It is said to contain the second enantiomer.

[0083] In certain embodiments, the therapeutic formulation is a compound represented by the formula (e.g., Formula (I) or (II) or ( III) can be enriched to provide predominantly one diastereomer of compound III). A stereomerically enriched mixture may be, for example, at least about 60 mole percent, more preferably Preferably, at least about 75, about 90, about 95, or even about 99 mole percent of It may contain two diastereomers.

[0084] As used herein, the term "stereoisomers" refers to compounds that have the same molecular constitution and bonding, but Stereoisomers are molecules that differ in the three-dimensional arrangement of their atoms. In some embodiments, "stereoisomers" are isomers that differ not in the structure but in the arrangement of the atoms in space. , various stereoisomeric forms of a compound containing one or more asymmetric centers or steric hindrance in the structure In some embodiments, a stereoisomer refers to an enantiomer, a mixture of enantiomers, or , atropisomers, or tautomers thereof. The compounds described in may be present as individual enantiomers, diastereomers, or geometric isomers. (e.g., atropisomers) or in the form of a racemic mixture and one or more isotopic It may be in the form of a mixture of stereoisomers, including a mixture enriched in one isomer. In this embodiment, the stereoisomers include diastereoisomer(s), enantiomers This includes mixtures of diastereoisomers, mixtures of diastereoisomers, and mixtures of enantiomers. In some embodiments, the compounds provided herein may be atropisomers. In certain embodiments, atropisomers arise due to hindered rotation about a single bond. are stereoisomers in which the energy differences due to steric strain or other factors This creates a rotational barrier high enough to allow the isolation of conformers of , chiral high performance liquid chromatography (HPLC) and chiral salt formation and crystallization The preferred isomers can be isolated from the mixture by methods known to those skilled in the art. can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enanti omers, Racemates and Resolutions(Wiley In terscience, New York, 1981), Wilen et al., T. etrahedron 33:2725(1977), Eliel, EL Stere ochemistry of Carbon Compounds(McGraw-Hi ll, NY, 1962) and Wilen, SHTables of Resolv. ing Agents and Optical Resolutions p.268 (ELEliel,Ed.,Univ.of Notre Dame Press, Notre Dame, IN 1972).

[0085] In some embodiments, some of the compounds exist as a mixture of tautomers. "Isomers" are structural isomers of moieties or compounds that readily interconvert with other structural isomers For example, the pyrazole ring exists in two tautomers: [ka] which differ in the position of the π bond and hydrogen atoms. A tautomer diagram of one of the compounds encompasses all possible tautomers.

[0086] The term "mammal" includes human subjects, primates, and commercially important mammals, e.g., bovine , pigs, horses, sheep, goats, cats, and / or dogs; and / or commercially important birds. Birds, including chickens, ducks, geese, quail, and / or turtles The term "subject" to which administration is intended is not limited. However, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants) , children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys). In some embodiments, the mammal is a human subject.

[0087] As used herein, a therapeutic agent that "prevents" a disorder or condition is an agent that, in a statistical sample, and detecting the presence or absence of the disorder or condition in the treated sample compared to the untreated control sample. Reduce the occurrence of or increase the risk of one or more of the disorders or conditions compared to untreated control samples. This refers to compounds that delay the onset or reduce the severity of the above symptoms.

[0088] The term "treating" includes prophylactic and / or therapeutic treatment. "Therapeutic" treatment is understood in the art and may be achieved by administering one of the compositions of the present disclosure. administration to one or more subjects. Treatment is prophylactic (i.e., administered prior to the clinical onset of an undesirable condition). The device prevents the subject from developing an undesired condition, while the device prevents the subject from developing an undesired condition. If administered later, the treatment is curative (i.e., the treatment is effective to alleviate an existing undesirable condition). (intended to attenuate, ameliorate, or stabilize the condition or its side effects).

[0089] The term "prodrug" refers to a compound that, under physiological conditions, is converted into a therapeutically active agent of the present disclosure. A common method for making prodrugs is to It contains one or more selected moieties that are hydrolyzed under physical conditions to expose the molecule of interest. In another embodiment, the prodrug is converted by the enzymatic activity of the subject. For example, esters or carbonates (e.g., esters of alcohols or carboxylic acids) ol or carbonate) are preferred prodrugs of the present disclosure. In the formulations shown above, some or all of the compounds disclosed herein may be used. can be replaced with a corresponding suitable prodrug, where, for example, the hydroxyl group of the parent compound The alkyloxyl may be provided as an ester, carbonate, or carboxylic acid.

[0090] As used herein, an "effective amount" is an amount sufficient to achieve a desired biological effect. As used herein, a "therapeutically effective amount" refers to an amount sufficient to achieve the desired therapeutic effect. For example, a therapeutically effective amount refers to an amount sufficient to ameliorate at least one sign or symptom of cancer. It can refer to an amount sufficient to improve the condition.

[0091] A "response" to a treatment regimen may include, among other things, a reduction or improvement in adverse symptoms, a decrease in the severity of a disease or is a reduction in the progression of symptoms, an increase in beneficial symptoms or an improvement in clinical outcome, a reduction in side effects, a reduction in the severity of the disease, This may include stabilization of the condition, partial or complete cure of the disease.

[0092] In certain embodiments, the pharmaceutically acceptable salt of the compound is an alkylammonium salt. , dialkylammonium salts, trialkylammonium salts, tetraalkylammonium salts L-arginine salt, benenthamine salt, benzathine salt , Betaine salt, Calcium hydroxide salt, Choline salt, Deanol salt, Diethanolamine salt, Diethylamine salt, 2-(diethylamino)ethanol salt, ethanolamine salt, ethyl diamine salt, N-methylglucamine salt, hydrabamine salt, 1H-imidazole salt, lithium salt ammonium salt, L-lysine salt, magnesium salt, 4-(2-hydroxyethyl)morpholine salt, Piperazine salt, potassium salt, 1-(2-hydroxyethyl)pyrrolidine salt, sodium salt , triethanolamine salt, tromethamine salt, Na salt, Ca salt, K salt, Mg salt, and Zn salt salts. In certain embodiments, pharmaceutically acceptable salts are obtained by dissolving in water, methanol, ethanol, and dimethylformamide. and methylformamide.

[0093] In certain embodiments, the compound is administered as a pharmaceutical preparation containing a pharmaceutically acceptable carrier or excipient. It is a composition.

[0094] In certain embodiments, the compositions are available in the form of tablets, capsules, granules, lyophilisates for reconstitution, etc. ophile), powder, solution, syrup, suppository, injection, suspension, infusion, transdermal delivery system ( creams, gels, ointments), and solutions suitable for topical administration. It is a form.

[0095] compound The present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, , in the formula, [ka] is a 3- to 10-membered heterocyclyl; [ka] is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, R 1 CN, C 1~5 Alkyl, C 1~5 Haloalkyl, C 2~5 Alkenyl, C 2~ 5-membered alkynyl, or 3- to 6-membered heterocyclyl, aryl, alkynyl, or heterocyclyl may be one or more R a is optionally replaced by occurrences of And, R a independently in each occurrence, halo, CN, N(R n1 )2, optionally substituted C1 ~5 Alkyl, -OC 1~5 Alkyl, -OC 1~5 Alkylene-OC 1~5 Al Kill, -CO2-C 1~5 Alkyl or optionally substituted 3- to 6-membered heterocyclyl or two R a taken together to form an optionally substituted alkenyl group And, Each R n1 are independently hydrogen or C 1~5 is alkyl, J is NR b and X 1 is CH or J is a bond and X 1 is N, R b is hydrogen or an optionally substituted C 1~5 is alkyl, R 2 independently in each occurrence represents an optionally substituted C 1~5 is alkyl, or Two geminal R's 2 are taken together to form an oxo moiety, or Two non-geminal R 2 The occurrences of are grouped together and labeled C1-C4 (e.g., C1-C2) forming an alkylene bridge or R d and R 2 The appearance of taken together to form a 5- to 8-membered heterocyclic ring, n is 0 or an integer from 1 to 3 (inclusive) as valence permits; X 2 is -C=, -CH-, or N, U is for CR c or N, R c is hydrogen, halo, or optionally substituted C 1~5 is an alkoxy, V is CR d or N, R d is hydrogen, halo, optionally substituted C 1~5 Alkyl or optionally substituted C 1~5 Alkoxy or R d and R 2 The appearance of are bound together to form a 3- to 6-membered heterocyclic ring, W is N or CR e and R e is hydrogen, halo (e.g., fluoro), or cyano; Y 1 and Y 2 are independently CH, CR 4 , or N, where Y 1 and Y 2 At least one of the 4 and R 4 represents, independently in each occurrence, halo, optionally substituted C 1~5 Alkyl, or C replaced arbitrarily 1~5 is an alkoxy, m is 0 or an integer from 1 to 4 (inclusive) as valence permits; R 5represents, independently in each occurrence, halo, optionally substituted C 1~5 Alkyl, or C replaced arbitrarily 1~5 is an alkoxy, p is 0 or an integer from 1 to 3 (inclusive) as far as valence allows, provides a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0096] In some embodiments of Formula (I), V is N, or [ka] but [ka] where: [ka] is a 5- or 6-membered heteroaryl, and Z 1 , Z 2 , Z 3 , and Z 4 are each unique It is C or N, [ka] Any atom in R can be 5 provided that it may be substituted by:

[0097] In some aspects, the present disclosure provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, , in the formula, [ka] is a 4- to 7-membered heterocyclyl; R 1teeth, [ka] and R a1 , R a2 , R a3 , and R a4 are each independently hydrogen, halo, CN, N(R n1 )2, optionally substituted C 1~5 Alkyl, optionally substituted -CH2O-C 1~5 Alkyl, optionally substituted -CH2O-(CH2) 1~2 -OC 1~5 Alkyl, arbitrarily substituted -CO2-C 1~5 Alkyl, or optionally substituted 3- to 6-membered heterocycle It is a krill, Each R n1 are independently hydrogen or C 1~5 is alkyl, R 2 independently in each occurrence represents an optionally substituted C 1~5 is alkyl, or Two geminal R's 2 are taken together to form an oxo moiety, or Two non-geminal R 2 The occurrences of are grouped together and labeled C1-C4 (e.g., C1-C2) It forms an alkylene bridge, n is 0 or an integer from 1 to 3 (inclusive) as valence permits; X 2 is -C=, -CH-, or N, U is for CR c or N, R c is hydrogen, halo, or optionally substituted C 1~5 is an alkoxy, V is CR d or N, R d is hydrogen, halo, optionally substituted C 1~5Alkyl, optionally substituted C 1~5 a alkoxy or R d and R 2 occurrences are grouped together with the intervening atoms. and form a heterocyclic ring, W is N or CR e and R e is hydrogen, halo (e.g., fluoro), or cyano; R 6 , R 7 , R 8 , and R 9 are each independently hydrogen, halo, or an optionally substituted C1 ~5 Alkyl, or optionally substituted C 1~5 is an alkoxy, R 10 is hydrogen, halo, or optionally substituted C 1~5 is alkyl, Q 1 , Q 2 , Q 3 , and Q 4 are each independently, NR f or CR g where , Q 1 , Q 2 , Q 3 , and Q 4 At least one of the g and R f represents, independently in each occurrence, hydrogen, optionally substituted C 1~5 Alkyl, or non Being, R g represents, independently in each occurrence, hydrogen, optionally substituted C 1~5 Alkyl, or non or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, Provide isomers.

[0098] In some aspects, the present disclosure provides a compound of formula (Ii): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, During the ceremony, [ka] is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, R 1 is C 1~5 Alkyl, C 1~5 Haloalkyl, C 2~5 Alkenyl, C 2~5 Al quinyl, or 3- to 6-membered heterocyclyl, A cyclic or heterocyclyl group may be one or more R a is optionally replaced by occurrences of , R a independently in each occurrence, halo, CN, N(R n1 )2, optionally substituted C1 ~5 Alkyl, optionally substituted -OC 1~5 Alkyl, optionally substituted -O-C1 ~5 Alkylene-OC 1~5 Alkyl, optionally substituted -CO2-C 1~5 Alkyl or an optionally substituted 3- to 6-membered heterocyclyl; Each R n1 are independently hydrogen or C 1~5 is alkyl, J is NR b and X 1 is CH or J is a bond and X 1 is N, s is 0, 1, or 2; t is 1 or 2, Rb is hydrogen or an optionally substituted C 1~5 is alkyl, R 2 independently in each occurrence represents an optionally substituted C 1~5 is alkyl, or Two geminal R's 2 are taken together to form an oxo moiety, or Two non-geminal R 2 The occurrence of,summarized,C 1~4 Forming an alkylene bridge And, n is 0 or an integer from 1 to 3 (inclusive) as valence permits; U is for CR c or N, V is CR d or N, with the proviso that at least one of U and V is N; R c is hydrogen, halo, or optionally substituted C 1~5 is an alkoxy, R d is hydrogen, halo, optionally substituted C 1~5 Alkyl or optionally substituted C 1~5 Alkoxy or R d and R 2 The appearance of It is bound to form a 5-6 membered heterocyclic ring, W is N or CR e and R e is hydrogen, halo, or cyano; Y 1 and Y 2 are independently CH, CR 4 , or N, where Y 1 and Y 2 At least one of the 4 and R 4 represents, independently in each occurrence, halo, optionally substituted C1~5 Alkyl, or C replaced arbitrarily 1~5 is an alkoxy, m is 0 or an integer from 1 to 4 (inclusive) as valence permits; R 5 represents, independently in each occurrence, halo, optionally substituted C 1~5 Alkyl, or C replaced arbitrarily 1~5 is an alkoxy, p is 0 or an integer from 1 to 3 (inclusive) as far as valence allows, provides a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0099] In certain embodiments, the compound of formula (Ii) has formula (Iia): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0100] In certain embodiments, the compound of formula (Iia) has the formula (Ii-a1): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, During the ceremony, R 6 , R 7 , R 8 , and R 9 are each independently hydrogen, halo, or an optionally substituted C1 ~5 Alkyl, or optionally substituted C 1~5 is an alkoxy, R 10 is hydrogen, halo, or optionally substituted C 1~5 is alkyl, Q 1 , Q 2 , Q 3 , and Q4 are each independently NR as far as valence allows. f or CR g where Q 1 , Q 2 , Q 3 , and Q 4 At least one of the g Yes the law of nature, R f represents, independently in each occurrence, hydrogen, optionally substituted C 1~5 Alkyl, or non Being, R g represents, independently in each occurrence, hydrogen, optionally substituted C 1~5 Alkyl, or non Being, R 11 , R 12 , R 13 , and R 14 are each independently hydrogen or an optionally substituted C 1~5 alkyl or R 11 , R 12 , R 13 , and R 14 2 of are joined together to form a C1-C4 alkylene bridge.

[0101] In certain embodiments, the compound of formula (Ii) has the formula (Ii-a0): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0102] In certain embodiments, the compound of formula (Ii-a1) has the following formula: [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0103] In certain embodiments, the compound of formula (Ii-a1) has the following formula: [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0104] In certain embodiments, the compound of formula (Ii-a1) has the following formula: [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0105] In certain embodiments, the compound of formula (Ii-a1) has the following formula: [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0106] In certain embodiments, the compound of formula (Ii-a1) has the following formula: [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0107] In certain embodiments, the compound of formula (Ii-a1) has the following formula: [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0108] In certain embodiments, the compound of formula (Ii-a1) has the following formula: [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0109] In certain embodiments, the compound of formula (Ii-a1) has the following formula: [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0110] In certain embodiments, the compound of formula (Ii-a1) has formula (Ii-a2): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0111] In certain embodiments, the compound of formula (Ii-a1) has formula (Ii-a3): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0112] In certain embodiments, the compound of formula (Ii-a1) has formula (Ii-a4): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0113] In certain embodiments, the compound of formula (Ii-a1) has formula (Ii-a5): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0114] In certain embodiments, the compound of formula (Ii-a1) has formula (Ii-a6): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0115] In certain embodiments, the compound of formula (Ii) has the formula (Iib): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0116] In certain embodiments, the compound of formula (Ii) has the formula (Iic): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0117] Formula (Ii), (Iia), (Ii-a1), (Ii-a2), (Iia 3), (Ii-a4), (Ii-a5), (Ii-a6), (Iib), (I In one embodiment of any of -ic), wherein s is 0 and t is 1 or 2. Formula (Ii), (Iia), (Ii-a1), (Ii-a2), (Ii-a3 ), (Ii-a4), (Ii-a5), (Ii-a6), (Iib), (I- In one embodiment of any of formulas (ic), s is 1 and t is 1 or 2. (Ii), (Iia), (Ii-a1), (Ii-a2), (Ii-a3) , (Ii-a4), (Ii-a5), (Ii-a6), (Iib), (Ii In one embodiment of any of formulas (c), s is 2 and t is 1 or 2. Ii), (Iia), (Ii-a1), (Ii-a2), (Ii-a3), (Ii-a4), (Ii-a5), (Ii-a6), (Iib), (Ii- In one embodiment of any of formulas c), wherein s is 1 and t is 1. Formula (Ii): (Iia), (Ii-a1), (Ii-a2), (Ii-a3), (Ii- a4), (Ii-a5), (Ii-a6), (Iib), or (Iic) In one embodiment, s is 1 and t is 2.

[0118] Formula (Ii), (Iia), (Ii-a1), (Ii-a2), (Iia 3), (Ii-a4), (Ii-a5), (Ii-a6), (Iib), (I In one embodiment of any of the above-ic), R 11 is an arbitrarily substituted C 1~5 Alkyl Formulas (Ii), (Iia), (Ii-a1), (Ii-a2), (I- i-a3), (Ii-a4), (Ii-a5), (Ii-a6), (Iib) In one embodiment of either (Iic), R 11 is methyl. Formula (Ii) , (Iia), (Ii-a1), (Ii-a2), (Ii-a3), (Ii -a4), (Ii-a5), (Ii-a6), (Iib), (Iic) In any one embodiment, R 12 is an arbitrarily substituted C 1~5 The formula (I) is an alkyl group. -i), (Iia), (Ii-a1), (Ii-a2), (Ii-a3), ( Ii-a4), (Ii-a5), (Ii-a6), (Iib), (Iic In one embodiment of any of the above, R 12 is methyl.

[0119] In certain aspects, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, , During the ceremony, [ka] is a 6- to 10-membered bicyclic heterocyclyl or a 3- to 5- or 7- to 8-membered monocyclic heterocyclyl. is cyclocyclyl, [ka] is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, R 1 CN, C 1~5 Alkyl, C 1~5 Haloalkyl, C 2~5 Alkenyl, C 2~ 5-membered alkynyl, or 3- to 6-membered heterocyclyl, nyl, or heterocyclyl is one or more R a is optionally replaced by occurrences of R a independently in each occurrence, halo, CN, N(R n1 )2, optionally substituted C1 ~5 Alkyl, -OC 1~5 Alkyl, -OC 1~5 Alkylene-OC 1~5 Al Kill, -CO2-C 1~5 Alkyl or optionally substituted 3- to 6-membered heterocyclyl or two Ra taken together to form an optionally substituted alkenyl group And, Each R n1 are independently hydrogen or C 1~5 is alkyl, J is NR b and X 1 is CH or J is a bond and X 1 is N, R b is hydrogen or an optionally substituted C 1~5 is alkyl, R 2 independently in each occurrence represents an optionally substituted C 1~5 is alkyl, or Two geminal R's 2 are taken together to form an oxo moiety, or Two non-geminal R 2 The occurrence of,summarized,C 1~4 Forming an alkylene bridge Iruka or R d and R 2 The occurrences of are grouped together with the intervening atoms, forming a heterocyclic ring of n is 0 or an integer from 1 to 3 (inclusive) as valence permits; X 2 is -C=, -CH-, or N, U is for CR c or N, V is CR d or N, W is N or CR e and R c is hydrogen, halo, or optionally substituted C 1~5 is an alkoxy, R d is hydrogen, halo, optionally substituted C 1~5 Alkyl or optionally substituted C 1~5 Alkoxy or R d and R2 The appearance of are bound together to form a 3- to 6-membered heterocyclic ring, R e is hydrogen, halo (e.g., fluoro), or cyano; Y 1 and Y 2 are independently CH, CR 4 , or N, where Y 1 and Y 2 At least one of the 4 and R 4 represents, independently in each occurrence, halo, optionally substituted C 1~5 Alkyl, or C replaced arbitrarily 1~5 is an alkoxy, m is 0 or an integer from 1 to 4 (inclusive) as valence permits; R 5 represents, independently in each occurrence, halo, optionally substituted C 1~5 Alkyl, or C replaced arbitrarily 1~5 is an alkoxy, p is 0 or an integer from 1 to 3 (inclusive) as far as valence allows, provides a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0120] In certain aspects, the present disclosure provides a compound of formula (aI): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, , in the formula, [ka] is a 3- to 10-membered heterocyclyl; [ka] is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, R 1 CN, C 1~5 Alkyl, C 1~5 Haloalkyl, C 2~5 Alkenyl, C 2~ 5-membered alkynyl, or 3- to 6-membered heterocyclyl, aryl, alkynyl, or heterocyclyl may be one or more R a is optionally replaced by occurrences of And, R a independently in each occurrence, halo, CN, N(R n1 )2, optionally substituted C1 ~5 Alkyl, -OC 1~5 Alkyl, -OC 1~5 Alkylene-OC 1~5 Al Kill, -CO2-C 1~5 Alkyl or optionally substituted 3- to 6-membered heterocyclyl or two R a taken together to form an optionally substituted alkenyl group And, Each R n1 are independently hydrogen or C 1~5 is alkyl, J is NR b and X 1 is CH or J is a bond and X 1 is N, R b is hydrogen or an optionally substituted C 1~4 is alkyl, K is a bond, C=O, or SO2; R 2 independently in each occurrence represents an optionally substituted C 1~5 is alkyl, or Two geminal R's 2 are taken together to form an oxo moiety, or Two non-geminal R 2 The occurrences of are grouped together and labeled C1-C4 (e.g., C1-C2) forming an alkylene bridge or R d and R 2 The appearance of taken together to form a 5- to 8-membered heterocyclic ring, n is 0 or an integer from 1 to 3 (inclusive) as valence permits; X 2 is -C=, -CH-, or N, U is for CR c or N, R c is hydrogen, halo, or optionally substituted C 1~5 is an alkoxy, V is CR d or N, R d is hydrogen, halo, optionally substituted C 1~5 Alkyl or optionally substituted C 1~5 Alkoxy or R d and R 2 The appearance of are bound together to form a 3- to 6-membered heterocyclic ring, W is N or CR e and R e is hydrogen, halo (e.g., fluoro), or cyano; Y 1 and Y 2 are independently CH, CR 4 , or N, where Y 1 and Y 2 At least one of the 4 and R 4 represents, independently in each occurrence, halo, optionally substituted C 1~5 Alkyl, or C replaced arbitrarily 1~5 is an alkoxy, m is 0 or an integer from 1 to 4 (inclusive) as valence permits; R 5 represents, independently in each occurrence, halo, optionally substituted C 1~5 Alkyl, or C replaced arbitrarily 1~5 is an alkoxy, p is 0 or an integer from 1 to 3 (inclusive) as valence permits; provided that K is C=O or V is N, or [ka] but [ka] where: [ka] is a 5- or 6-membered heteroaryl, and Z 1 , Z 2 , Z 3 , and Z 4 are each unique It is C or N, [ka] Any atom in R can be 5 the compound, optionally substituted by provides a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0121] In certain aspects, the present disclosure provides a compound of formula (aI): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, During the ceremony, [ka] is a 3- to 10-membered heterocyclyl; [ka] is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, K is a bond or SO2, R 1 CN, C 1~5 Alkyl, C 1~5 Haloalkyl, C 2~5 Alkenyl, C 2~ 5-membered alkynyl, or 3- to 6-membered heterocyclyl, nyl, or heterocyclyl is one or more R a is optionally replaced by occurrences of R a independently in each occurrence, halo, CN, N(R n1 )2, optionally substituted C1 ~5 Alkyl, -OC 1~5 Alkyl, -OC 1~5 Alkylene-OC 1~5 Al Kill, -CO2-C 1~5 Alkyl or optionally substituted 3- to 6-membered heterocyclyl or two R a taken together to form an optionally substituted alkenyl group And, Each R n1 are independently hydrogen or C 1~5 is alkyl, J is NR b and X 1 is CH or J is a bond and X 1 is N, R b is hydrogen or an optionally substituted C 1~5 is alkyl, R 2 independently in each occurrence represents an optionally substituted C 1~5 is alkyl, or Two geminal R's 2 are taken together to form an oxo moiety, or Two non-geminal R 2 The occurrences of are grouped together and labeled C1-C4 (e.g., C1-C2) forming an alkylene bridge or R d and R 2 The appearance of taken together to form a 5- to 8-membered heterocyclic ring, n is 0 or an integer from 1 to 3 (inclusive) as valence permits; X 2 is -C=, -CH-, or N, U is for CR c or N, V is CR d or N, W is N or CR e and R c is hydrogen, halo, or optionally substituted C 1~5 is an alkoxy, R d is hydrogen, halo, optionally substituted C 1~5 Alkyl or optionally substituted C 1~5 Alkoxy or R d and R 2 The appearance of are bound together to form a 3- to 6-membered heterocyclic ring, R e is hydrogen, halo (e.g., fluoro), or cyano; Y 1 and Y 2 are independently CH, CR 4 , or N, where Y 1 and Y 2 At least one of the 4 and R 4 represents, independently in each occurrence, halo, optionally substituted C 1~5Alkyl, or C replaced arbitrarily 1~5 is an alkoxy, m is 0 or an integer from 1 to 4 (inclusive) as valence permits; R 5 represents, independently in each occurrence, halo, optionally substituted C 1~5 Alkyl, or C replaced arbitrarily 1~5 is an alkoxy, p is 0 or an integer from 1 to 3 (inclusive) as far as valence allows, provides a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0122] In one embodiment of formula (aI) (or a subformula thereof), K is a bond. In one embodiment of formula (aI) (or a subformula thereof), K is C=O. In one embodiment of formula (aI) (or a subformula thereof), K is SO2. In one embodiment of X, J is a bond and X 1 is N and K is C=O. In other embodiments of aI) (or subformulas thereof), J is a bond and X 1 is N and K is SO2. In other embodiments of formula (aI) (or subformulas thereof), J is , is a bond, and X 1 is N and K is a bond. In other embodiments of X, J is a bond and X 1 is N, K is a bond, and R 1 is CN.

[0123] A compound of formula (I), (II), (Ii), or (aI) (or a subformula thereof) In the embodiment, [ka] but, [ka] and [ka] but, [ka] and Y 1 and Y 2 However, each independently, CR 4 If Y 2 R in 4 teeth, is alkyl, and Y 1 R in 4 is halo. Y 2 R in 4 is methyl. In one embodiment, Y 1 R in 4 is fluoro In one embodiment, Y 2 R in 4 is methyl, and Y 1 R in 4 is full It's Oro.

[0124] In certain aspects, the present disclosure provides a compound of formula (B): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, , During the ceremony, [ka] is a 3- to 10-membered heterocyclyl; [ka] is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, R 1 CN, C 1~5 Alkyl, C 1~5 Haloalkyl, C 2~5 Alkenyl, C 2~ 5-membered alkynyl, or 3- to 6-membered heterocyclyl, nyl, or heterocyclyl is one or more R a is optionally replaced by occurrences of R a independently in each occurrence, halo, CN, N(R n1 )2, optionally substituted C1 ~5 Alkyl, -OC 1~5 Alkyl, -OC 1~5 Alkylene-OC 1~5 Al Kill, -CO2-C 1~5 Alkyl or optionally substituted 3- to 6-membered heterocyclyl or two R a taken together to form an optionally substituted alkenyl group And, Each R n1 are independently hydrogen or C 1~5 is alkyl, J is NR b and X 1 is CH or J is a bond and X 1 is N, R b is hydrogen or an optionally substituted C 1~5 is alkyl, R 2 independently in each occurrence represents an optionally substituted C 1~5 is alkyl, or Two geminal R's 2 are taken together to form an oxo moiety, or Two non-geminal R 2 The occurrences of are grouped together and labeled C1-C4 (e.g., C1-C2) forming an alkylene bridge or R d and R 2 The appearance of taken together to form a 5- to 8-membered heterocyclic ring, n is 0 or an integer from 1 to 3 (inclusive) as valence permits; X 2 is -C=, -CH-, or N, R d Halo, optionally substituted C 1~5 Alkyl or optionally substituted C 1~5 Alkoxy or R d and R 2 The occurrences of are grouped together with the intervening atoms. and form a 3- to 6-membered heterocyclic ring, Y 1 and Y 2 are independently CH, CR 4 , or N, where Y 1 and Y 2 At least one of the 4 and R 4 represents, independently in each occurrence, halo, optionally substituted C 1~5 Alkyl, or C replaced arbitrarily 1~5 is an alkoxy, m is 0 or an integer from 1 to 4 (inclusive) as valence permits; R 5 represents, independently in each occurrence, halo, optionally substituted C 1~5 Alkyl, or C replaced arbitrarily 1~5 is an alkoxy, p is 0 or an integer from 1 to 3 (inclusive) as far as valence allows, provides a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0125] In certain embodiments, the compound of formula (B) has the formula (Bi): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, In the formula, R 4a and R 4b each independently represents a halo, an optionally substituted C 1~5 Alkyl , or an optionally substituted C 1~5 It is an alkoxy.

[0126] In certain embodiments of formula (Bi) (or subformulas thereof), R 4a is the halo and R 4b is an arbitrarily substituted C 1~5 is alkyl. Formula (Bi) (or a subformula thereof) In certain embodiments of 4a is F or Cl, and R 4b is methyl. In certain embodiments of Bi) (or a subformula thereof), R 4b is the halo and R 4a teeth , optionally substituted C 1~5 Alkyl. Identification of formula (Bi) (or its subformula) In an embodiment of the present invention, R 4b is F or Cl, and R 4a is methyl. In certain embodiments of (or subformulas thereof), R 4a and R 4b each of which independently Halo, optionally substituted C 1~5 Alkyl, or optionally substituted C 1~5 Alkoxy and R d Halo, optionally substituted C 1~5 Alkyl or optionally substituted C 1~5 Alkoxy or R d and R 2 The appearance of, along with the intervening atoms, taken together form a 3- to 6-membered heterocyclic ring. 4a and R 4b each independently represents a halo (e.g., F or Cl), an optionally substituted C 1~5 alkyl (e.g., methyl), and R d is a halo (e.g., F). In the embodiment, R 4a and R 4b each independently represents halo (e.g., F or Cl), any C replaced arbitrarily 1~5 alkyl (e.g., methyl), and R d is an arbitrarily substituted C 1~5 In certain embodiments, R 4a and R 4b Each of the and halo (e.g., F or Cl), optionally substituted C 1~5 Alkyl (e.g., methyl Chill) and R d is an arbitrarily substituted C 1~5 Alkyl or optionally substituted C1 ~5 is alkoxy, and R 2 The occurrences of are grouped together with the intervening atoms, It forms a heterocyclic ring of 1,200 atoms.

[0127] In certain aspects, the present disclosure provides a compound of formula (C): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, , During the ceremony, [ka] is a 3- to 10-membered heterocyclyl; [ka] is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, R 1 CN, C 1~5 Alkyl, C 1~5 Haloalkyl, C 2~5 Alkenyl, C 2~ 5-membered alkynyl, or 3- to 6-membered heterocyclyl, nyl, or heterocyclyl is one or more R a is optionally replaced by occurrences of R a independently in each occurrence, halo, CN, N(R n1 )2, optionally substituted C1 ~5 Alkyl, -OC 1~5 Alkyl, -OC 1~5 Alkylene-OC 1~5 Al Kill, -CO2-C 1~5 Alkyl or optionally substituted 3- to 6-membered heterocyclyl or two R a taken together to form an optionally substituted alkenyl group And, Each R n1 are independently hydrogen or C 1~5 is alkyl, J is NR b and X 1 is CH or J is a bond and X 1 is N, R b is hydrogen or an optionally substituted C 1~5 is alkyl, R 2 independently in each occurrence represents an optionally substituted C 1~5 is alkyl, or Two geminal R's 2 are taken together to form an oxo moiety, or Two non-geminal R 2 The occurrence of,summarized,C1~4 Forming an alkylene bridge And, n is 0 or an integer from 1 to 3 (inclusive) as valence permits, provided that: [ka] is a 6-membered monocyclic heterocyclyl having 1 or 2 N ring atoms, then n is 2 or 3, X 2 is -C=, -CH-, or N, Y 1 and Y 2 are independently CH, CR 4 , or N, where Y 1 and Y 2 At least one of the 4 and R 4 represents, independently in each occurrence, halo, optionally substituted C 1~5 Alkyl, or C replaced arbitrarily 1~5 is an alkoxy, m is 0 or an integer from 1 to 4 (inclusive) as valence permits; R 5 represents, independently in each occurrence, halo, optionally substituted C 1~5 Alkyl, or C replaced arbitrarily 1~5 is an alkoxy, p is 0 or an integer from 1 to 3 (inclusive) as far as valence allows, provides a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0128] In certain aspects, the present disclosure provides a compound of formula (D): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, , During the ceremony, [ka] is a 3- to 10-membered heterocyclyl; [ka] is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, R 1 CN, C 1~5 Alkyl, C 1~5 Haloalkyl, C 2~5 Alkenyl, C 2~ 5-membered alkynyl, or 3- to 6-membered heterocyclyl, nyl, or heterocyclyl is one or more R a is optionally replaced by occurrences of R a independently in each occurrence, halo, CN, N(R n1 )2, optionally substituted C1 ~5 Alkyl, -OC 1~5 Alkyl, -OC 1~5 Alkylene-OC 1~5 Al Kill, -CO2-C 1~5 Alkyl or optionally substituted 3- to 6-membered heterocyclyl or two R a taken together to form an optionally substituted alkenyl group And, Each R n1 are independently hydrogen or C 1~5 is alkyl, J is NR b and X 1 is CH or J is a bond and X 1 is N, R b is hydrogen or optionally substituted alkyl; R 2 is independently in each occurrence optionally substituted alkyl or gemina Two R 2 occurrences of are grouped together to form an oxo moiety or are non-geminate Two null R's 2 The occurrences of are grouped together to form C1-C4 (e.g., C1-C2) alkylene It forms a polyimide bridge. n is 0 or an integer from 1 to 3 (inclusive) as valence permits; X 2 is -C=, -CH-, or N, R 4a and R 4b each independently represents a halo, an optionally substituted C 1~5 Alkyl, also is an arbitrarily substituted C 1~5 is an alkoxy, R 5 is independently in each occurrence halo, optionally substituted alkyl, or optionally substituted is an alkoxy group, p is 0 or an integer from 1 to 3 (inclusive) as far as valence allows, provides a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0129] In certain aspects, the present disclosure provides compounds of formula (E): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, , During the ceremony, [ka] is a 3- to 10-membered heterocyclyl; [ka] is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, R 1 CN, C 1~5 Alkyl, C1~5 Haloalkyl, C 2~5 Alkenyl, C 2~ 5-membered alkynyl, or 3- to 6-membered heterocyclyl, nyl, or heterocyclyl is one or more R a is optionally replaced by occurrences of R a independently in each occurrence, halo, CN, N(R n1 )2, optionally substituted C1 ~5 Alkyl, -OC 1~5 Alkyl, -OC 1~5 Alkylene-OC 1~5 Al Kill, -CO2-C 1~5 Alkyl or optionally substituted 3- to 6-membered heterocyclyl or two R a taken together to form an optionally substituted alkenyl group And, Each R n1 are independently hydrogen or C 1~5 is alkyl, J is NR b and X 1 is CH or J is a bond and X 1 is N, R b is hydrogen or an optionally substituted C 1~5 is alkyl, R 2 independently in each occurrence represents an optionally substituted C 1~5 is alkyl, or Two geminal R's 2 are taken together to form an oxo moiety, or Two non-geminal R 2 The occurrence of,summarized,C 1~4 Forming an alkylene bridge And, n is 0 or an integer from 1 to 3 (inclusive) as valence permits; X 2is -C=, -CH-, or N, R 5 represents, independently in each occurrence, halo, optionally substituted C 1~5 Alkyl, or C replaced arbitrarily 1~5 is an alkoxy, p is 0 or an integer from 1 to 3 (inclusive) as far as valence allows, provides a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0130] Formulas (I), (aI), (B), (Bi), (C), (D), and (E), and In particular embodiments of any of those subformulas, [ka] is a heterocyclyl containing at least one nitrogen atom. [ka] is a 3- to 10-membered heterocyclyl. [ka] is a 6- to 10-membered bicyclic heterocyclyl or a 3- to 5- or 7- to 8-membered monocyclic heterocyclyl. In some embodiments, [ka] is a 4- to 7-membered ring containing at least one nitrogen (e.g., 1 or 2 nitrogen) ring atom In some embodiments, [ka] is a 6-membered monocyclic heterocyclyl. [ka] is a 6-membered monocyclic heterocyclyl having 1 or 2 nitrogen atoms. In this state, [ka] is a 6- to 10-membered spiro bicyclic heterocyclyl. [ka] is a 6- to 10-membered fused bicyclic heterocyclyl. [ka] is a partially unsaturated heterocyclyl. [ka] contains only one double bond. In certain embodiments, [ka] is azetidinyl, spirocyclic bisazetidinyl, pyrrolidinyl, pyrrolinyl, piperidinyl piperazinyl, tetrahydropyridinyl, azepanyl, or tetrahydroazepi In certain such embodiments, [ka] is piperazinyl or tetrahydropyridinyl. In some embodiments, [ka] is tetrahydropyridinyl. In another embodiment, [ka] is piperazinyl. [ka] is a spirocyclic bisazetidinyl.

[0131] Formula (I), (Ii) (Iia), (Iib), (Iic), (aI) , (B), (Bi), (C), (D), and (E), and any of their subformulas In certain embodiments, [ka] is a 6- to 10-membered aryl. In some embodiments, [ka] is a 5- to 10-membered heteroaryl. [ka] contains 1 to 3 nitrogen atoms. In certain such embodiments, [ka] contains only three nitrogen atoms. [ka] is a bicyclic heteroaryl. In certain embodiments, [ka] is a 9- or 10-membered bicyclic heteroaryl. In certain such embodiments, [ka] is a 9-membered bicyclic heteroaryl.

[0132] Formula (I), (Ii) (Iia), (Iib), (Iic), (aI) , (B), (Bi), (C), (D), and (E), and any of their subformulas In certain embodiments, [ka] teeth, [ka] and [ka] is a 5- or 6-membered heteroaryl, and Z 1 , Z 2 , Z 3 , and Z 4 are each unique It is C or N, [ka] Any atom in R can be 5 In some embodiments, So, Z 1 , Z 2 , Z 3 , and Z 4 At least one of is N. In terms of form, Z 1 , Z 2 , Z 3 , and Z 4 and only one of them is N. In this state, Z 1 or Z 2 is N. In some embodiments, Z 1 is C and Z 2 teeth In certain embodiments, Z 1 and Z 2 Contains [ka] contains 1 to 3 nitrogen atoms. In certain such embodiments, Z 1 and Z 2Contains [ka] contains only three nitrogen atoms.

[0133] Formula (I), (Ii) (Iia), (Iib), (Iic), (aI) , (B), (Bi), (C), (D), and (E), and any of their subformulas In certain embodiments, [ka] teeth, [ka] and [ka] Any atom in R can be 5 In some embodiments, So, [ka] teeth, [ka] and [ka] Any atom in R can be 5 Optionally, the substituted alkyl group may be substituted with: In this state, [ka] teeth, [ka] and [ka] Any atom in R can be 5 may be substituted by:

[0134] In some embodiments, R 5 represents, independently in each occurrence, halo, optionally substituted C 1~5 Alkyl, or optionally substituted C 1~5 In some embodiments, So, R 5 independently in each occurrence represents an optionally substituted C 1~5 It is alkyl.

[0135] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0136] In some embodiments, R 1 CN, C 1~5 Alkyl, C 1~5 Haloalkyl, C 2~5 Alkenyl, C 2~5 alkynyl, or 3- to 6-membered heterocyclyl, , the alkyl, alkenyl, alkynyl, or heterocyclyl may be one or more R a of Optionally substituted wherever it appears. Formulas (I), (Ii), (Iia), (Ii- a1), (Ii-a2), (Ii-a3), (Ii-a4), (Ii-a5), (Ii-a6), (Iib), (Iic), (aI), (B), (Bi) In some embodiments of any of (C), (D), and (E) (and subformulas thereof), is R 1 is C 1~5 Alkyl, C 1~5 Haloalkyl, C 2~5 Alkenyl, C 2~5 alkynyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkenyl , alkynyl, or heterocyclyl may be one or more R a is arbitrarily replaced by the occurrence of In some embodiments, R 1 is C 2~5 Alkenyl or C 2~5 In alkynyl wherein the alkenyl or alkynyl is selected from one or more R a With the appearance of It has been replaced.

[0137] Formulas (I), (Ii), (Iia), (Ii-a1), (Ii-a2), (I -i-a3), (Ii-a4), (Ii-a5), (Ii-a6), (Iib ), (Iic), (aI), (B), (Bi), (C), (D), and (E)( In some embodiments of any of the formulas (and subformulas thereof), R 1 is one or more R a The C optionally replaced by 1~5 In some embodiments, R 1 is C 1~5 In some embodiments, R 1 is C 1~5 It is haloalkyl. In some embodiments, R 1 is one or more R a C optionally replaced by occurrences of 2~5 In some embodiments, R is alkenyl. 1 is one or more R a With the appearance of Substituted C 2~5 In some embodiments, R is alkynyl. 1 is ethenyl, ethy In some embodiments, R is methyl, ethyl, or oxiranyl. 1 Is, E In some embodiments, R 1 is ethenyl. , R 1 is ethynyl.

[0138] In some embodiments, R a independently in each occurrence, halo, CN, N(R n1 ) 2, optionally substituted C 1~5 Alkyl, optionally substituted -OC 1~5 Alkyl, -OC replaced by 1~5 Alkylene-OC 1~5 Alkyl, optionally substituted - CO2-C 1~5 alkyl, or optionally substituted 3- to 6-membered heterocyclyl, R n1 are independently hydrogen or C 1~5 The formula (I), (Ii), (I -ia), (Ii-a1), (Ii-a2), (Ii-a3), (Ii-a4 ), (Ii-a5), (Ii-a6), (Iib), (Iic), (aI ), (B), (Bi), (C), (D), and (E) (and their subformulas) In some embodiments, R a is C 1~5 alkyl (e.g., methyl or ethyl) In certain embodiments, R a is C 1~5 haloalkyl. In the embodiment, R a -OC 1~5 alkyl (e.g., methoxy). In embodiments, R a is halogen (e.g., F or Cl). So, R a is CN. In certain embodiments, R ais N(R n1 )2. In certain embodiments, R a is N(CH3)2.

[0139] Formulas (I), (Ii), (Iia), (Ii-a1), (Ii-a2), (I -i-a3), (Ii-a4), (Ii-a5), (Ii-a6), (Iib ), (Iic), (aI), (B), (Bi), (C), (D), and (E)( In some embodiments of any of the formulas (and subformulas thereof), R 1 is an arbitrarily substituted C 1~5 At least one R is alkyl a In certain such cases, In the embodiment, R a is optionally substituted with an amine or heterocycle, The heterocycle is optionally substituted with alkyl. In some embodiments, R 1 teeth , at least one R is dialkylaminomethyl a It has been replaced by a certain In an embodiment of the present invention, R 1 has only one R which is dialkylaminomethyl a is replaced by In certain such embodiments, dialkylaminomethyl is dimethylaminomethyl. In another embodiment, R 1 is fluoro, methyl, morpholinomethyl, or at least one R that is pyrrolidinyl a In a further embodiment, R 1 is R a In one embodiment, R 1 is non-substituted.

[0140] Formulas (I), (Ii), (Iia), (Ii-a1), (Ii-a2), (I -i-a3), (Ii-a4), (Ii-a5), (Ii-a6), (Iib ), (Iic), (aI), (B), (Bi), (C), (D), and (E)( In some embodiments of any of the formulas (and subformulas thereof), R 1 is alkynyl. In certain embodiments, R a is optionally substituted alkyl. In embodiments, R a is methyl.

[0141] Formulas (I), (Ii), (Iia), (Ii-a1), (Ii-a2), (I -i-a3), (Ii-a4), (Ii-a5), (Ii-a6), (Iib ), (Iic), (aI), (B), (Bi), (C), (D), and (E)( In some embodiments of any of the formulas (and subformulas thereof), R 1 is ethenyl, ethynyl , methyl, ethyl, or oxiranyl, and CN, F, Cl, -CH3, -CH2O CH3, -CH2O(CH2)2OCH3, -CO2CH3, -N(CH3)2, -CH 2N(CH3)2, -(CH2)2N(CH3)2, morpholinomethyl, or pyrrolidine At least one R that is nil a In some embodiments, R 1 teeth , ethenyl or ethynyl, and CN, F, Cl, -CH3, -CH2OCH3, -C H2O(CH2)2OCH3, -CO2CH3, -N(CH3)2, -CH2N(CH3 )2, -(CH2)2N(CH3)2, morpholinomethyl, or pyrrolidinyl At least one R aIn some embodiments, R 1 is methyl, nitrile, or oxiranyl, and can be substituted with CN, F, Cl, -CH3, -CH2OCH3, -C H2O(CH2)2OCH3, -CO2CH3, -N(CH3)2, -CH2N(CH3 )2, -(CH2)2N(CH3)2, morpholinomethyl, or pyrrolidinyl At least one R a is replaced by

[0142] Formula (I), (Ii) (Iia), (Iib), (Iic), (aI) , (B), (Bi), (C), (D), and (E), and any of their subformulas In some embodiments, J is NR b and X 1 is CH. Formula (I), (Ii )(Iia), (Iib), (Iic), (aI), (B), (Bi) , (C), (D), and (E), and some embodiments of any of their subformulas. So, R b is hydrogen or methyl. ib), (Iic), (aI), (B), (Bi), (C), (D), and ( E), as well as in some embodiments of any of their subformulas, R b is hydrogen. Formula (I), (Ii) (Iia), (Iib), (Iic), (aI), (B), (Bi), (C), (D), and (E), and any of their subformulas In some embodiments of 1 is N.

[0143] In some embodiments, R 2 independently in each occurrence represents an optionally substituted C 1~5 Alkyl or two geminal R 2 The occurrences of are grouped together to form an oxo moiety. or two non-geminal R 2 The occurrences of are summarized as C1~C 4 alkylene bridges are formed. Formulas (I), (Ii), (Iia), (Iib) ), (Iic), (aI), (B), (Bi), (C), (D), and (E), and in some embodiments of any of these subformulas, R 2 is unique in each occurrence Stand up, C 1~5 The formula (I), (Ii), (Iia), (Iib) ), (Iic), (aI), (B), (Bi), (C), (D), and (E), and in some embodiments of any of these subformulas, R 2 is unique in each occurrence The formula (I), (Ii), (Iia), (Iib), (I- ic), (aI), (B), (Bi), (C), (D), and (E), and In some embodiments of any of these subformulas, R 2 independently in each occurrence, C 1~5 haloalkyl. Formula (I), (Ii), (Iia), (Iib), ( Iic), (aI), (B), (Bi), (C), (D), and (E), as well as In some embodiments of any of those subformulas, R 2 is independently , CH2F. Formula (I), (Ii), (Iia), (Iib), (Ii- c), (aI), (B), (Bi), (C), (D), and (E), as well as those In some embodiments of any of the subformulas, R 2is independently in each occurrence CHF 2. Formula (I), (Ii), (Iia), (Iib), (Iic), ( aI), (B), (Bi), (C), (D), and (E), and their subformulas In some embodiments of any of the above, two geminal R 2 The appearance of, summarized, Forming an oxo moiety. Formula (I), (Ii), (Iia), (Iib), ( Iic), (aI), (B), (Bi), (C), (D), and (E), as well as In some embodiments of any of those subformulas, R 2 is independently , methyl, or CHF, or two geminal R 2 The emergence of The formulas (I), (Ii), (Iia), and (Iib) are ), (Iic), (aI), (B), (Bi), (C), (D), and (E), and in some embodiments of any of those subformulas, two non-geminal R 2 The occurrences of are taken together to form a methylene or ethylene bridge. -i)(Iia), (Iib), (Iic), (aI), (B), (B- i), (C), (D), and (E), and some implementations of any of their subformulas In terms of form, R d and R 2 occurrences of , together with the intervening atoms, form heterocycles. It is completed.

[0144] Formula (I), (Ii) (Iia), (Iib), (Iic), (aI) , (B), (Bi), (C), (D), and (E), and any of their subformulas In some embodiments, n is 0 or an integer from 1 to 2 (inclusive) as valence allows. Formulas (I), (Ii), (Iia), (Iib), (Iic), ( aI), (B), (Bi), (C), (D), and (E), and their subformulas In some embodiments of any of formulas (I), (Ii) (Iia), n is 0. ), (Iib), (Iic), (aI), (B), (Bi), (C), (D In some embodiments of (E), and (E), and any of their subformulas, n is 1 and In other embodiments, n is 2.

[0145] Formula (I), (Ii) (Iia), (Iib), (Iic), (aI) , (B), (Bi), (C), (D), and (E), and any of their subformulas In some embodiments, n is 1 and R 2 is X 1 is bonded to an atom adjacent to ( For example, R 2 is the X of the six-membered ring A 1 (ortho position relative to the formula (I), (Ii) (I -ia), (Iib), (Iic), (aI), (B), (Bi), (C In some embodiments of formulas (D), (E), and any of their subformulas, n is 1 and R 2 is X 2 is attached to an atom adjacent to (e.g., R 2 is the six-membered ring A X 2 (ortho to R) 2 The existence of R 2 Chiral center at the atom to which In one embodiment, the compound may be 2 has the R configuration at the atom to which it is attached In one embodiment, the compound is R2 has an S configuration at the atom to which is attached. In this state, the compound is 2 is a racemic mixture at the atom to which it is bonded.

[0146] Formula (I), (Ii) (Iia), (Iib), (Iic), (aI) , (B), (Bi), (C), (D), and (E), and any of their subformulas In some embodiments, n is 1 and R 2 is NC(=O)-R 1 adjacent to child (e.g., R 2 is the NC(=O)-R of the six-membered ring A 1 Ortho position to In one embodiment, n is 1 and R 2 is X 2 is bonded to an atom adjacent to ( For example, R 2 is the X of the six-membered ring A 2 (ortho to R) 2 The existence of R 2 is combined This may result in a chiral center at the atom in question. Iib), (Iic), (aI), (B), (Bi), (C), (D), and In some embodiments of (E), and any of their subformulas, the compound is R 2 The formula (I), (Ii), (Iia), (I-) has an R configuration at the atom to which it is attached. ib), (Iic), (aI), (B), (Bi), (C), (D), and ( E), as well as any of their subformulas, in some embodiments, the compound is R 2 Conclusion The bonded atoms have the S configuration. b), (Iic), (aI), (B), (Bi), (C), (D), and (E) and in some embodiments of any of these subformulas, the compound is R 2 is combined It is a racemic mixture with the atoms in

[0147] Formula (I), (Ii) (Iia), (Iib), (Iic), (aI) , (B), (Bi), (C), (D), and (E), and any of their subformulas In some embodiments, m is 0 or an integer from 1 to 2 (inclusive) as valence allows. Formulas (I), (Ii), (Iia), (Iib), (Iic), ( aI), (B), (Bi), (C), (D), and (E), and their subformulas In some embodiments of any of formulas (I), (Ii) (Iia), m is 0. ), (Iib), (Iic), (aI), (B), (Bi), (C), (D In some embodiments of (E), and (E), and any of their subformulas, m is 1. In other embodiments, m is 2.

[0148] In one embodiment, ring A (with optional substituent R 2 (including [ka] In one embodiment, ring A (with optional substituent R 2 (including [ka] In one embodiment, ring A (with optional substituent R 2 (including [ka] In one embodiment, ring A (with optional substituent R2 (including [ka] In one embodiment, ring A (with optional substituent R 2 (including [ka] In one embodiment, ring A (with optional substituent R 2 (including [ka] In one embodiment, ring A (with optional substituent R 2 (including [ka] In one embodiment, ring A (with optional substituent R 2 (including [ka] As used herein, * represents -C(=O)-R 1 J indicates the point of attachment to the bond. It is a combination.

[0149] In certain embodiments, the compound of formula (II) has formula (III): [ka] or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, , in the formula, R 11 , R 12 , R 13 , and R 14 are each independently hydrogen or an optionally substituted C 1~5 alkyl or R 11 , R 12 , R 13 , and R 14 Of the non Two geminal occurrences are grouped together to form a C1-C4 (e.g., C1-C2) alkylene The compound, or a pharmaceutically acceptable salt, stereoisomer, or or tautomers.

[0150] In some embodiments, R 11 and R 12 At least one of the TaC 1~5 In certain such embodiments, R 11 and R 12 Of At least one is methyl. In some embodiments, R 13 and R 14 A few of At least one optionally substituted C 1~5 In certain embodiments, R 13 and R 14 At least one of R is methyl. d and R 13 and R 14 One of the atoms is grouped together with the intervening atoms, In a further embodiment, R 11 , R 12 , R 13 , and R 14 is water It is natural.

[0151] In one embodiment, R 11 , R 12 , R 13 , and R 14 None of these are hydrogen. In the embodiment, R 11 , R 12 , R 13 , and R 14 One of the is hydrogen and R 11 , R 12 , R 13 , and R14 The other three of R are not hydrogen. 11 , R 12 , R 13 , and R 14 Two of the are hydrogen, and R 11 , R 12 , R 13 , and BiR 14 The other two are not hydrogen.

[0152] In one embodiment, R 11 , R 12 , R 13 , and R 14 Three of the atoms are hydrogen, and R 11 , R 12 , R 13 , and R 14 and the other one of is not hydrogen. R 12 , R 13 , and R 14 is hydrogen and R 11 is not hydrogen. In one embodiment, R 11 , R 13 , and R 14 is hydrogen and R 12 is not hydrogen. In one embodiment, R 1 1 , R 12 , and R 14 is hydrogen and R 13 is not hydrogen. In one embodiment, R 11 , R 12 , and R 13 is hydrogen and R 14 is not hydrogen. In one embodiment, the non-hydrogen group is optionally substituted alkyl. In one embodiment, the non-hydrogen group is methyl.

[0153] Non-hydrogen R 11 , R 12 , R 13 , or R 14The presence of non-hydrogen R 11 , R 12 , R 13 , or R 14 This can result in a chiral center at the atom to which it is attached. In embodiments, the compound has a non-hydrogen R 11 , R 12 , R 13 , or R 14 are combined In one embodiment, the compound has an R configuration at the atom that is a non-hydrogen R 11 , R 12 , R 13 , or R 14 In one embodiment, the compound has an S configuration at the atom to which it is attached. The substance is non-hydrogen R 11 , R 12 , R 13 , or R 14 The race at the atom to which It is a mixture of

[0154] In one embodiment, [ka] teeth, [ka] In one embodiment, the ring is [ka] In one embodiment, the ring is [ka] In one embodiment, the ring is [ka] In one embodiment, the ring is [ka] In one embodiment, the ring is [ka] In one embodiment, the ring is [ka] In one embodiment, the ring is [ka] As used herein, * represents -C(=O)-R 1 Refers to the attachment point to

[0155] In certain embodiments, X 2 and R 13 The bond between the carbon bonded to In another embodiment, X 2 and R 13 The bond between the carbon bonded to be.

[0156] In some embodiments, R 1 teeth, [ka] In a further embodiment, R 1 teeth, [ka] is.

[0157] As used herein, R a1 are independently hydrogen, halo, CN, N(R n1 )2, Optionally substituted C 1~5 Alkyl, optionally substituted -CH2O-C 1~5 Alkyl, Optionally substituted -CH2O-(CH2) 1~2 -OC 1~5 Alkyl, optionally substituted CO2-C1~5 alkyl, or optionally substituted 3- to 6-membered heterocyclyl Each R n1 are independently hydrogen or C 1~5 In certain such embodiments, In terms of form, R a1 is hydrogen. In certain embodiments, R a1 is CN. In certain embodiments, R a1 is CN. In certain embodiments, R a1 teeth,- CH2O-C 1~5 In certain embodiments, R a1 is -CH2OC H3. In certain embodiments, R a1 is an optionally substituted -CHO-(CH 2) 1~2 -OC 1~5 In certain embodiments, R a1 is -CH 2O-(CH2) 1~2 -OC 1~5 In certain embodiments, R a 1 is —CH2O—(CH2)2—O—CH3. In certain embodiments, R a1 is an optionally substituted -CO2-C 1~5 In certain embodiments, R a1 is -CO2CH3.

[0158] As used herein, R a2 are independently hydrogen, halo, CN, N(R n1 )2, Optionally substituted C 1~5 Alkyl, optionally substituted -CH2O-C 1~5 Alkyl, Optionally substituted -CH2O-(CH2) 1~2 -OC 1~5 Alkyl, optionally substituted CO2-C 1~5 alkyl, or optionally substituted 3- to 6-membered heterocyclyl Each R n1 are independently hydrogen or C 1~5 In certain such embodiments, In terms of form, R a2 is hydrogen. In some embodiments, R a2 is an arbitrarily substituted C 1~5 alkyl or optionally substituted 3- to 6-membered heterocyclyl. In terms of form, R a2 is methyl, -CH2-N(CH3)2, -CO2CH3, -CH2O CH3, -CH2O(CH2)2CH3, morpholinomethyl, or pyrrolidinyl In some embodiments, R a2 is an arbitrarily substituted C 1~5 It is an alkyl. In certain embodiments, R a2 is optionally substituted with an amine or a 3- to 6-membered heterocycle; and the amine or the heterocycle is C 1~5 Optionally substituted with alkyl. In some embodiments, R a2 is dialkylaminomethyl. is R a2 is dimethylaminomethyl. In another embodiment, R a2 is hydrogen In certain embodiments, R a2 is CN. In certain embodiments, R a2 teeth , CN. In certain embodiments, R a2 is -CH2O-C 1~5 Alkyl In certain embodiments, R a2 is —CH2OCH3. So, R a2 is an optionally substituted -CH2O-(CH2)1~2 -OC 1~5 Archi In certain embodiments, R a2 is -CH2O-(CH2) 1~2 -OC 1~5 In certain embodiments, R a2 is -CH2O-(CH2)2 In certain embodiments, R a2 is an optionally substituted -CO2- C 1~5 In certain embodiments, R a2 is -CO2CH3.

[0159] As used herein, R a3 are independently hydrogen, halo, CN, N(R n1 )2, Optionally substituted C 1~5 Alkyl, optionally substituted -CH2O-C 1~5 Alkyl, Optionally substituted -CH2O-(CH2) 1~2 -OC 1~5 Alkyl, optionally substituted CO2-C 1~5 alkyl, or optionally substituted 3- to 6-membered heterocyclyl Each R n1 are independently hydrogen or C 1~5 In certain such embodiments, In terms of form, R a3 is hydrogen. In some embodiments, R a4 is an arbitrarily substituted C 1~5 In certain such embodiments, R a3 is methyl. In certain such embodiments, R a3 is CN. In certain such embodiments, R a3 is F.

[0160] In some embodiments, Ra1 are independently hydrogen or C 1~5 alkyl, and R a2 are independently hydrogen, halo, CN, N(R n1 ) 2 , optionally substituted C 1~5 Al Kill, optionally substituted -CH2O-C 1~5 Alkyl, optionally substituted -CH2O- (CH2) 1~2 -OC 1~5 Alkyl, optionally substituted -CO2-C 1~5 Archi or optionally substituted 3- to 6-membered heterocyclyl, and each R n1 independently, water element or C 1~5 alkyl, and R a3 are independently hydrogen, halo, CN, optionally substituted C 1~5 It is alkyl.

[0161] In some embodiments, R a1 and R a2 are linked to form an alkenyl group do.

[0162] In some embodiments, R a1 and R a2 is hydrogen. In some embodiments, R a1 , R a3 , and R a3 is hydrogen.

[0163] In certain embodiments, X 2 is -C=. In another embodiment, X 2 is N In another embodiment, X 2 is -CH-.

[0164] In some embodiments, U is CR c In certain such embodiments, R c teeth , fluoro. In some embodiments, R c is hydrogen. In another embodiment, U is N.

[0165] In certain embodiments, V is CR d In some embodiments, R d is hydrogen , fluoro, methyl, or methoxy. d Is Metoki In certain embodiments, R d In other embodiments, V is fluoro. , N.

[0166] In some embodiments, W is N. In some embodiments, W is CR e is In some embodiments, W is CH or CF.

[0167] In some embodiments, Y 1 and Y 2 is C R4 In some embodiments, Y 1 is C R4 and Y 2 is N.

[0168] In some embodiments, R 4 is independently in each occurrence fluoro, chloro, methyl , methoxy, or difluoromethyl.

[0169] In certain embodiments, R 6 and R 7 are each independently hydrogen, halo, optionally substituted In some embodiments, the alkyl group is an optionally substituted alkoxy, or an optionally substituted alkyl. R 6 and R 7 are each independently hydrogen, fluoro, methoxy, or difluoromethyl. In certain embodiments, R 6 and R 7 is hydrogen. is R 8 and R 9 are each independently hydrogen, halo, or optionally substituted alkyl In certain embodiments, R 8 and R 9 are each independently hydrogen, chloro, or methyl. In some embodiments, R 8 is methyl. , R 9 is hydrogen. In some embodiments, R 10 is hydrogen, fluoro, chloro, methyl In some embodiments, R is methyl, ethyl, or methoxy. 10 is hydrogen.

[0170] In one embodiment, R 6 , R 7 , R 8 , and R 9 None of these is hydrogen.

[0171] In one embodiment, R 6 , R 7 , R 8 , and R 9 One of the is hydrogen and R 6 , R 7 , R 8 , and R 9 The other three of R are not hydrogen. 7 is hydrogen , R 6 , R 8 , and R 9 is not hydrogen. In one embodiment, R 9 is hydrogen and R 6 , R 7 , and R 8 is not hydrogen.

[0172] In one embodiment, R 6 , R 7 , R 8 , and R 9 Two of the are hydrogen, and R 6 , R 7 , R 8 , and R 9 The other two of R 7 and R 9 is water It is elementary and R 6 and R 8 is not hydrogen. In one embodiment, R 6 and R 9 is hydrogen, R 7 and R 8 is not hydrogen.

[0173] In one embodiment, R 6 , R 7 , R 8 , and R 9 Three of the atoms are hydrogen, and R 6 , R 7 , R 8 , and R 9 and the other one of R is not hydrogen. 6 , R 7 , and R 9 is hydrogen and R 8 is not hydrogen. In one embodiment, R 7 , R 8 , and R 9 is hydrogen and R 6 is not hydrogen.

[0174] In one embodiment, R 7 and R 9 is hydrogen and R 6 and R 8 One of the is a substituted alkyl, and R 6 and R 8 and the other one of is halo. So, R 7and R 9 is hydrogen and R 6 is optionally substituted alkyl, and R 8 Ha halo In one embodiment, R 7 and R 9 is hydrogen and R 8 is an optionally substituted alkyl and R 6 is halo. In one embodiment, the optionally substituted alkyl is methyl. In one embodiment, halo is fluoro. In one embodiment, R 7 and R 9 is hydrogen Yes, R 8 is methyl and R 6 is fluoro.

[0175] In some embodiments, Q 1 is CR g and Q 2 is CR g and Q 3 is CR g Yes Ri, Q 4 is NR f In another embodiment, Q 1 is NR f and Q 2 is CR g and , Q 3 is CR g and Q 4 is NR f In a further embodiment, Q 1 is CR g and , Q 2 is CR g and Q 3 is NR f and Q 4 is NR f In some embodiments, Q 1 is NRf and Q 2 is NR f and Q 3 is CR g and Q4 is NR f Yes In yet another embodiment, Q 1 is NR f and Q 2 is NR f and Q 3 is NR f and Q 4 is CR g In yet another embodiment, Q 1 is CR g and Q 2 is N R f and Q 3 is CR g and Q 4 is NR f In yet another embodiment, Q 1 is CR g and Q 2 is NR f and Q 3 is NR f and Q 4 is CR g How many? In some embodiments, R f is hydrogen, methyl, or absent. is R f is hydrogen or absent. In some embodiments, R g is hydrogen. In some embodiments, R g is non-existent.

[0176] In one embodiment, [ka] teeth, [ka] In one embodiment, [ka] teeth, [ka] In one embodiment, [ka] teeth, [ka] is.

[0177] In one embodiment, the compound has the following formula: [ka] or any of its enantiomers, mixtures of enantiomers, if or a mixture of diastereomers, or a pharmaceutically acceptable salt thereof, In the formula, R 1 , R 4 , R 5 , R 11 , R 12 , R 13 , R 14 , R c , R d , Y 1 , Y 2 , Rings B, m, and p are as defined herein or elsewhere.

[0178] In one embodiment, the compound has the following formula: [ka] or any of its enantiomers, mixtures of enantiomers, if or a mixture of diastereomers, or a pharmaceutically acceptable salt thereof, In the formula, R a1 , R a2 , R a3 , R 6 , R 7 , R 8 , R 9 , R 10 , R11 , R 12 , R 13 , R 14 , R c , R d , Q 1 , Q 2 , Q 3 , and Q 4 is defined herein or elsewhere. As it is justified.

[0179] In one embodiment, the compound has the following formula: [ka] or any of its enantiomers, mixtures of enantiomers, if or a mixture of diastereomers, or a pharmaceutically acceptable salt thereof, In the formula, R 6 , R 8 , R 11 , R 12 , R 13 , R 14 , R c , and R d is also included in this specification. is as defined elsewhere.

[0180] In certain embodiments, the compound of formula (III) has the formula (III-I-1): [ka] or a pharmaceutically acceptable salt thereof, wherein Q 1 ~Q 4 , R 1 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is as defined herein .

[0181] In certain embodiments, the compound of formula (III) has the formula (III-I-2): [ka] or a pharmaceutically acceptable salt thereof, wherein Q 1 ~Q 4 , R 1 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is as defined herein .

[0182] In certain embodiments, the compound of formula (III) has the formula (III-I-3): [ka] or a pharmaceutically acceptable salt thereof, wherein Q 1 ~Q 4 , R 1 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is as defined herein .

[0183] In certain embodiments, the compound of formula (III) has the formula (III-I-4): [ka] or a pharmaceutically acceptable salt thereof, wherein Q 1 ~Q 4 , R 1 , R 6 , R 7 , R 8 , R 9 , R 10, R 11 , and R 12 is as defined herein .

[0184] In certain embodiments, the compound of formula (III) has the formula (III-I-5): [ka] or a pharmaceutically acceptable salt thereof, wherein Q 1 ~Q 4 , R 1 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is as defined herein .

[0185] In certain embodiments, the compound of formula (III) has the formula (III-I-6): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is as defined herein.

[0186] In certain embodiments, the compound of formula (III) has the formula (III-I-7): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is as defined herein.

[0187] In certain embodiments, the compound of formula (III) has the formula (III-I-8): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is as defined herein.

[0188] In certain embodiments, the compound of formula (III) has the formula (III-I-9): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is as defined herein.

[0189] In certain embodiments, the compound of formula (III) has the formula (III-I-10): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 6 , R 7 , R 8 , R 9 , R 10 , R11 , and R 12 is as defined herein.

[0190] In certain embodiments, the compound of formula (III) has the formula (III-I-11): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is as defined herein.

[0191] In certain embodiments, the compound of formula (III) has the formula (III-I-12): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is as defined herein.

[0192] In certain embodiments, the compound of formula (III) has the formula (III-I-13): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12is as defined herein.

[0193] In one embodiment of any of formulas (III-I-1) to (III-I-13), R 1 teeth, [ka] where R a1 , R a2 , and R a3 is as defined herein In certain embodiments, R a1 , R a2 , and R a3 is H.

[0194] In one embodiment of any of formulas (III-I-1) to (III-I-13), R 6 , R 7 , R 8 , and R 9 each independently represents H, a halogen, C 1~4 Alkyl, also is C 1~4 In certain embodiments, R 7 and R 9 is H, R 6 and R 8 are each independently a halogen or C 1~4 It is alkyl.

[0195] In one embodiment of any of formulas (III-I-1) to (III-I-13), R 11 and R 12 each independently represents H or C 1~4 In certain embodiments, In terms of form, R 11 is H and R 12 is C1-C4 alkyl. In terms of form, R 12 is H and R 11 is C1~4 It is alkyl.

[0196] In one embodiment of any of formulas (III-I-1) to (III-I-13), R 10 is H, halogen, or C1-C4 alkyl.

[0197] In one embodiment of any of formulas (III-I-1) to (III-I-13), R 1 teeth, [ka] and R 6 , R 7 , R 8 , and R 9 each independently represents H, a halogen, or C 1~ 4 alkyl, and R 11 and R 12 each independently represents H or C 1~4 With alkyl Yes, R 10 is H, halogen, or C 1~4 It is alkyl.

[0198] Formula (III-A-1), (III-B-1), (III-C-1), (III-D-1 ), (III-E-1), (III-F-1), (III-G-1), (III-H-1 ), and in one embodiment of any of (III-I-1) to (III-I-13), , R 8 is an arbitrarily substituted C 1~4 alkyl, and R 6 is halo. Now, let's consider an arbitrarily substituted C 1~4 Alkyl is methyl. In one embodiment, halo is In one embodiment, R 8 is methyl and R 6 is fluoro.

[0199] In some embodiments, there are provided herein compounds having the following structure: [ka] TIFF2025134754000187.tif233165TIFF2025134754000188.tif227165TIFF2025134754000189.tif197165TI FF2025134754000190.tif227165TIFF2025134754000191.tif212165TIFF2025134754000192.tif233165TIFF 2025134754000193.tif217165TIFF2025134754000194.tif222165TIFF2025134754000195.tif222165TIFF2025134754000196.tif233165TIFF2025134754000197.tif99165, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. can be.

[0200] In some embodiments, there are provided herein compounds having the following structure: [ka] TIFF2025134754000199.tif222165TIFF2025134754000200.tif233165TIFF2025134754000201.tif191165TIFF2025134754000202.tif212165TIFF2025134754000203.tif207165TIFF2025134754000204.tif42165, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof is disclosed. can be.

[0201] In some embodiments, there are provided herein compounds having the following structure: [ka] TIFF2025134754000206.tif197165TIFF2025134754000207.tif233165TIFF2025134754000208.tif78165, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. can be.

[0202] Provided herein are methods for treating cancer, comprising administering a therapeutically effective amount of the compounds described herein. the method comprising administering the indicated compound to a mammal in need of cancer treatment. In some embodiments, the cancer is non-small cell lung cancer. In certain embodiments, the cancer is head and neck squamous cell carcinoma. In certain embodiments, the non-small cell lung cancer is one or more In another embodiment, the non-small cell lung cancer has one or more of the ErbB family mutations listed above. In some embodiments, the non-small cell lung cancer has one or more EGFR ex20 insertion mutations. In certain embodiments, the mammal is a human. In some embodiments, the compound is administered orally or intravenously.

[0203] How to use In one aspect, a subject (e.g., a person in need of preventing and / or treating a proliferative disorder, such as cancer) is Methods for preventing and / or treating a proliferative disorder, such as cancer, in a subject are provided herein. The method includes administering a compound of the present disclosure (e.g., an effective amount, e.g., a therapeutically effective amount) to a subject. ) to a subject.

[0204] Cancer is a disease of uncontrolled cell growth caused by alterations in certain genes. Some of these changes transduce signals from outside the cell, affecting cell survival, growth, and Receptor tyrosine kinases (RTKs), a family of membrane-bound proteins that promote proliferation, Aberrant RTK activation occurs in genes encoding RTKs. Abnormal RTK activation leads to excessive cell proliferation and This can lead to cancer. Generally, RTKs have an N-terminal domain that binds to extracellular ligands. domain, transmembrane domain, and C-terminal kinase domain that catalyzes intracellular signaling It has.

[0205] Human EGFR, also known as ErbB1 or HER1, is a gene encoding the EGFR gene on chromosome 7. RTK encoded by the gene. Epidermal growth factor (EGF), transforming growth factor Transforming growth factor α (TGF-α), amphiregulin (AREG), heparin-binding EGFR-like Hepatocyte growth factor (HB-EGF), betacellulin (BTC), epiregulin (EPR), and epi Several ligands for EGFR have been identified, including EGFR-1, EGFR-2, and EGFR-3. is thought to play an essential role in the development, proliferation, differentiation, and migration of mammalian cells. EGFR-deficient mice die within a few weeks of birth and exhibit, but are not limited to, It shows improper development of various organs, including the skin, digestive tract, and nervous system. EGFR overexpression and activating mutations are well-documented causes of cancer. Overexpression is frequently found in many solid tumors and is regulated by the following FDA-approved monoclonal antibodies: It can be targeted by monoclonal antibodies: cetuximab, panitumumab, and necitumumab.

[0206] In some embodiments, the compounds of the present disclosure are modulators of HER2. The well-known human HER2 RTK is encoded by the ERBB2 gene on chromosome 17. Although the ligand for HER2 is unknown, HER2 binds to H Regulates downstream signaling by heterodimerizing with other RTKs of the ER2 family Mouse studies have demonstrated a profound effect on mammalian development and cell proliferation, particularly in the cardiac and nervous systems. Demonstrated an essential role for HER2 in differentiation. HER2 deficiency results in abnormal cardiac development. HER2 is embryonic lethal in mice, and conditional deletion of HER2 inhibits neuronal maturation. In humans, HER2 overexpression and Activating mutations are a known cause of cancer. HER2 overexpression is associated with a number of solid tumors. Most notably, it is found in 15-25% of breast cancers. The range is esophageal and gastric cancer, breast cancer, peritoneal cancer, salivary gland cancer, bladder cancer, endometrial cancer, ampullary cancer, small intestine cancer, vaginal cancer Cancer, cervical cancer, hepatobiliary tract cancer, ovarian cancer, colorectal cancer, NSCLC, head and neck cancer, pancreatic cancer, skin cancer , appendix cancer, B lymphoblastic leukemia / lymphoma, melanoma, germ cell tumors, small cell lung cancer, mature B observed in cancers including gliomas, prostate cancer, soft tissue sarcomas, and gliomas Monoclonal antibodies (trastuzumab and pertuzumab), antibody-drug conjugates ( ado-trastuzumab emtansine and fam-trastuzumab deruxtecan), and small molecule kinase inhibitors (lapatinib, neratinib, and tucatinib), A number of targeted therapies have been developed for the treatment of ER2-positive breast cancer. Tucatinib, a HER2 inhibitor, demonstrated an objective response rate of 23% to 4% compared with placebo. 1% increase in median progression-free survival (PFS) of 5.6 to 7.8 months and median overall survival of 1.5 to 2.5 months. In contrast, HER2 exon 20 insertions were associated with a median survival time of 17.4 to 21.9 months in NSCLC. These mutations are found in approximately 2% of cases, but there are no approved targeted therapies for these mutations.

[0207] Erlotinib, gefitinib, afatinib, dacomitinib, lapatinib, and neratinib Many existing HER2 therapies, including nib, are also potent inhibitors of wild-type EGFR. Native EGFR plays an important role in epithelial biology, including the integrity of the skin and gastrointestinal lining. This is a serious drawback because wild-type EGFR plays an important role in the treatment of rheumatoid arthritis. Common adverse reactions include diarrhea and stomatitis. Therefore, there is a need in the art for novel therapies that selectively target mutant HER2. .

[0208] In one embodiment, a method of treating and / or preventing a proliferative disorder comprises administering to a subject a method of treating and / or preventing a proliferative disorder, the method comprising ... The method is provided herein, wherein inhibition of HER2 and / or mutant HER2 results in a therapeutic effect. In certain embodiments, the method is a method for treating and / or preventing a proliferative disorder. Therefore, the method is based on the present invention, in which inhibition of exon 20 mutant HER2 protein brings about a therapeutic effect. Provided in the specification.

[0209] In another aspect, a subject in need of inhibiting wild-type and / or mutant HER2 A method of inhibiting wild-type and / or mutant HER2, comprising administering a therapeutically effective amount of a compound described herein. The method comprises administering to a subject a compound described herein or a pharmaceutically acceptable salt thereof. In another embodiment, a method for inhibiting exon 20 mutant HER2 is provided herein. 1. A method for inhibiting exon 20 mutant HER2 in a subject in need of treatment, comprising: administering to a subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof; Such a method is provided herein, comprising:

[0210] In another aspect, a method of treating cancer comprises administering a therapeutically effective amount of a compound described herein. or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. administering the compound to a mammal (e.g., a human subject) in need of cancer treatment. Such methods are provided herein. In some embodiments, the cancer is HER2-associated In some embodiments, the HER2-associated cancer is a cancer characterized by HER2 overexpression and / or is associated with HER2 amplification and / or HER2 mutation(s).

[0211] In some embodiments, "associated with" refers to the cause of cancer. , "related to" indicates a characteristic of cancer.

[0212] In another aspect, a method of treating cancer comprises administering a therapeutically effective amount of a compound described herein. or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. administering the compound to a mammal (e.g., a human subject) in need of treatment for cancer; The method is provided herein, wherein the cancer is associated with a HER2 exon 20 mutation. In some embodiments, the HER2 exon 20 mutation is a YVMA insertion, a VC insertion, or and GSP insertions. The variant 20 mutation is one or more from the group consisting of a YVMA insertion and a VC insertion.

[0213] In certain embodiments, the HER2 exon 20 insertion mutation is A775_G776in sYVMA, P780_Y781insGSP, G776>VC, G776>IC, G7 76>LC, G778_S779insCPG, G780_P781dupGSP, Y7 72_A775dup, G778_P780dup, E770_A771insGIRD , G778_S779insLPS, M774_A775insAYVM, G778_S 779insLPG, G778dup, G776delinsVC, M774delin Select from sWLV, A775_G776insSVMA, and A775_G776insI. In certain embodiments, the HER2 exon 20 insertion mutation is one or more of: A775_G776insYVMA, P780_Y781insGSP, G776>VC , G776>IC, G776>LC, G778_S779insCPG, and G780_ P781dupGSP. In certain embodiments, the HER 2 Exon 20 insertion mutations: A775_G776insYVMA, P780_Y781i nsGSP, G776>VC, G776>IC, G776>LC, and G778_S77 9insCPG.

[0214] In another aspect, a method of treating cancer comprises administering a therapeutically effective amount of a compound described herein. administering the compound or a pharmaceutically acceptable salt thereof to a subject in need of cancer treatment. wherein the cancer is characterized by HER2 overexpression, HER2 amplification, and / or HER2 exon Provided herein are methods characterized by 20 mutation(s).

[0215] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is brain cancer. , breast cancer, biliary tract cancer, bladder cancer, cervical cancer, colorectal cancer, endometrial cancer, skin cancer, esophageal tumor, head and neck cancer The cancer is selected from the group consisting of gastrointestinal cancer, gallbladder tumor, kidney cancer, liver cancer, lung cancer, and prostate cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is NSCLC. In some embodiments, the cancer is small cell lung cancer. The cancer is breast cancer. In some embodiments, the cancer is metastatic cancer.

[0216] In certain embodiments, the compounds provided herein are CNS-penetrating compounds. In one embodiment, after administration of a therapeutically effective amount of a compound provided herein, The compounds penetrate the CNS (e.g., the blood-brain barrier) and still inhibit HER2 overexpression and and / or inhibit HER2 amplification and / or HER2 mutation(s) (e.g., select It is possible to achieve concentrations in the CNS (e.g., brain) sufficient to effectively inhibit (effectively inhibit) the

[0217] In one embodiment, a method for treating CNS metastasis of cancer is provided, comprising administering a therapeutically effective amount of the compounds described herein. Compounds provided in, for example, compounds of formula (I), or enantiomers thereof, A mixture of the anantiomers, or tautomers, or a pharmaceutically acceptable salt thereof, and administering the compound to a mammal (e.g., a human subject) in need of treatment for CNS metastases of cancer. In one embodiment, the CNS metastases are brain metastases. In one embodiment, the cancer is a HER-associated cancer (e.g., HER2 overexpression, and / or HER2 amplification and / or HER2 exon 20 mutation(s) (This is the case.)

[0218] In another embodiment, a subject in need of inhibiting exon 20 mutant HER2(s) 20. A method for inhibiting exon 20 mutant HER2(s) in a subject, comprising administering a therapeutically effective amount a compound described herein (e.g., of Formula (I) or any subformula) or a pharmaceutical The method comprises administering to a mammal (e.g., a human subject) a physiologically acceptable salt of the present invention. Provided in the specification.

[0219] In certain embodiments, compounds of the present disclosure inhibit wild-type HER2 as compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure selectively inhibit wild-type EGFR and 2. In certain embodiments, the HER2 inhibitor selectively inhibits wild-type HER2 by about 10 to about 100 times more than wild-type HER2 inhibitors. In other words, the compounds of the present disclosure selectively inhibit wild-type HER2 by about 20 to about 80 times more than wild-type EGFR. In certain embodiments, the compounds of the present disclosure selectively inhibit EGFR as compared to wild-type EGFR. In a specific embodiment, the present invention selectively inhibits wild-type HER2 by about 30 to about 80 times. The compounds shown are as follows: In certain embodiments, the compounds of the present disclosure selectively inhibit wild-type HER2. Approximately 100% of wild-type HER2 compared to wild-type EGFR(s) (e.g., EGFR exon 20) In certain embodiments, compounds of the present disclosure selectively inhibit the mutation. Approximately 100% of wild-type HER2 compared to wild-type EGFR(s) (e.g., EGFR exon 20) In certain embodiments, compounds of the present disclosure selectively inhibit wild-type Selectively inhibits mutant HER2(s) relative to EGFR. In this case, the compounds of the present disclosure inhibit mutant HER2(s) by about 10% compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure selectively inhibit wild-type E It inhibits mutant HER2(s) approximately 20 to 100 times more selectively than GFR. In certain embodiments, compounds of the present disclosure have an exon 20 mutation compared to wild-type EGFR. In certain embodiments, compounds of the present disclosure selectively inhibit HER2 type(s). , about 10 to about 100% of exon 20 mutant HER2(s) compared to wild-type EGFR In certain embodiments, compounds of the present disclosure inhibit EGFR more selectively than wild-type EGFR. It inhibits exon 20 mutant HER2(s) approximately 20 to 80 times more selectively than HER2. In certain embodiments, compounds of the present disclosure have an exon 30 mutation compared to wild-type EGFR. In certain embodiments, the HER2-type inhibitor selectively inhibits HER2(s) by about 20 to about 80 times. The compounds of the present disclosure are directed to mutated EGFR(s) (e.g., EGFR exon 20) to selectively inhibit mutant HER2(s) (e.g., HER2 exon 20). In certain embodiments, compounds of the present disclosure may be used to treat mutated EGFR(s) (e.g., EG Mutant HER2(s) (e.g., HER2 exon 2) compared with HER2 exon 20 0) with about 10 to about 100-fold selectivity. is associated with mutant HE compared with mutant EGFR(s) (e.g., EGFR exon 20) Selectively inhibits R2(s) (e.g., HER2 exon 20) approximately 20-80 times In some embodiments, the compounds of the present disclosure target wild-type EGFR and / or exon 20. Selectively target exon 20 mutant HER2(s) compared to mutant EGFR(s) In some embodiments, compounds of the present disclosure inhibit wild-type leukemia compared to current therapies. In addition to the improved efficacy profile of sparing EGFR, Furthermore, some compounds of the present invention exhibit improved pharmacokinetic and pharmacological properties. In some embodiments, the compounds described herein exhibit a specific profile related to It has minimal activity against kinases that inhibit it (e.g., wt EGFR). Inhibition of ATP can result in unwanted side effects (e.g., steroids) that can affect quality of life and treatment compliance. For example, diarrhea and skin rash.

[0220] In some embodiments, the human subject is a patient receiving a vaccine (e.g., a regulatory approved, e.g., FD HER2 overexpression and and / or HER2 amplification and / or HER2 exon 20 mutation(s) In some embodiments, the patient has been identified or diagnosed as having HER2-associated cancer. Subjects are to: HER2 overexpression and / or HER2 amplification and / or HER2 exon 20 mutation Subjects have tumors that are positive for HER2 overexpression and and / or HER2 amplification and / or HER2 exon 20 mutation(s) (e.g., where the tumor itself is a regulatory approved, e.g., FDA In some embodiments, the antibody is identified using a commercially available assay or kit. In some embodiments, the subject is suspected of having a HER2-associated cancer. ER2 overexpression and / or HER2 amplification and / or HER2 exon 20 mutations (multiple Have clinical records showing that the patient has a tumor with a marker of pulmonary function (acceptable).

[0221] In some embodiments of any of the methods or uses described herein, a subject-derived The sample is used to determine whether the subject has HER2 overexpression and / or HER2 amplification and / or HER2 Assays used to determine whether a patient has an exon 20 mutation(s) For example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR) As is well known in the art, assays typically involve, for example, At least one labeled nucleic acid probe or at least one labeled antibody or its The assay is performed using an antigen-binding fragment of HER2 overexpression and / or HER2. 2. State of the Art for Detecting Amplification and / or HER2 Exon 20 Mutation(s) Other detection methods known in the art may be utilized (see, for example, the references cited herein). In some embodiments, the sample is a biological sample or biopsy sample from a subject (see In some embodiments, the subject is a patient with a HER2-associated subjects suspected of having a HER2-associated cancer, subjects with one or more symptoms of a HER2-associated cancer, and and / or are at high risk of developing HER2-associated cancer.

[0222] In some embodiments, HER2 overexpression and / or HER2 amplification and / or HE R2 exon 20 mutation(s) can be identified by liquid biopsy (variously referred to as liquid biopsy or liquid-phase biopsy) For example, Karachialiou et al., "R eal-time liquid biopsies become a realit y in cancer treatment”,Ann.Transl.Med.,3 (3):36, 2016. Liquid biopsy methods are used to assess total tumor burden and / or HER2 gene, HER2 kinase, or the expression or activity or level of either of them Liquid biopsies can be taken relatively easily (e.g., from a subject) to detect dysregulation of the blood. It can be performed on biological samples obtained (e.g., by simple blood sampling) and typically assesses tumor burden and / or H ER2 gene, HER2 kinase, or the expression or activity of either of them is less invasive than traditional methods used to detect dysregulation of levels. In this embodiment, liquid biopsy detects HER2 overexpression and / or or to detect the presence of HER2 amplification and / or HER2 exon 20 mutation(s). In some embodiments, the biological sample used in the liquid biopsy may be blood. fluid, plasma, urine, cerebrospinal fluid, saliva, sputum, bronchoalveolar lavage, bile, lymph, cyst fluid, stool, abdominal In some embodiments, the liquid biopsy may include circulatory In some embodiments, liquid biopsies can be used to detect tumor cells (CTCs). In some embodiments, liquid biopsies can be used to detect cell-free DNA. The cell-free DNA detected in the tumor is circulating tumor DNA (ctDNA) derived from tumor cells. Analysis of ctDNA (e.g., highly sensitive detection techniques, including, but not limited to, Next-generation sequencing (NGS), conventional PCR, digital PCR, or microarray analysis HER2 overexpression and / or HER2 amplification and / or HE R2 can be used to identify exon 20 mutation(s).

[0223] In some embodiments, compounds of the present disclosure inhibit exon 1 expression in subjects with NSCLC. In some embodiments, exon 20 mutant HER2 is inhibited. , YVMA insertion, VC insertion, and GSP insertion. In embodiments, the compounds of the present disclosure inhibit non-exon 20 mutant HER2. In some embodiments, the compounds are wild-type and / or (e.g., exon 20) mutant forms. Selectively inhibits non-exon 20 mutant HER2(s) compared to EGFR. In some embodiments, the non-exon 20 mutant HER2 is S310X, (e.g., S310 F and S310Y), R678Q, V842I, L755S, G776V, and V777 X. In some embodiments, the non-exon 20 mutation is one or more from the group consisting of L7 One or more selected from 55S, S310F, R678Q, V842I, and V777X is.

[0224] In some embodiments, the inhibitors inhibit wild-type HER2 and / or mutant HER2 in cells. a method of damaging a cell comprising contacting the cell with a compound of the present disclosure, the method comprising contacting the cell with a compound of the present disclosure. In some embodiments, the mutant HER2 is a mutant HER2 polypeptide comprising one or more exons. Possesses the Son20 mutation.

[0225] In some embodiments, the HER2 (wild-type HER2 and / or mutant ( a method for increasing the level of a compound or compounds of the present disclosure, comprising treating the cells with a compound or compounds thereof. contacting the compound with a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; A method is provided herein.

[0226] In some embodiments, the HER2 (wild-type HER2 and / or mutant ( a method for decreasing phosphorylation of a target protein (a target protein or targets), comprising treating the cell with a compound of the disclosure, or a pharmaceutically acceptable salt, stereoisomer, or tautomer of The method is provided herein. In another embodiment, the method comprises: A method for inhibiting HER2 having a mutation, comprising treating the cell with a compound of the present disclosure or a compound thereof. the method, including contacting the compound with a physiologically acceptable salt, stereoisomer, or tautomer. Methods are provided herein.

[0227] In some embodiments, the expression of wild-type HER2 and / or mutant HER2 in cells is a method for inhibiting phosphorylation of the cells, the method comprising treating the cells with a compound of the present disclosure, or a pharmaceutically acceptable salt thereof; The method comprises contacting a compound of formula (I) with a salt, stereoisomer, or tautomer of the compound of formula (I) described herein. In some embodiments, the mutant HER2 is located in one or more exons 2 0 mutations.

[0228] In some embodiments, the method is a method for treating and / or preventing a disease and / or condition. and wherein inhibition of wild-type and / or mutant HER2 is therapeutically useful. In another embodiment, a method for treating or preventing a disease and / or condition is provided. The method, wherein inhibition of exon 20 mutant HER2 protein is therapeutically useful. Methods are provided herein.

[0229] In some embodiments, a human subject in need of inhibiting wild-type and / or mutant HER2 is 1. A method for inhibiting wild-type and / or mutant HER2 in a subject, comprising administering a therapeutically effective amount of or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. Such methods are provided herein, comprising administering to the subject

[0230] The compounds of the present disclosure are useful for inhibiting HER2 in vitro or in vivo. Thus, a method for inhibiting HER2 in a cell (e.g., a cell that expresses HER2) is The cells are then treated with a compound of the present disclosure (e.g., a compound of the present disclosure, e.g., a compound of formula (I), (I- i), (Iia), (Ii-a1), (Ii-a2), (aI), (II), or (III), or a pharmaceutically acceptable salt, stereoisomer, or Such methods are provided herein, comprising contacting a compound with a tautomer (such as a tautomer). In embodiments, the cells are derived from a subject, such as a human (e.g., a patient suffering from a disease, disorder, or a condition in which HER2 is required to be inhibited (e.g., and inhibiting HER2 in a subject (e.g., a subject having a disease, disorder, or condition described herein). A method of inhibiting a tumor comprising administering a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of the present disclosure, e.g., , formula (I), (Ii), (Iia), (Ii-a1), (Ii-a2), (a - a compound of formula I), (II), or (III), or a pharmaceutically acceptable salt thereof, The method also includes administering to the subject a compound (e.g., a tautomer, or isomer) of the compound described herein. It is provided at.

[0231] In some embodiments, the cell is present in a mammal. In some embodiments, the cells are present in a human subject having cancer. In some embodiments, the cells are HER2 overexpressing and / or HER2 amplified and / or or present in human subjects with cancer associated with HER2 mutation(s). In embodiments, the cells are isolated from a mammal (eg, a human subject with cancer).

[0232] "Proliferative disease" refers to a disease caused by abnormal growth or expansion of cells due to proliferation. (Walker, Cambridge Dictionary of Biology; Cambridge University Press:Cambridge,UK, 1990). Proliferative disorders are (1) the pathological proliferation of normally quiescent cells; (2) the proliferation of normally quiescent cells; (3) pathological migration from a non-specific site (e.g., metastasis of neoplastic cells); Proteases such as enzymes (e.g., collagenase, gelatinase, and elastase) and / or (4) pathological angiogenesis, such as in proliferative retinopathy and tumor metastasis. Non-limiting examples of proliferative diseases include cancer (i.e., "malignant neoplasms"), These include benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.

[0233] The terms "neoplasm" and "tumor" are used interchangeably herein and refer to an abnormal mass of tissue. abnormal tissue growth in which the growth of the mass exceeds and is not coordinated with normal tissue growth Neoplasms or tumors are classified as "benign" or "malignant" depending on, for example, the following characteristics: "The degree of cell differentiation (including morphology and function), growth rate, local invasion, and and metastasis.

[0234] "Benign neoplasms" are generally well differentiated and characteristically slower growing than malignant neoplasms; In addition, benign neoplasms may invade, invade, or grow to distant sites. Non-limiting examples of benign neoplasms include, but are not limited to: Lipoma, chondroma, adenoma, acrochordon, senile hemangioma, seborrheic keratosis, lentigines, and and sebaceous gland hyperplasia.

[0235] In some cases, a benign tumor can later give rise to a malignant neoplasm, which occurs when the tumor cells of the tumor These tumors can arise as a result of further genetic alterations in a subpopulation of the tumor. An exemplary premalignant neoplasm is a teratoma.

[0236] A "malignant neoplasm" is generally poorly differentiated (anaplastic) and shows progressive infiltration, invasion, and proliferation. They have characteristically rapid growth accompanied by tissue destruction. Furthermore, malignant neoplasms generally spread to distant sites. The terms "metastasis," "metastatic," or "metastasize" refer to a tumor that has the ability to metastasize to a primary tumor. or refers to the spread or migration of cancer cells from the original tumor to another organ or tissue, typically includes the primary tumor or organ or tissue that the secondary (metastatic) tumor is located in, but not in. Identifiable by the presence of "secondary tumors" or "secondary cell masses" of the histology of the original tumor .

[0237] In certain embodiments, the proliferative disease is cancer. Thus, a subject (e.g., a patient with cancer) A method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of the present disclosure. Such methods are provided herein, comprising administering to the subject an agent.

[0238] The term "cancer" refers to a cancer that grows uncontrollably and has the ability to invade and destroy normal body tissue. It refers to a type of disease characterized by the development of abnormal cells with high blood pressure.

[0239] A wide variety of cancers are contemplated herein, including solid tumors, leukemia, lymphoma, and myeloma. In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is a solid tumor (e.g., colorectal tumor, breast tumor, prostate tumor, tumors, including tumors of the lung, pancreas, kidney, or ovary. In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is a lung cancer, a brain cancer ( For example, neuroblastoma, glioblastoma, anaplastic astrocytoma), cancer of the digestive tract, skin cancer, urinary The cancer is selected from one or more of reproductive cancer, head and neck cancer, sarcoma, carcinoma, and neuroendocrine cancer. In various embodiments, the solid tumor cancer is breast cancer, bladder cancer, endometrial cancer, esophageal cancer, liver cancer, pancreatic cancer, or Cancer, lung cancer, cervical cancer, colon cancer, colorectal cancer, stomach cancer, kidney cancer, ovarian cancer, prostate cancer, testicular cancer, In some embodiments, the cancer is a uterine cancer, a virally induced cancer, a melanoma, or a sarcoma. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is lung cancer (e.g., non-small cell lung cancer). In other embodiments, the cancer is liver cancer. In some embodiments, the cancer is sarcoma, In some embodiments, the cancer is prostate cancer (e.g., castration-induced cancer). In other embodiments, the cancer is bladder cancer, pancreatic cancer, or ovarian cancer. Pancreatic cancer, colorectal cancer, glioblastoma, kidney cancer, non-small cell lung cancer, prostate cancer, sarcoma, skin cancer, thyroid cancer In some embodiments, the cancer is an adenocarcinoma (e.g., anaplastic thyroid carcinoma), testicular cancer, or vulvar cancer. Cancers include endometrial cancer, pancreatic cancer, testicular cancer, kidney cancer, melanoma, colorectal cancer, thyroid cancer, and bladder cancer. In some embodiments, the cancer is a pancreatic cancer, a vulvar cancer, a sarcoma, a prostate cancer, a lung cancer, or anal cancer. In some embodiments, the cancer is a sarcoma. In some embodiments, the cancer is a renal cell carcinoma.

[0240] In some embodiments, the cancer is a non-solid tumor cancer. Hematological cancers that can be treated by the methods described herein include leukemia, (e.g., acute leukemia, chronic leukemia), lymphoma (e.g., B-cell lymphoma, T-cell lymphoma) Non-limiting examples of hematological cancers include leukemia (e.g., myeloma), leukemia (e.g., myeloma), and multiple myeloma. For example, acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute bone marrow leukemia (ABLE), Myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), early precursor T-cell leukemia (E TP) acute lymphoblastic leukemia, chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CL) Lymphoma (e.g., Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell HL)); L), non-Hodgkin's lymphoma (NHL) (e.g., B-cell NHL, e.g., diffuse large cell diffuse large B-cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom's lymphoma) macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, Precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma, T-cell NHL, e.g. For example, precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g. , cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), blood Tumor immunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathic T-cell lymphoma lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); heavy chain disease (e.g., alpha Myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), Myeloid Metaplasia of Unknown Origin (AM), also known as Myelofibrosis (MF), and Myeloproliferative Disorders (TDS) M), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CN L), hypereosinophilic syndrome (HES); multiple myeloma (MM); plasma cell neoplasm; familial hyperplasia eosinophilia; inflammatory myofibroblastic tumor; and immune cell amyloidosis In some embodiments, the hematological cancer is multiple myeloma, myelodysplastic syndrome (MDS), acute myeloma, or leukemia. Myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), acute lymphocytic leukemia, lymphocytic lymphoma, mycosis fungoides, chronic lymphocytic leukemia, chronic lymphocytic leukemia (CLL) ), mantle cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, Hojiki The cancer is selected from lymphoma, non-Hodgkin's lymphoma, or myelofibrosis.

[0241] Examples of cancers treatable by the methods described herein include, but are not limited to, However, adenocarcinoma of the breast, prostate, and colon; all types of bronchogenic lung carcinoma; myeloid; melanoma (e.g., metastatic melanoma); astrocytoma (e.g., anaplastic astrocytoma); hepatocellular carcinoma; neuroblastoma tumor; papilloma; apodoma; choristoma; branchiomas; malignant carcinoid syndrome; carcinoid heart disease and carcinomas (e.g., Walker's carcinoma, basal cell carcinoma, basal squamous cell carcinoma, Brown-Pierre's carcinoma, Earth carcinoma, ductal carcinoma, Ehrlich carcinoma, Krebs 2 carcinoma, Merkel cell carcinoma, mucinous carcinoma, lung cancer (e.g. For example, large cell lung cancer, e.g. squamous cell carcinoma, non-small cell lung cancer (NSCLC)), oat cell Carcinoma, papillary carcinoma, sclerotic carcinoma, bronchiolar carcinoma, bronchogenic lung carcinoma, squamous cell carcinoma, and transitional cell carcinoma Additional examples of cancers treatable by the methods described herein include: These include, but are not limited to, histiocytic disorders; leukemia; malignant histiocytosis; Hodgkin's disease; leukemia Hemophilia; Malignant histiocytosis; Hodgkin's disease; Hypereosinophilia, immunoproliferative disorders; Non-Hodgkin's disease Plasmoma; Plasmacytoma; Reticuloendotheliosis; Melanoma (e.g., metastatic melanoma); Chondroblastoma; Chondroma; chondrosarcoma; fibrous carcinoma (e.g., myelofibrosis), pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), renal pancreatic cancer, liver cancer, lung cancer (e.g., large cell lung cancer, e.g., squamous cell carcinoma), breast cancer (e.g., inflammatory breast cancer), ovarian cancer (e.g., high-grade serous ovarian cancer), endometrial cancer, uterine cancer, uterine meat tumors (e.g., uterine leiomyosarcoma), renal cell carcinoma, sarcomas (e.g., soft tissue sarcomas), malignant fibrous carcinoma Histiocytoma, fibrosarcoma (e.g., dermatofibrosarcoma protuberans); hepatocellular carcinoma; fibroma; fibrosarcoma; giant Histiocytoma; Lipoma; Liposarcoma; Mesothelioma; Myxoma; Myxosarcoma; Osteoma; Osteosarcoma; Pediatric Malignant tumors: chordoma; craniopharyngioma; dysgerminoma; hamartoma; mesenchymal tumor; mesonephroma; sarcoma ;ameloblastoma;cementoma;odontoma;teratoma;thymoma;trophoblastic tumor. Additionally, the following types of cancer are also contemplated as being suitable for treatment: adenoma; cholangiomas; cholesteatomas; cylindromas; Cystadenocarcinoma; Cystadenoma; Granulosa cell tumor; Male and female germ cell tumor; Hepatocellular carcinoma, liver cancer; Hidradenoma; Islet cell Tumor; Leydig cell tumor; Papilloma; Sertoli cell tumor; Theca cell tumor; Leiomyoma; Smooth Myosarcoma; myoblastoma; myoma; myosarcoma; rhabdomyoma; rhabdomyosarcoma; ependymoma; gangliocytoma; Glioma; Medulloblastoma; Meningioma; Schwannoma; Neuroblastoma; Neuroepithelioma; Neurofibroma; Neuroma; Paraganglioma; non-chromaffin paraganglioma, treatable by the methods described herein Further examples of eosinophilic leukemia include, but are not limited to, angiokeratoma; Lymphoid hyperplasia; sclerosing hemangioma; hemangiomatosis; glomus hemangioma; hemangioendothelioma; hemangioma ;Hemangiopericytoma;Hemangiosarcoma;Lymphangioma;Lymphangioleiomyoma;Lymphangiosarcoma;Pinealoma;Carcinoma Sarcoma; Chondrosarcoma; Phyllodes Cystic Sarcoma; Fibrosarcoma; Angiosarcoma; Leiomyosarcoma; Leukemia; Fatty Sarcoma Lymphangiosarcoma; Myosarcoma; Myxosarcoma; Ovarian cancer; Rhabdomyosarcoma; Sarcoma; Neoplasm; Neurofibroma and cervical dysplasia.

[0242] In certain embodiments, a method for treating cancer comprises administering a therapeutically effective amount of any of the compounds described herein. The method comprises administering to a subject in need of cancer treatment a compound described in the present invention. In certain embodiments, the present invention relates to cancers of the esophagus, stomach, breast, peritoneum, salivary gland, and the like. Cancer, bladder cancer, endometrial cancer, papillary cancer, small intestine cancer, vaginal cancer, cervical cancer, hepatobiliary tract cancer, ovarian cancer, colon Rectal cancer, NSCLC, head and neck cancer, pancreatic cancer, skin cancer, appendix cancer, B lymphoblastic leukemia / lymphoma Cancer, melanoma, germ cell tumors, small cell lung cancer, mature B-cell tumors, prostate cancer, soft tissue sarcomas, A method for treating a tumor or glioma, comprising administering a therapeutically effective amount of a compound described herein to: Esophagogastric cancer, breast cancer, peritoneal cancer, salivary gland cancer, bladder cancer, endometrial cancer, papillary cancer, small intestine cancer, vaginal cancer, child Cervical cancer, hepatobiliary tract cancer, ovarian cancer, colorectal cancer, NSCLC, head and neck cancer, pancreatic cancer, skin cancer, appendix Cancer, B-lymphoblastic leukemia / lymphoma, melanoma, germ cell tumor, small cell lung cancer, mature B-cell tumor administering the compound to a subject in need of treatment for tumors, prostate cancer, soft tissue sarcoma, or glioma. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is lung cancer. It is SCLC.

[0243] HPV-associated cancers can also be treated by the methods described herein. Non-limiting examples include cervical cancer, oropharyngeal cancer, anal cancer, vulvar / vaginal cancer, and penile cancer. can be done.

[0244] Liver cancer, e.g., hepatocellular cancer (HCC) ) (e.g., hepatocellular carcinoma, hepatoblastoma) Cancers of the biliary tract (e.g., cholangiocarcinoma), hepatocellular carcinoma, ... Treatment is possible using the methods described in the literature.

[0245] Musculoskeletal cancers can also be treated by the methods described herein. Non-limiting examples include bone cancers (e.g., osteosarcoma, osteoid osteoma, malignant fibrous histiocytoma, uterine leukemia, thyroid cancer ... Sarcoma, chordoma, malignant giant cell tumor, chordoma, chondrosarcoma, osteochondroma, benign chondroma, chondroblastoma cysts, chondromyxoid fibromas, myelodysplastic syndromes (MDS), muscle cancers (e.g., rhabdomyosarcoma, Rhabdomyoma), connective tissue cancer, and synoviomas.

[0246] Cancers of the nervous system can also be treated by the methods described herein. Typical examples include brain cancers (e.g., astrocytoma, medulloblastoma), gliomas (e.g., astrocytoma, oligodendroma), Dextrose-like tumors), glioblastoma, glioblastoma multiforme, medulloblastoma, ependymoma, germinoma (i.e., pineal gland tumors) tumors), oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, craniopharyngioma), spinal cord cancer , neurofibromas (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis), neuroblastoma Cysts, primitive neuroectodermal tumors (PNT), meningeal carcinomatosis (e.g., meningiomas, meningeal sarcomas, gliomatosis), skull cancer, acoustic neuroma, ependymoma, hemangioblastoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), pleomorphic xanthoastrocytoma (PXA), and childhood PXA.

[0247] Endocrine / exocrine cancers can also be treated by the methods described herein. Non-limiting examples of thyroid cancers include thyroid cancer (e.g., papillary thyroid cancer, follicular thyroid cancer, thyroid cancer, Medullary thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, pheochromocytoma, paraganglioma), pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPM) N), islet cell tumor, tubular adenocarcinoma, insulinoma, glucagonoma, vipoma), adrenal carcinoma, Neuroendocrine cancers (e.g., gastrointestinal pancreatic neuroendocrine tumors (GEP-NETs), carcinoid tumors) ), sebaceous gland carcinoma, and cancer of the sweat glands (e.g., sweat gland carcinoma).

[0248] Head and neck cancers, such as squamous cell carcinoma of the head and neck (SCCHN) and adenoid cystic carcinoma, are also described herein. It can be treated by the method described below.

[0249] Oral cancer, e.g. cancer), lip cancer, tongue cancer, mouth cancer, pharyngeal cancer, hypopharynx cancer Cancer (hypopharynx cancer) (e.g. hypopharyngeal cancer) ingeal carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, mesopharyngeal cancer, Pharyngeal cancer, and salivary gland cancers are also treatable by the methods described herein.

[0250] Esophageal cancer, such as esophageal squamous cell carcinoma, esophageal adenocarcinoma, Barrett's adenocarcinoma, and esophageal leiomyosarcoma are also treatable by the methods described herein.

[0251] Gastrointestinal cancers can also be treated by the methods described herein. Non-Limiting Examples of Gastrointestinal Cancers Cancer of the anus, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), gallbladder cancer, stomach gastric cancer (e.g. stomach cancer) (e.g., gastric adenocarcinoma), gastrointestinal stromal tumors (GIST), small bowel cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumors (GIST), cancer) (e.g. appendiceal cancer, small bowel cancer) ma) (e.g., small intestine adenocarcinoma), small intestine cancer r), large bowel cancer, and large i Examples include pulmonary cancer.

[0252] Cancers of the cardiovascular system can also be treated by the methods described herein. Non-limiting examples of cancers include primary cardiac tumors, angiosarcomas (e.g., lymphangiosarcomas, lymphomas), and intraductal sarcoma, hemangioendothelioma), intraductal sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma) , left atrial myxoma, and cardiac rhabdomyoma.

[0253] Lung cancers can also be treated by the methods described herein. Non-limiting examples of lung cancers include: , bronchogenic carcinoma (e.g., bronchogenic adenoma), alveolar adenocarcinoma, mesothelioma, small cell lung cancer ( SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, cartilaginous hamartoma, and papillary adenocarcinoma. It can be obtained.

[0254] Genitourinary cancers are also treatable by the methods described herein. Non-limiting examples include bladder cancer (e.g., urothelial carcinoma), urethral cancer, kidney cancer (e.g., virion cancer), and the like. Nephroblastoma, also known as Lumus tumor, renal cell carcinoma), testicular cancer (e.g., seminoma, testicular embryonal carcinoma) cancer), germ cell cancer, prostate cancer (e.g., prostate adenocarcinoma), and penile cancer (e.g., penis and scrotum cancer) Paget's disease).

[0255] Gynecological cancers can also be treated by the methods described herein. Notable examples include breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, medullary carcinoma of the breast, triple negative HER-2 positive breast cancer, HER-2 negative breast cancer), endometrial cancer (e.g., uterine cancer uterine sarcoma, choriocarcinoma), endometrial cancer), cervical cancer (e.g., cervical adenocarcinoma), ovarian cancer ( cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), germ cell carcinoma and vulvar cancer (e.g., vulvar pancreatic cancer). Jet's disease), vaginal cancer, and fallopian tube cancer.

[0256] Skin cancers can also be treated by the methods described herein. Non-limiting examples of skin cancers include: These include squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, and basal cell carcinoma ( BCC), and dermatofibroma.

[0257] Soft tissue cancers, e.g., intraepithelial neoplasia, epithelial carcinoma, epithelial sarcoma, adenocarcinoma, adenoma, fibrosarcoma, fibrosarcoma Tumors, liposarcoma, lipoma, myxoma, and teratoma can also be treated by the methods described herein. is.

[0258] Myeloproliferative neoplasms can also be treated by the methods described herein. Non-limiting examples include myelofibrosis, polycythemia vera, and essential thrombocythemia.

[0259] Fibrotic carcinomas are also treatable by the methods described herein. "Fibrotic carcinoma" is cancer accompanied by fibrosis. Fibrosis is a cancer or may precede treatment for cancer (e.g., may be the cause of cancer or treatment for cancer); or may occur after them (e.g., may be caused by them); Additionally, fibrosis can be present along with cancer in fibrous carcinomas. Non-limiting examples of fibrous carcinomas include: are used in myelofibrosis, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), kidney cancer, liver cancer, and lung cancer (e.g., large cell lung cancer). Lung cancer (e.g., squamous cell carcinoma), breast cancer (e.g., inflammatory breast cancer), ovarian cancer (e.g., high-grade serous ovarian cancer), endometrial cancer, uterine cancer, uterine sarcoma (e.g. uterine leiomyosarcoma), renal cell carcinoma cystic carcinoma, sarcoma (e.g., soft tissue sarcoma), malignant fibrous histiocytoma, fibrosarcoma (e.g., protruding Dermatofibrosarcoma), gastric cancer, esophageal cancer, head and neck cancer, cervical cancer, vulvar cancer, and hepatocellular carcinoma (HEPA tocellular cancer) (for example, hepatocellular carcinoma In some embodiments, fibroid carcinoma. solid tumor cancers (e.g., kidney cancer, liver cancer, lung cancer, breast cancer, ovarian cancer, endometrial cancer, uterine cancer, and / or pancreatic cancer). In some embodiments, the fibrous cancer is a visceral cancer (e.g., pancreatic cancer). It is a cancer of the liver (pulmonary, lung, kidney, or liver).

[0260] Further examples of cancers treatable by the methods described herein include, but are not limited to: Notably, acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); adrenal epithelial cell carcinoma (ADEC); adrenal cortical carcinoma; childhood adrenocortical carcinoma; AIDS-related cancers (e.g., Kaposi's sarcoma, AIDS-related lymphoma) , primary central nervous system lymphoma); anal cancer; anal cancer; appendix cancer; pediatric astrocytoma; pediatric central nervous system Nervous system (CNS) atypical teratoid / rhabdoid tumor; CNS neoplasm (e.g., central nervous system primary system lymphoma, spinal axis tumor, medulloblastoma, brainstem glioma, or pituitary adenoma), Barrett's Esophagus (e.g., premalignant syndrome), and mycosis fungoides, basal cell carcinoma of the skin; bile duct cancer; bladder cancer pediatric bladder cancer; bone cancer (including Ewing's sarcoma, osteosarcoma, and malignant fibrous histiocytoma) Brain tumor / cancer; Breast cancer; Burkitt's lymphoma; Carcinoid tumor (gastrointestinal); Pediatric carcinoid Cardiac tumors; pediatric cardiac tumors (heart tumors); pediatric embryonal tumors; pediatric germ cell tumors; primary central nervous system lymphoma cervical cancer; pediatric cervical cancer; bile duct cancer; pediatric chordoma; chronic lymphocytic leukemia (CLL); Chronic myeloid leukemia (CML); chronic myeloproliferative neoplasms; colorectal cancer; pediatric colorectal cancer; pediatric Craniopharyngioma; cutaneous T-cell lymphoma (e.g., mycosis fungoides and Sézary syndrome); breast Ductal carcinoma in situ (DCIS); childhood central nervous system embryonal tumors; cancers of the endocrine system (e.g., thyroid , pancreatic, parathyroid, or adrenal cancer); endometrial cancer (uterine cancer); childhood ependymoma; esophageal cancer; Pediatric esophageal cancer; neuroepithelioma; Ewing's sarcoma; pediatric extracranial germ cell tumor; extragonadal germ cell tumor; Eye cancer; Pediatric intraocular melanoma; Intraocular melanoma; Retinoblastoma; Fallopian tube carcinoma; Malignant bone fibroids fibrous histiocytoma and osteosarcoma; gallbladder cancer; gastric cancer tomach cancer); childhood gastric cancer stomach cancer); gastrointestinal carcinoid tumor; gastrointestinal stromal tumor (GIS) T); pediatric gastrointestinal stromal tumors; germ cell tumors; pediatric central nervous system germ cell tumors (e.g., pediatric cranial Extragonadal germ cell tumors, extragonadal germ cell tumors, ovarian germ cell tumors, testicular cancer); gestational trophoblastic disease; Women's tumors (e.g., uterine sarcoma, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, or vulvar cancer), hair Langerhans cell leukemia; head and neck cancer; pediatric heart tumors; hepatocellular carcinoma (liver cancer); Langerhans cell carcinoma Hodgkin's lymphoma; hypopharyngeal carcinoma; cutaneous or intraocular melanoma; pediatric intraocular melanoma ;Islet cell tumor, pancreatic neuroendocrine tumor;Kaposi's sarcoma;Kidney (renal cell) carcinoma;Langerhans cell Histiocytosis; Laryngeal cancer; Leukemia; Lip and oral cancer; Liver cancer; Lung cancer (non-small cell and small cell) ); childhood lung cancer; lymphoma; male breast cancer; malignant fibrous histiocytoma and osteosarcoma of bone; melanoma; Pediatric melanoma; intraocular melanoma (ocular melanoma); pediatric intraocular melanoma; Merkel cell carcinoma; malignant melanoma mesothelioma; childhood mesothelioma; metastatic cancer; metastatic cervical squamous cell carcinoma of unknown primary; NUT gene mutation midline carcinoma; oral cancer; multiple endocrine neoplasia syndrome; multiple myeloma / plasmacytoma; mycosis fungoides Myelodysplastic syndromes, myelodysplastic tumors / myeloproliferative neoplasms; chronic myeloid leukemia (CML) acute myeloid leukemia (AML); chronic myeloproliferative neoplasms; nasal and paranasal sinus cancer; nasopharyngeal cancer Neuroblastoma; Non-Hodgkin's lymphoma; Non-small cell lung cancer; Oral cancer ), lip and oral cavity cancer, and oropharyngeal cancer; Osteosarcoma and malignant fibrous histiocytoma of bone; ovarian cancer; pediatric ovarian cancer; pancreatic cancer; pediatric pancreatic cancer; pancreatic cancer Transendocrine tumors; papillomatosis (pediatric laryngeal papillomatosis); paraganglioma; pediatric paraganglioma; paranasal sinus cancer and nasal cancer; parathyroid cancer; penile cancer; pharyngeal cancer; pheochromocytoma; pediatric pheochromocytoma; pituitary tumor ;Plasmacytoma / Multiple Myeloma;Pleuropulmonary Blastoma;Pregnancy-Related Breast Cancer;Primary Central Nervous System (CNS) Malignancies Lymphoma; Primary peritoneal cancer; Prostate cancer; Rectal cancer; Recurrent cancer; Renal cell (kidney) cancer; Retinoblastoma ; pediatric rhabdomyosarcoma; salivary gland carcinoma; sarcomas (e.g., pediatric rhabdomyosarcoma, pediatric vascular tumor, Eugene Kaposi's sarcoma, osteosarcoma (bone cancer), soft tissue sarcoma, uterine sarcoma); Sézary syndrome; Skin cancer; pediatric skin cancer; small cell lung cancer; small intestine cancer; soft tissue sarcoma; squamous cell carcinoma of the skin; primary Metastatic squamous cell carcinoma of the neck of unknown origin; gastric cancer (gastric cancer) ric cancer); childhood gastric cancer tric cancer); cutaneous T-cell lymphoma (e.g., mycosis fungoides and sezarione) - syndrome); testicular cancer; childhood testicular cancer; throat cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer); Thymoma and thymic carcinoma; thyroid carcinoma; transitional cell carcinoma of the renal pelvis and ureter; ureter and renal pelvis (e.g. , renal cell carcinoma, renal pelvic carcinoma), benign prostatic hyperplasia, parathyroid carcinoma, transitional cell carcinoma; urethral cancer; uterine (uterine Endometrial cancer; uterine sarcoma; vaginal cancer; childhood vaginal cancer; vascular tumors; vulvar cancer; and Wilms' tumor and and other childhood kidney tumors.

[0261] Metastases of the aforementioned cancers may also be treated by the methods described herein. In embodiments, the cancer is a metastatic cancer. In other embodiments, the cancer is a pre-metastatic cancer. do.

[0262] In certain embodiments, the cancer is a rare cancer. The term "rare cancer" refers to a cancer that is caused by a relatively small number of This refers to cancer that occurs in patients with

[0263] In some embodiments, the proliferative disease, such as cancer (e.g., fibroid carcinoma), is Tumor stromal cells (e.g., cancer-associated fibroblasts (CAFs), stellate cells, or myofibroblasts and / or immune cells, e.g., in the tumor immune microenvironment By targeting tumor-associated immune cells (e.g., tumor stromal microenvironment and / or or by modulating the tumor immune microenvironment.

[0264] Also, targeting tumor stromal cells or immune cells (e.g., tumor-associated immune cells), and and / or (e.g., by) modifying the tumor microenvironment in vivo or in vitro (e.g., to regulate (e.g., normalize) the tumor stromal microenvironment and / or the tumor immune microenvironment The method comprises administering to a subject a tumor stromal cell or an immune cell (e.g., a tumor-associated immune cell) in a manner consistent with the present disclosure. Such methods are also provided herein, comprising contacting a compound of formula (I) with a compound of formula (I). In embodiments, the inhibition occurs in vivo in a subject. The harm occurs in vitro (e.g., in a cell line, tissue, or biological sample). In certain embodiments, the tumor stromal cells are cancer-associated fibroblasts (CAFs), astrocytes, or Myofibroblasts.

[0265] Without wishing to be bound by any particular theory, it is believed that certain compounds It can normalize the tumor microenvironment, thereby improving vascular perfusion and drug delivery. It is believed that the enhanced drug delivery can result in the drug, e.g., The efficacy of immunomodulatory agents (e.g., immunosuppressants), including any of the immunomodulatory agents described. Therefore, it is expected that the tumor microenvironment (e.g., to regulate (e.g., normalize) the tumor stromal microenvironment and / or the tumor immune microenvironment The method includes contacting the tumor with a compound of the present disclosure. It is provided at.

[0266] Also, viral infection and / or viral replication in a subject in need of inhibition. A method for inhibiting viral infection and / or viral replication, comprising administering an effective amount (e.g., a therapeutically effective amount) of The method also includes administering to the subject a compound of the present disclosure in a therapeutically effective amount (prophylactically effective amount, prophylactically effective amount). Provided in the specification.

[0267] The compounds of the present disclosure can be administered as monotherapy or in combination with other compounds as described herein. It may also be administered as part of a combination therapy with other therapeutic agents and / or therapies. In some embodiments, the methods described herein may be administered in combination with one or more additional therapies (e.g., The compound of the present disclosure and one or more additional therapeutic agents (one or more additional therapeutic agents) are administered to the subject. The treatment(s) may be co-administered, e.g., simultaneously or substantially simultaneously. The combination and additional treatment(s) may also or alternatively be administered at about the same time or at different times. For example, the compounds of the present disclosure may be administered prior to the additional treatment(s). Alternatively, the compounds of the present disclosure may be administered after the additional treatment(s). Suitable additional therapeutics for use in the disclosed methods include, in the context of a combination: Examples include those described herein.

[0268] Therapeutic agents (e.g., compounds of the present disclosure) and pharmaceutical compositions thereof may be prepared by combining the compounds and the specific target of treatment. Depending on the disease, for example, oral administration route, feed administration route, topical administration route, transdermal administration route, Rectal administration route, parenteral administration route (e.g., intra-arterial, intravenous, intramuscular, subcutaneous injection, intradermal injection) ), intravenous infusion routes of administration, and inhalation routes of administration (e.g., intrabronchial, intranasal, or oral inhalation). The drug can be administered by a variety of routes, including intranasal administration (intravenous, intranasal, intranasal drops). The preferred mode of administration will depend on the particular compound selected. In some embodiments, the therapeutic agent (e.g., a compound of the present disclosure) is administered orally. In some embodiments, the therapeutic agent (e.g., a compound of the present disclosure) is administered intravenously. .

[0269] Combination therapy The term "combination therapy" refers to a combination of therapies for treating a disease, disorder, or condition described herein. refers to the administration of two or more therapeutic agents in a substantially simultaneous manner, e.g., at regular intervals. This includes co-administration of the therapeutic agents in a single capsule having the active ingredients in the same ratio. The administration may be performed in multiple containers or separate containers (e.g., capsules, powders, Such administration may be at about the same time or at different times. Therapeutic agents in combination therapy may be administered in the same route. The powder and / or liquid may be administered by one or more of the following routes: Typically, the treatment regimen is administered to treat the conditions described herein. The present invention provides a beneficial effect of the drug combination in the treatment of a disease or disorder.

[0270] Therapies used in combination with compounds of the present disclosure include those that are modulated by compounds of the present disclosure. Other pathway(s) other than the pathway, other pathways of the same pathway as the pathway modulated by the compounds of the present disclosure The component(s) (e.g., enzyme) or even target modulated by the compounds of the present disclosure. a target known to regulate one or more of the same targets (e.g., target enzyme(s)) as the target of the In one aspect, the combination therapy may include agents that, for example, have a synergistic or additive therapeutic effect. To achieve this, compounds of the present disclosure and chemotherapeutic agents, immunomodulatory agents, and / or radiation therapy may be used. Includes treatment.

[0271] in combination with compounds of the present disclosure (e.g., in combination therapy, in drug combinations, ) Examples of treatments used include standard therapies and / or standard treatment regimens (e.g., standard of care), e.g., first-line standard of care (e.g., chemotherapy), intermediate standard of care treatment (e.g., chemotherapy), or the final standard treatment (e.g., chemotherapy). A standard of care is a clinically appropriate treatment for a particular type of patient, disease, and / or clinical condition. This is a treatment that should be used by the clinical physician. Which organizations describe best practices for the treatment of certain patients, diseases, and / or clinical conditions? nccn.org publishes guidelines and / or treatment algorithms that address these issues. These guidelines often define the standard of care and and / or summarizing.

[0272] In some embodiments, the method of treating or preventing cancer comprises administering to a patient a compound of Formula (I), (Ii), (Iii), (Iiii), (Iiv), (Iv), (Ivi), (Iv ... Iia), (Ii-a1), (Ii-a2), (aI), (II), or (III), or any of the embodiments thereof disclosed herein, , may include administration in conjunction with one or more other chemotherapeutic agent(s).

[0273] In some embodiments, one or more immunomodulatory agents are used in combination with the compounds of the present disclosure. Non-limiting examples of immunomodulatory agents (e.g., immunosuppressants) include afutuzumab (available from ROCHE®); pegfilgrastim (NEULASTA®); lenalidomide (CC-5013, REVLIMID®); salivary gland erythropoietin (SAE); thalomide (THALOMID®); actimid (CC4047); and IRX -2 (human serum containing interleukin 1, interleukin 2, and interferon gamma) Itokine Compound, CAS951209-71-5, IRX Therapeutic (Available from s).

[0274] In certain embodiments, the immunomodulatory agent is a chimeric antigen receptor T cell (CAR-T) therapy. , for example, Tisagenlecleucel (Novartis), Axicabtagenesilolu Cell (Kite), and tocilizumab (atlizumab; Roche).

[0275] In certain embodiments, the immunomodulatory agent is an immune checkpoint inhibitor, e.g., PD -1 inhibitors, PD-L1 inhibitors, cytotoxic T lymphocyte-associated modulators (e.g., C TLA-4 inhibitor), LAG-3 inhibitor, and TIM-3 inhibitor.

[0276] In certain embodiments, the immunomodulatory agent is a PD-1 inhibitor, e.g., pembrolizumab. (lambrolizumab, MK-3475, MK03475, SCH-900475, or KEYTRUDA®) and other anti-PD-1 antibodies (Hamid, O .et al.(2013) New England Journal of Med icine 369 (2):134-44, US8,354,509, and WO200 9 / 114335 (incorporated by reference in their entirety), Lumab (MDX-1106, MDX-1106-04, ONO-4538, BMS-93 6558, or also known as OPDIVO®) and other anti-PD-1 antibodies (U S8,008,449 and WO2006 / 121168 (incorporated by reference in their entirety) (disclosed in the accompanying publication), cemiplimab (LIBTAYO®), scintigraphy limab, spartalizumab (PDR001), pidilizumab (CureTech), M EDI0680 (Medimmune), dostallimab (TSR-042), PF-0 6801591 (Pfizer), sintilimab, toripalimab, tislelizumab (BG B-A317), camrelizumab (INCSHR1210, SHR-1210), AMP -224 (Amplimmune), CBT-501 (CBT Pharmaceuti) cals), CBT-502 (CBT Pharmaceuticals), JS001 (Junshi Biosciences), IBI308 (Innovent Bio logics), also known as SHR-1210 (Hengrui Medicine) INCSHR1210 (Incyte), BGBA317 (Beigene), BGB -108 (Beigene), BAT-I306 (Bio-Thera Solutio ns), GLS-010 (Gloria Pharmaceuticals; WuXi Biologics), AK103, AK104, AK105 (Akesio Biop harma;Hangzhou Hansi Biologics;Hanzhong Biologics), LZM009 (Livzon), HLX-10 (Henlius) Biotech), MEDI0680(Medimmune), PDF001(Nov artis), PF-06801591 (Pfizer), also known as CT-011 Pidilizumab (CureTech) and other anti-PD-1 antibodies (Rosenblatt, J.et al.(2011) J Immunotherapy 34(5):409 -18, US7,695,715, US7,332,582, and US8,686,1 19 (which are incorporated by reference in their entireties), REGN2810 (Regeneron), and TSR-042 (Tes aro), or CS1003 (CStone Pharmaceuticals) MEDI0680 (Medimmune) is also known as AMP-514. MEDI0680 and other anti-PD-1 antibodies are disclosed in US9,205,148 and WO2012 / 145493 (incorporated by reference in their entirety). Known anti-PD-1 antibody molecules include those described in, for example, WO2015 / 112800 and WO2016 / 092419, WO2015 / 085847, WO2014 / 179664, WO20 14 / 194302, WO2014 / 209804, WO2015 / 200119, US 8,735,553, US7,488,802, US8,927,697, US8,99 3,731, and US 9,102,727 (incorporated by reference in their entireties). In one embodiment, the PD-1 inhibitor is a PD-1 inhibitor as described in "Antibody Molecules to PD-1 and U ses Thereof" (see US2015 / 0210769 in its entirety) In one embodiment, the anti-PD-1 antibody molecule is an anti-PD-1 antibody molecule described in The PD-1 antibody molecule is BAP049-C, which is disclosed in US2015 / 0210769. CDRs, variable regions, heavy chain and / or The antibody molecules described herein include those described in US2015 / 0210769 ( (which is incorporated by reference in its entirety) In one embodiment, the PD-1 inhibitor may be, for example, a PD-1 inhibitor as described in US 8,907,053 ( inhibiting the PD-1 signaling pathway, as described in In one embodiment, the PD-1 inhibitor is an immunoadhesin (e.g., PD-L1 or PD-L2 fused to a constant region (e.g., the Fc region of an immunoglobulin sequence) - an immunoadhesin comprising the extracellular portion of L2 or the PD-1 binding portion of L2. In certain embodiments, the PD-1 inhibitor is AMP-224 (see, e.g., WO2010 / 027827 and WO2011 / 066342 (which are incorporated by reference in their entirety). The antibody used is B7-DCIg (Amplimmune).

[0277] In certain embodiments, the immunomodulatory agent is a PD-L1 inhibitor, e.g., atezolizumab. (MPDL3280A, RG7446, RO5541267, YW243.55.S70 , or also known as TECENTRIQ®) and U.S. Pat. No. 8,217,149 ( Other anti-PD-L1 antibodies disclosed in Avelma, which is incorporated by reference in its entirety (BAVENCIO®, also known as MSB0010718C) and WO2 Other anti-P disclosed in US Pat. No. 5,993,493 (incorporated by reference in its entirety). D-L1 antibody, durvalumab (IMFINZI® or MEDI4736) and others disclosed in US Pat. No. 8,779,108 (incorporated by reference in its entirety). anti-PD-L1 antibody FAZ053 (Novartis), and BMS-93655 9 (Bristol-Myers Squibb). In certain embodiments, P The D-L1 inhibitor is KN035 (Alphamab; 3DMed; Ascletis P harma), emvafolimab (TRACON Pharmaceuticals), BMS 936559 (Bristol-Myers Squibb), CS1001 ( CStone Pharmaceuticals, Ligand Pharmaceut icals), CX-072 (CytomX Therapeutics), FAZ05 3 (Novartis), SHR-1316 (Hengrui Medicine), T QB2450 (Chiatai Tianqing), STI-A1014 (Zhaok e Pharm;Lee's Pharm, Lonza, Sorrento Thera peutics, NantWorks), LYN00102 (Lynkcell), A1 67 (Harbour BioMed, Kelun Group), BGB-A333 ( Beigene), MSB2311 (Mabspace Biosciences), or or HLX-20 (Henlius Biotech). In one embodiment, the anti-PD The -L1 antibody molecule is BMS-93655, also known as MDX-1105 or 12A4. 9 (Bristol-Myers Squibb). BMS-936559 and others The anti-PD-L1 antibodies are disclosed in US Pat. No. 7,943,743 and WO2015 / 081158 (the (the entirety of which is incorporated by reference). In certain embodiments, PD-L1 inhibitors include cosibelimab (Fortress Biotech) and LY33 00054 or rodapolimab (Eli Lilly), GS-4224 (Gilea d Sciences), STI-A1015 (Yuhan, Sorrento The rapeutics), BCD-135 (BIOCAD), cosibelimab (Dana-F arber Cancer Institute, TG Therapeutics), APL-502 (Apollomics), AK106 (Akeso Biopharm a), MSB2311(Transcenta Holding), TG-1501(T G Therapeutics), or FAZ053 (Novartis). In certain embodiments, the PD-L1 inhibitor is MT-6035 (Molecular T emplates), Icaritin or ZKAB001 (Lonza, Lee's Pharmaceuticals pharmaceutical Holdings, Sorrento Therapeu tics, Shenogen Pharma Group), TRIDENT antibody (Ma croGenics, Zai Lab), YBL-007 (Anh-Gook Phar maceutical, Y-Biologics), HTI-1316 (Hengrui Therapeutics), PD-L1 Oncology Project (We izmann Institute of Sciences), JS003(Shan ghai Junshi Biosciences), ND021(Numab The rapeutics, CStone Pharmaceuticals), Toca 5 21 (Tocagen), or STT01 (STCube). In this setting, PD-L1 inhibitors include DB004 (DotBio) and MT-5050 (Mole cular Templates), KD036 (Kadmon). In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody molecule. The harmful agent was released on April 21, 2016, in the book "Antibody Molecules to PD-L1 and Uses Thereof” 108123, which is incorporated by reference in its entirety. In one embodiment, the anti-PD-L1 antibody molecule is (incorporated by reference in its entirety) or BAP058-Clone N CDRs, variable regions, heavy chains, and / or light chains Further known anti-PD-L1 antibodies include those described in, for example, WO2015 / 181342, W O2014 / 100079, WO2016 / 000619, WO2014 / 022758 , WO2014 / 055897, WO2015 / 061668, WO2013 / 0791 74, WO2012 / 145493, WO2015 / 112805, WO2015 / 10 9124, WO2015 / 195163, US8,168,179, US8,552,1 54, US 8,460,927, and US 9,175,082 (incorporated by reference in their entireties). Examples of such compounds include those described in US Pat. No. 6,499,999 (incorporated herein).

[0278] In certain embodiments, the immunomodulatory agent is a CTLA-4 inhibitor, e.g., ipilimumab. (YERVOY®), tremelimumab, ALPN-202 (Alpine I mmune Sciences), RP2 (Replimune), BMS-98624 9(Bristol-Myers Squibb), BMS-986218(Bristol-Myers Squibb) ol-Myers Squibb), zalifrelimab (Agenus, Ludwig I Institute for Cancer Research, UroGen Phar ma, Recepta Biopharma), BCD-217(BIOCAD), On c-392 (Pfizer, OncoImmune), IBI310 (Innovent Biologics), KN046 (Alphamab), MK-1308 (Merc k & Co), REGN4659 (Regeneron Pharmaceutica ls), XmAb20717 (Xencor), XmAb22841 (Xencor), Anti-CTLA-4 NF (Bristol-Myers Squibb), MEDI575 2 (AstraZeneca), AGEN1181 (Agenus), MGD019 (M acroGenics), ATOR-1015(Alligator Bioscien ce)、BCD-145(BIOCAD)、PSB205(Sound Biology). cs) CS1002 (CStone Pharmaceuticals) ADU-1 604(Aduro Biotech) PF-06753512(Pfizer)B ioInvent-Transgene Research Program(Tran sgene)、AGEN2041(Agenus、Recepta Biopharam )、ATOR-1144(Alligator Bioscience)、CTLA-4 Research Project(Sorrento Therapeutics) PD-L1 / CTLA-4 Research Project(Sorrento Therapeutics)、HLX13(Shanghai Henlius Bio tech)、ISA203(ISA Pharmaceuticals)、PRS-30 No. 0 A(Pieris Pharmaceuticals) BA3071(Bi oAtla)、CTLA4 Cancer Research Program(Bio sortia Pharmaceuticals) RP3(Replimune)C G0161 (Cold Genesys) APL-509 (Apollomics). SR)、AGEN2041(Ludwig Institute for Cancer Research)、APC 101(Advanced Proteome)、CT LA-4 Enclosure (Advanced Proteome) and BA3071 (BeiGen e) BPI-002 (BeyondSpring Pharmaceuticals) CTLA-4 (Tikcro Technologies) Immuno-On cology Research Program II (OliPass), PBP1 701 (Prestige BioPharma), DB002 (DotBio), DB 003 (DotBio), OR-2299 (OncoResponse), and NK04 4 (Alphamab).

[0279] In some embodiments, the immunomodulatory agent is a LAG-3 inhibitor, e.g., LAG525(N ovartis), BMS-986016 (Bristol-Myers Squibb ), and TSR-033 (Tesaro). In one embodiment, the LAG-3 inhibitor is , an anti-LAG-3 antibody molecule. In one embodiment, the LAG-3 inhibitor is "Antibody Molecules to LAG-3 and US2015 / 0259420 (the entirety of which is hereby incorporated by reference) entitled "Drug Uses Thereof" (which is incorporated by reference). The anti-LAG-3 antibody molecule is the BAP disclosed in US2015 / 0259420. CDRs, variable regions, heavy chains of 050-Clone I or BAP050-Clone J In one embodiment, the anti-LAG-3 antibody molecule comprises BMS9860, and / or a light chain. BMS-986016 (Bristol-Myers Squibb), also known as 16 BMS-986016 and other anti-LAG-3 antibodies are disclosed in WO2015 / 1165 39 and US 9,505,839 (incorporated by reference in their entireties). In one embodiment, the anti-LAG-3 antibody molecule is TSR-033 (Tesaro). In one embodiment, the anti-LAG-3 antibody molecule is IMP731 or GSK28317. 81 (GSK and Prima BioMed). IMP731 and other anti-LAG- The three antibodies are described in WO2008 / 132601 and US Pat. No. 9,244,059 (the entire disclosures of which are incorporated herein by reference). In one embodiment, the anti-LAG-3 antibody molecule is Another known anti-LAG-3 antibody is IMP761 (Prima BioMed). For example, WO2008 / 132601, WO2010 / 019570, WO201 4 / 140180, WO2015 / 116539, WO2015 / 200119, WO2 016 / 028672, US9,244,059, US9,505,839 (all of which In one embodiment, anti-LA antibodies include those described in The G-3 inhibitor may be a soluble G-3 protein, e.g., a G-3 inhibitor as described in WO2009 / 044273 ( IMP321 (Prima Biennis) disclosed in oMed).

[0280] In some embodiments, the immunomodulatory agent is a TIM-3 inhibitor, e.g., MGB453 (N ovartis) and TSR-022 (Tesaro). In one embodiment, the TIM In one embodiment, the TIM-3 inhibitor is an anti-TIM-3 antibody molecule. "Antibody Molecules to TIM" released on August 6, 2015 -3 and Uses Thereof" (incorporated by reference in its entirety). In one embodiment, the anti-TIM-3 antibody molecule is a molecule as described in US2015 / 0218274 (in its entirety). ABTIM3-hum11 or ABTIM disclosed in In one embodiment, the antibody comprises the CDRs, variable regions, heavy chain, and / or light chain of 3-hum03. The anti-TIM-3 antibody molecule is TSR-022 (AnaptysBio / Tesaro). In one embodiment, the anti-TIM-3 antibody molecule is APE5137 or APE5121. One or more of the CDR sequences (or collectively all of the CDR sequences), which may be heavy or light chain APE5137, APE5121, and and other anti-TIM-3 antibodies are described in WO2016 / 161270 (incorporated by reference in its entirety). In one embodiment, the anti-TIM-3 antibody molecule is antibody clone F 38-2E2. Further known anti-TIM-3 antibodies include those described in WO2016 / 111947, WO2016 / 071448, WO2016 / 144803, US8,5 52,156, US 8,841,418, and US 9,163,087 (the entire (incorporated by reference).

[0281] In some embodiments, platinum analogs may be used in combination with the compounds of the present disclosure. In certain embodiments, platinum analogs (e.g., cisplatin, paclitaxel, carboplatin, platinum) and combination therapy including platinum analogs (e.g., docetaxel and carboplatin; Clitaxel and carboplatin; carboplatin and liposomal doxorubicin (do x)) may be used in combination with the compounds of the present disclosure.

[0282] In some embodiments, exemplary chemotherapeutic agents that may be co-administered with compounds of the present disclosure include: , including: 1-amino-4-phenylamino-9,10-dioxo-9,10 -Dihydroanthracene-2-sulfonate (Acid Blue 25), 1-amino-4- [4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene Helical-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10 -dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[ 1-Naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonyl sulfonate, 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9, 10-Dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4 -[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene ABT-263, ado-trastuzumab emtansine, afa Tinib dimaleate, axitinib, aminoglutethimide, amsacrine, anastrozole Zol, APCP, asparaginase, AZD5363, Bacillus Calmette-Guerin vaccine BCG, bicalutamide, bleomycin, bortezomib, β-methylene-ADP ( AOPCP), buserelin, busulfan, cabazitaxel, cabozantinib, campto Campothecin, capecitabine, carboplatin, carfilzomib , carmustine, ceritinib, chlorambucil, chloroquine, cisplatin, cladrivir clodronate, cobimetinib, colchicine, crizotinib, cyclophosphamide, Cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demetriacin Xpiridine, dexamethasone, dichloroacetate, dienestrol, diethylstilbe Strol, docetaxel, doxorubicin, epirubicin, eribulin, erlotinib , estradiol, estramustine, etoposide, everolimus, exemestane, Fam-trastuzumab deruxtecan, filgrastim, fludarabine, fludro Cortisone, fluorouracil, fluoxymesterone, flutamide, gefitinib, Mucitabine, genistein, goserelin, GSK1120212, hydroxyurea, Ida Rubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepi Lon, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, Lon medroxyprogesterone, megestrol, methicone, lonidamine, mechlorethamine, Lupharan, mercaptopurine, mesna, metformin, methotrexate, miltefosi , mitomycin, mitotane, mitoxantrone, MK-2206, mutamycin, N -(4-Sulfamoylphenylcarbamothioyl)pivalamide, NF279, NF4 49, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, Clitaxel, pamidronate, pazopanib, pemetrexed, pentostatin, periformam Shin, PF-04691502, plicamycin, pomalidomide, porfimer, PPA DS, procarbazine, quercetin, raltitrexed, ramucirumab, reactive Roux-2, rituximab, rolofylline, romidepsin, rucaparib, selumetinib, sirolimus Limus, sodium 2,4-dinitrobenzenesulfonate, sorafenib, streptozotocin Shin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temcillo Limus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, dichloride Titanocene, tonapofylline, topotecan, trametinib, trastuzumab, tretinoin veliparib, vinblastine, vincristine, vindesine, vinorelbine, and boluspine Rinostat (SAHA). In other embodiments, chemotherapy agents that may be co-administered with compounds of the present disclosure include: Legal medications include: ABT-263, dexamethasone, 5-fluorouracil Sil, PF-04691502, romidepsin, and vorinostat (SAHA). In embodiments, chemotherapeutic agents that may be co-administered with compounds of the present disclosure include: : 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthra Benzene-2-sulfonate (Acid Blue 25), 1-amino-4-[4-hydroxybenzoate Phenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfo Phosphate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,1 0-Dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino ]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-a Amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9 ,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracene Nylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonic acid Salt, APCP, β-methylene-ADP (AOPCP), capecitabine, cladribine, Tarabin, fludarabine, doxorubicin, gemcitabine, N-(4-sulfamoyl) Phenylcarbamothioyl)pivalamide, NF279, NF449, PPADS, Kelce Chin, Reactive Blue 2, Rolofylline 2,4-dinitrobenzenesulfonate sodium Um, sumarin, and tonapophilin.

[0283] A number of combination therapies have been developed for the treatment of cancer. The compounds shown (e.g., compounds of formula (I) or (II) or (III)) may be one or more Examples of combination therapies with which the compounds of the present disclosure can be co-administered are listed below. Included. [Table 1] TIFF2025134754000210.tif233165TIFF2025134754000211.tif236165TIFF2025134754000212.tif23316 5TIFF2025134754000213.tif230165TIFF2025134754000214.tif229165TIFF2025134754000215.tif83165

[0284] In certain embodiments, the co-therapy of the present disclosure may be administered in combination with other types of chemotherapy drugs, e.g., This includes co-administration with immunotherapeutic agents. Cancer cells often contain specific molecules that can be recognized by the immune system. Therefore, tumor immunotherapeutic agents, such as monoclonal antibodies, They can selectively bind to cancer cell antigens and cause cell death. Suppress tumor-mediated inhibition of the innate immune response or otherwise inhibit the immune response activating the immune system, which can facilitate tumor recognition by the immune system. Antibody drugs for tumor immunotherapy include, but are not limited to, abagovomab and adecatumumab , afutuzumab, alemtuzumab, anatumomab, mafenatox, apolizumab, bri Natumomab, BMS-936559, catumaxomab, durvalumab, epacadostat epratuzumab, indoximod, inotuzumab ozogamicin, intelmumab, Ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL328 0A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, oratuzumab, Pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, and In some embodiments, the tumor immunotherapy antibody drug is anti-CD7 Three monoclonal antibodies (mAbs): anti-CD39 mAb, anti-PD-1 mAb, and anti-CTL A4 mAb. Thus, in some embodiments, the methods of the present disclosure comprise one or more Co-administration of tumor immunotherapeutic agents, such as those mentioned above.

[0285] In some embodiments, the combination therapy includes a compound of the present disclosure, e.g., a compound of Formula (I) or (II) ) or (III) and an SH2 inhibitor, such as CGP78850, CPG85 793, C90, C126, G7-18NATE, G7-B1, and NSC642056 Including co-administration with

[0286] In some embodiments, the combination therapy includes a compound of the present disclosure, e.g., a compound of Formula (I) or (II) ) or (III) with a MEK inhibitor, e.g., trametinib, cobimetinib, Binimetinib, selumetinib, PD-325901, CI-1040, and TAK-73 Including co-administration with 3.

[0287] In some embodiments, the combination therapy includes a compound of the present disclosure, e.g., a compound of Formula (I) or (II) ) or (III) and compounds of formula (II), JNJ-38877605, PF-04217903, Foretinib, AMG458, tivantinib, cabozantinib, capmatinib hydrochloride, Co-administration with a MET inhibitor selected from potinib hydrochloride, savolitinib, and crizotinib Includes giving.

[0288] In some embodiments, the combination therapy comprises a compound of formula (I) or (II) or (III), such as A compound of the present disclosure and TNO-155, RMC-4630, JAB-3068, or RL and co-administration with an SHP2 inhibitor selected from Y-1971.

[0289] In some embodiments, an ataxia telangiectasia mutated (ATM) kinase inhibitor is disclosed herein. Non-limiting examples of ATM inhibitors include M-40 76 and AZD-1390.

[0290] In some embodiments, the combination therapy comprises a compound of the present disclosure and osimertinib, gefitinib, or and an EGFR inhibitor selected from rivaroxaban, erlotinib, afatinib, or dacomitinib. This includes co-administration of

[0291] In some embodiments, the combination therapy comprises a compound of the present disclosure and aliskiren, captopril , losartan, irbesartan, olmesartan, candesartan, valsartan, Masartane, azilsartan, telmisartan, eprosartan, benazepril, enalapril Pril, lisinopril, perindopril, quinapril, ramipril, and trandolapril and co-administration with a RAS inhibitor selected from the group consisting of:

[0292] In some embodiments, the combination therapy includes co-administration of a compound of the present disclosure with an anti-PD-1 therapy. In certain embodiments, the combination therapy includes co-administration of a compound of the present disclosure with oxaliplatin. In other embodiments, the combination therapy includes co-administration of a compound of the present disclosure with doxorubicin. Includes.

[0293] In certain embodiments, compounds of the present disclosure may be co-administered with non-chemical cancer treatments. In certain embodiments, compounds of the present disclosure may be co-administered with radiation therapy. In embodiments, the compounds of the present disclosure are administered in combination with surgery, thermal ablation, focused ultrasound therapy, cryotherapy, or other It may be co-administered with any combination of these.

[0294] Optionally, a compound of the present disclosure is used in combination with one or more additional therapeutic agent(s). For example, to treat cancer, it may be advantageous to administer a compound of the present disclosure (e.g., For example, a compound of formula I or a subformula thereof, or a pharmaceutically acceptable salt thereof, For example, anti-cancer drugs (e.g., chemotherapy drugs), anti-allergic drugs, anti-emetic drugs, analgesics, immunomodulatory drugs and one or more additional therapeutic agents independently selected from the group consisting of a cytoprotective agent and a cytoprotective agent. It may be advantageous to do so.

[0295] In some embodiments, the compounds of the present disclosure are administered in combination with radiation therapy. Non-limiting examples of radiation therapy include external beam radiation therapy, internal beam radiation therapy, brachytherapy, and stereotactic radiation therapy. Surgical irradiation, total body radiation therapy, radiotherapy, and permanent or temporary interstitial brachytherapy are available. As used herein, the term "brachytherapy" refers to the treatment of tumors or tumors in the body. Spatially confined radioactive material inserted into or near other proliferative tissue disease sites This term refers to radiation therapy delivered by radioactive material, including but not limited to: Radioactive isotopes (e.g., At211, I131, I125, Y90, Re186, Re1 88, Sm153, Bi212, P32, and Lu) Suitable radiation sources for use as cell conditioners include solid and liquid sources. By way of non-limiting example, the radiation source may be a radionuclide, e.g., I125, I1 31, Yb169, Ir192 as a solid source, I125 as a solid source, or other radionuclides that emit photons, beta particles, gamma rays, or other therapeutic radiation. The radioactive material may be a solution of any radionuclide(s), e.g., I125 or I1 31 solution, or the radioactive liquid may be Au198, Y9 It is produced using a slurry of a suitable liquid containing small particles of a solid radionuclide such as 0. Additionally, the radionuclide(s) may be incorporated into a gel or radioactive microspheres. It can be rare.

[0296] The compounds of the present disclosure may be effective in sensitizing abnormal cells to radiation therapy. Thus, a subject (e.g., a subject in which abnormal cells need to be sensitized to treatment with radiation) 1. A method for sensitizing abnormal cells in a subject to treatment with radiation, comprising: administering to the subject an amount of a compound of the present disclosure effective to sensitize the subject to treatment with radiation. Also provided herein are methods for treating abnormal cells with radiation, the methods comprising: The amount of a compound of the present disclosure effective to sensitize to a compound of the present invention can be determined, for example, by administering the active ingredient described herein. The amount can be determined by one skilled in the art according to the means for ascertaining efficacy.

[0297] In some embodiments, the standard of care includes radiation therapy.

[0298] DNA damaging agents may also be used in combination with the compounds of the present disclosure. A "DNA damaging agent" is a DNA damaging agent that directly or indirectly damages a target gene so that the damage can be repaired by homologous recombination. DNA damaging agents refer to any agent that damages DNA. Non-limiting examples of DNA damaging agents include DNA damaging agents These include drugs, chemotherapy drugs, radiochemotherapy, and ionizing radiation or ultraviolet light. Non-limiting examples of chemotherapeutic agents include alkylating agents, nitrosoureas, antimetabolites, plant alginates, and the like. Non-limiting examples of DNA damaging chemotherapy drugs include hydroxybenzoates, benzocaine, benzophenone, benzocaine ... Typical examples include DNA damaging drugs such as 5-fluorouracil (5-FU), capsaicin, Tabine, gemcitabine, temozolomide, S-1 (tegafur, 5-chloro-2,4-dihydrobenzofuran), hydroxypyridine, and oxonic acid), 5-ethynyluracil, arabinosylcytosine ( ara-C), 5-azacytidine (5-AC), 2',2'-difluoro-2'-deoxy cytidine (dFdC), purine antimetabolites (e.g., mercaptopurine, azathioprine) thioguanine), gemcitabine hydrochloride (Gemzar), pentostatin, allopurinol ol, 2-fluoro-arabinosyl adenine (2F-ara-A), hydroxyurea, Sulfur mustard (bischloroethyl sulfide), mechlorethamine, melphalan, Chlorambucil, cyclophosphamide, ifosfamide, thiotepa, AZQ, mitomycin Syn C, dianhydrogalactitol, dibromodulcitol, alkyl sulfonate ( busulfan), nitrosoureas (BCNU, CCNU, 4-methyl CCNU, or AC NU), procarbazine, dacarbazine, rebeccamycin, anthracyclines, e.g. For example, doxorubicin (adriamycin; ADR), daunorubicin (cerubicin), Darubicin (Idamycin), and epirubicin (Ellence), anthracyclines thiazol-3-one analogues, e.g., mitoxantrone, actinomycin D, topoisomerase inhibitors ( For example, non-intercalating topoisomerase inhibitors, such as epipodophyllotoxins. anticoagulants (etoposide or VP16, teniposide or VM-26), PARP inhibitors, Dophyllotoxin, bleomycin, pepleomycin, adducts with nucleic acids Compounds that form, for example, platinum derivatives, such as cisplatin (CDDP), cisplatin trans-analogues of platin, carboplatin, iproplatin, tetraplatin, and oxalin Platinum, as well as camptothecin, topotecan, irinotecan (CPT-11), and Also included is SN-38. Radiation, such as ultraviolet (UV), infrared (IR), or alpha Radiation, beta radiation, or gamma radiation are also DNA damaging agents.

[0299] In some embodiments, the standard of care includes a DNA damaging agent, such as a DNA cross-linking agent.

[0300] Agents that induce endoplasmic reticulum (ER) stress may also be used in combination with the compounds of the present disclosure. Non-limiting examples of agents that induce ER stress include increasing levels of reactive oxygen species (ROS). drugs that increase HSP90 activity (e.g., napabucasin), chaperone inhibitors, HSP90 inhibitors, These include SP70 inhibitors, PDI inhibitors, and proteasome inhibitors. Further non-limiting examples of agents that induce 157, STF-083010, TKI (e.g., sorafenib), phospho-eIF2α Phosphatases (e.g., Sal003), diindolylmethane derivatives, proteasomes inhibitors (e.g., bortezomib), levistride A, andrographolide, tolfenam Acid, cantharidin, carnosic acid, casticin, cryptotanshinone, curcumin, flavonoids Boca Wine B, Fucoidan, 2-3,4-dihydroxyphenylethanol, 7-dimethicone Xiflavone, SMIP004 (N-(4-butyl-2-methylphenyl)acetamide ), Licochalcone A, Neferine, Paeonol, Paradaxin, Parthenolide, Piperine , Polyphenon E, Porphyrin D, Resveratrol, Dehydrocostus lactone, γ- Tocotrienol, Ω-hydroxyundec-9-enoic acid, ampelopsin, Aldisia Non, Genistein, Gucciferone H, Guggulsterone, Marcantin M, Salsasapo Genin, saxifragifolin, prodigiosin, quercetin, honokiol, brev Ergin A, alpha-tocopheryl succinate, verrucarin A, vitamin E succinate, ultrafine, and zerumbone. For example, Walczak, A., et al. Oxida tive Medicine and Cellular Longevity Vol. ume 2019, Article ID 5729710 (the entire contents of which are incorporated herein by reference) See U.S. Pat. No. 6,49 ... incorporated herein by reference.

[0301] Anti-cancer agents of particular interest for use in combination with the compounds of the present disclosure include: It can be obtained.

[0302] Topoisomerase inhibitors, such as type I topoisomerase inhibitors, such as irinotecan benzodiazepines, topotecan, and camptothecin, and type 2 topoisomerase inhibitors, such as Etoposide, doxorubicin, and epirubicin.

[0303] Poly(ADP-ribose) polymerase (PARP) inhibitors, e.g., olaparib, luca pariparib, niraparib, talazoparib, veliparib, pamiparib, and iniparib.

[0304] In some embodiments, the compounds of the present disclosure are useful as DNA cross-linking agents, e.g., cisplatin, cinnamate, thiamin ... It is administered in combination with ruboplatin and oxaliplatin.

[0305] Agents that increase levels of reactive oxygen species (ROS), such as napabucasin.

[0306] PARP inhibitors, such as olaparib, rucaparib, niraparib, veliparib, and taparin Razoparib.

[0307] Purine antimetabolites and / or inhibitors of de novo purine synthesis, e.g., pemetrexed (A limta®), gemcitabine (Gemzar®), 5-fluorouracil (Fenibacillus subtilis), Uracil (Adrucil®, Carac®, and Efudex®) ®), methotrexate (Trexall®), capecitabine (Xe loda®), floxuridine (FUDR®), decitabine (D acogen®), azacitidine (Vidaza® and Azadi ne (registered trademark), 6-mercaptopurine (Purinethol (registered trademark)), Ladribine (Leustatin®, Litak® and Movec®) tro®), fludarabine (Fludara®), pentostatin (Nipent®), Nelarabine (Arranon®), Clofa Rabine (Clolar® and Evoltra®), and cytarabine (Cytosar®).

[0308] Anti-angiogenic agents, such as matrix metalloproteinase (MMP) inhibitors (e.g. , MMP-2 inhibitor, MMP-9 inhibitor), rapamycin, temsirolimus (CCI-7 79), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab , as well as COX-II inhibitors, such as CELEBREX™ (celecoxib), Valdecoxib and rofecoxib: useful matrix metalloproteinase inhibitors Examples of this are WO96 / 33172 (published October 24, 1996), WO96 / 2 7583 (published March 7, 1996), European Patent Application No. 97304971.1 (filed July 8, 1997), European Patent Application No. 99308617.2 (199 WO98 / 07697 (filed October 29, 1999), WO98 / 07697 (published February 26, 1998) WO98 / 03516 (published January 29, 1998), WO98 / 3 4918 (published August 13, 1998), WO98 / 34915 (published August 13, 1998) WO98 / 33768 (published August 6, 1998), WO98 / 30566 (published July 16, 1998), European Patent Application Publication No. 6,046 (published July 13, 1994), European Patent Application Publication No. 931,78 No. 8 (published July 28, 1999), WO90 / 05719 (May 3, 1990) WO99 / 52910 (published October 21, 1999), WO99 / 52889 (published October 21, 1999), WO99 / 29667 (Published June 17, 1999), PCT International Patent Application No. PCT / IB98 / 01 113 (filed July 21, 1998), European Patent Application No. 99302232.1 No. (filed March 25, 1999), UK Patent Application No. 9912961.1 (filed March 25, 1999), U.S. Provisional Application No. 60 / 148,464 (filed June 3, 1999) No. 5,863,949 (issued January 26, 1999) No. 5,861,510 (issued January 19, 1999), and and European Patent Application Publication No. 780,386 (published June 25, 1997) (these (all of which are incorporated herein by reference in their entireties). Specific examples of MMP-2 and / or MMP-9 inhibitors include those that have little or no activity inhibiting MMP-1. Other specific examples include those that have other matrix metalloproteinases. Proteinases (e.g., MMP-1, MMP-3, MMP-4, MMP-5, MMP-6 , MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and / or MMPs that selectively inhibit MMP-2 and / or MMP-9 relative to MMP-13 In some embodiments, specific examples of useful MMP inhibitors include A G-3340, RO323555, and RS13-0830.

[0309] In some embodiments, the compounds of the present disclosure are autophagy inhibitors, e.g., chloroquine. 3-methyladenine, hydroxychloroquine (Plaquenil™), buff Iromycin A1, 5-amino-4-imidazolecarboxamide riboside (AICAR ), okadaic acid, type 2A or type 1 protein phosphatase inhibiting autophagy Inhibitory algal toxins, cAMP analogs, and drugs that increase cAMP levels, e.g., Denosine, LY204002, N6-mercaptopurine riboside, and vinblastine, and ATG5 (associated with autophagy), Administered in combination with antisense or siRNA that inhibits the expression of a protein will be done.

[0310] In some embodiments, the compounds of the present disclosure are B-cell lymphoma 2 (BCL-2) inhibitors, For example, it is administered in combination with venetoclax.

[0311] In some embodiments, the compounds of the present disclosure are B cell receptor signaling antagonists , for example, in combination with a Bruton's tyrosine kinase (BTK) inhibitor (e.g., ibrutinib). They are administered in combination.

[0312] In some embodiments, compounds of the present disclosure are administered in combination with a bromodomain inhibitor. Bromodomain inhibitors are inhibitors of at least one bromodomain protein, e.g. , Brd2, Brd3, Brd4, and / or BrdT, e.g., inhibiting Brd4. Non-limiting examples of bromodomain inhibitors include JQ-1 (Nature 2010 Dec 23;468(7327):1067-73), BI2536(ACS Che m.Biol.2014 May 16;9(5):1160-71;Boehring er Ingelheim), TG101209(ACS Chem.Biol.201 4 May 16;9(5):1160-71), OTX015(Mol.Cancer Ther.November 201312;C244;Oncoethix), IB ET762(J Med Chem.2013 Oct 10;56(19):7498 -500;GlaxoSmithKline), IBET151(Bioorg.Med .Chem.Lett.2012 Apr 15;22(8):2968-72;Gla xoSmithKline), PFI-1 (J.Med.Chem.2012 Nov 26;55(22):9831-7, Cancer Res.2013 Jun 1;7 3(11):3336-46;Structural Genomics Consor tium), CPI-0610(Constellation Pharmaceuti In some embodiments, the bromodomain inhibitor is TG101. 209, BI2536, OTX015, C244, IBET762, IBET151, or PFI-1.

[0313] Histone deacetylase (HDAC) inhibitors. HDAC proteins are the enzymes responsible for the production of yeast HDAC proteins. Based on their homology to proteins, HDAC1, HDAC2, HDAC3, and HDAC4 Class I, consisting of HDAC4, HDAC5, HDAC7, and HDAC8; Class IIa, consisting of HDAC 9; Class II, consisting of HDAC 6 and HDAC 10 b; and Class IV, which consists of HDAC11. Non-limiting examples of inhibitors include trichostatin A, vorinostat (Proc. Natl. Acad. Sci. USA 2004, 103:111-112, 2004), and thrombin inhibitors (Proc. Natl. Acad. Sci. USA 2004, 103:111-112, 2004). l.Acad.Sci.USA1998 Mar 17;95(6):3003- 7), givinostat, abexinostat (Mol. Cancer Ther. 200 6 May;5(5):1309-17), belinostat (Mol. Cancer T her.2003 Aug;2(8):721-8), panobinostat (Clin.C Ancer Res.2006 Aug 1;12(15):4628-35), Resmi Nostat (Clin.Cancer Res.2013 Oct 1;19(19): 5494-504), xinostat (Clin.Cancer Res.2013 A ug 1;19(15):4262-72), depsipeptide (Blood.2001 Nov 1;98(9):2865-8), entinostat (Proc. Natl. A cad.Sci.USA1999 Apr 13;96(8):4592-7), Mocetinostat (Bioorg.Med.Chem.Lett.2008 Feb 1 ;18(3):106771), and valproic acid (EMBO J.2001 Dec 1 7;20(24):6969-78). In some embodiments, HDAC inhibitors Antineoplastic agents include panobinostat, vorinostat, MS275, belinostat, SAHA, Or LBH589.

[0314] In some embodiments, the compounds of the present disclosure are epidermal growth factor receptor (EGFR) tyrosine Kinase inhibitors, e.g., erlotinib, osimertinib, cetuximab, gefitinib , necitumumab, lapatinib, neratinib, panitumumab, vandetanib, and necitumumab The combination of the compounds described herein and an EGFR inhibitor is administered in combination with a vasopressin-releasing hormone (vasopressin) inhibitor. The combination may be used to treat, for example, cancers associated with EGFR dysregulation, such as non-small cell lung cancer (NSC). EGFR may be useful in the treatment of pancreatic cancer, breast cancer, and colon cancer. It can be dysregulated due to activating mutations in genes 18, 19, 20, or 21. In certain embodiments, the EGFR inhibitor is erlotinib or osimertinib. In certain embodiments, the combination of a compound of the present disclosure and an EGFR inhibitor is In certain embodiments, the compounds of the present disclosure and EGFR are used to treat NSCLC. Combinations of EGFR inhibitors are used to treat EGFR inhibitor-resistant cancers, e.g. For example, the compounds of the present disclosure sensitize the cancer to EGFR inhibitors.

[0315] EGFR antibodies, such as cetuximab (Erbitux®).

[0316] Methylthioadenosine phosphorylase (MTAP) inhibitors, such as (3R,4S)- 1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methyl)-4 -((Methylthio)methyl)pyrrolidin-3-ol (MT-DADMe-Immucillin A, CAS:653592-04-2).

[0317] Methylthioadenosine ((2R,3R,4S,5S)-2-(6-amino-9H-purine) (methyl-9-yl)-5-((methylthio)methyl)tetrahydrofuran-3,4-diol , CAS:2457-80-9).

[0318] Epidermal growth factor receptor (EGFR) inhibitors, such as erlotinib hydrochloride (Tarcev a®) and gefitinib (Iressa®).

[0319] Epithelial-mesenchymal transition (MET) inhibitors, such as capmatinib (INC280, CAS:10 29712-80-8).

[0320] In some embodiments, the compounds of the present disclosure are platelet-derived growth factor (PDGF) receptor inhibitors. anti-inflammatory drugs, such as imatinib (Gleevec®); linifanib (N-[4- (3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5 (-methylphenyl)urea, also known as ABT 869, available from Genentech sunitinib malate (Sutent®); quizartinib (AC220 , CAS:950769-58-1); pazopanib (Votrient®); axitinib (Inlyta®); sorafenib (Nexavar®) )); Balagatef (BIBF1120, CAS:928326-83-4); Telatinib (BAY57-9352, CAS:332012-40-5); Vatalanib dihydrochloride (P TK787, CAS: 212141-51-0); and motesanib diphosphate (AMG70 6, CAS:857876-30-3, N-(2,3-dihydro-3,3-dimethyl-1 H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridine carboxamides, as described in PCT Publication No. WO 02 / 066470 It is administered in a timely manner.

[0321] In some embodiments, HER2 (receptor protein tyrosine kinase erbB-2 ) antibodies may be used in combination with the compounds described herein. The HER2 antibody or biologic agent is fam-trastuzumab deruxtecan-n xki, trastuzumab, pertuzumab, ado-trastuzumab emtansine, or It is margetuximab-cmkb.

[0322] In some embodiments, compounds of the present disclosure inhibit phosphoinositide 3 kinase (PI3K) inhibitors, such as 4-[2-(1H-indazol-4-yl)-6-[[4-(methyl Sulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl

[0023] morpholine (also known as GDC 0941, PCT Publication No. WO 09 / 036 082 and WO09 / 055730); 4-(trifluoromethyl) (2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine (B Also known as KM120 or NVP-BKM120, PCT Publication No. WO2007 / 084786); alpelisib (BYL719); (5Z)-5- [[4-(4-pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione 5-[8-methyl-9 -(1-methylethyl)-2-(4-morpholinyl)-9H-purin-6-yl]-2- Pyrimidinamine (VS-5584, CAS: 1246560-33-7); and Everoli It is administered in combination with mus (AFINITOR®).

[0323] Cyclin-dependent kinase (CDK) inhibitors, such as ribociclib (LEE011, CAS: 1211441-98-3; Aloisine A; Alvocidib (Flavopiridol) or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[ (3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromenone and is described in U.S. Pat. No. 5,621,002); crizotinib (PF-02341066, CAS:877399-52-5); 2-(2-chlorophenoxy) 5,7-dihydroxy-8-[(2R,3S)-2-(hydroxymethyl)-1 -methyl-3-pyrrolidinyl]-4H-1-benzopyran-4-one hydrochloride (P276- 00, CAS:920113-03-7; 1-methyl-5-[[2-[5-(trifluoromethyl) (4-pyridinyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4 -(trifluoromethyl)phenyl]-1H-benzimidazol-2-amine (RAF 265, CAS:927880-90-8); Indisulam (E7070); Roscovici 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperidine) radin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin thiazol-7-one hydrochloride (PD0332991); dinaciclib (SCH727965); N-[5-[[(5-tert-butyloxazol-2-yl)methyl]thio]thiazo [2-(2-yl)piperidine-4-carboxamide (BMS 387032, CAS:3 45627-80-7;4-[[9-chloro-7-(2,6-difluorophenyl)- 5H-Pyrimido[5,4-d][2]benzazepin-2-yl]amino]-benzoic acid ( MLN8054, CAS:869363-13-3;5-[3-(4,6-difluoro -1H-benzimidazol-2-yl)-1H-indazol-5-yl]-N-ethyl 4-methyl-3-pyridinemethanamine (AG-024322, CAS: 83736 4-57-5); 4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3- Carboxylic acid N-(piperidin-4-yl)amide (AT7519, CAS: 844442 -38-2);4-[2-methyl-1-(1-methylethyl)-1H-imidazole-5 -yl]-N-[4-(methylsulfonyl)phenyl]-2-pyrimidinamine (AZD5 438, CAS:602306-29-6); Palbociclib (PD-0332991) and (2R,3R)-3-[[2-[[3-[[S(R)]-S-cyclopropylsulfonyl] [Phenimidoyl]-phenyl]amino]-5-(trifluoromethyl)-4-pyrimidinyl [N-[(2-methyl-2-hydroxypropyl)amino]-2-butanol (BAY 10000394).

[0324] In some embodiments, compounds of the present disclosure are p53-MDM2 inhibitors, e.g., (S) -1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-{methyl 4-(4-methyl-3-oxo-piperazin-1-yl)-trans-cyclo[ ... hexylmethyl]-amino}-phenyl)-1,4-dihydro-2H-isoquinoline-3 -one, (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridyl 2-(2,4-dimethoxy-pyrimidin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-3-yl)- (5-dihydro-1H-pyrrolo[3,4-d]-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d] Imidazol-4-one, [(4S,5R)-2-(4-tert-butyl-2-ethoxy)-2-imidazol-4-one] (4-chlorophenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethylimidazole 1-yl]-[4-(3-methylsulfonylpropyl)piperazin-1-yl]methanone (RG7112), 4-[[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro) (4-chloro-2-fluorophenyl)-4-cyano-5-(2, 2-Dimethylpropyl)pyrrolidine-2-carbonyl]amino]-3-methoxybenzoic acid (RG7388), SAR299155, 2-((3R,5R,6S)-5-(3-chloro (S)-1-(isopropylsulfophenyl)-6-(4-chlorophenyl)-1-( ... Nyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl ) acetic acid (AMG232), {(3R,5R,6S)-5-(3-chlorophenyl)-6- (4-chlorophenyl)-1-[(2S,3S)-2-hydroxy-3-pentanyl]- 3-Methyl-2-oxo-3-piperidinyl}acetic acid (AM-8553), (±)-4-[ 4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl) Nyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one ( Nutlin-3), 2-methyl-7-[phenyl(phenylamino)methyl]-8-quinolin Nol (NSC 66811), 1-N-[2-(1H-indol-3-yl)ethyl ]-4-N-pyridin-4-ylbenzene-1,4-diamine (JNJ-2685416 5), 4-[4,5-bis(3,4-chlorophenyl)-2-(2-isopropoxy-4 -Methoxy-phenyl)-4,5-dihydro-imidazole-1-carboxyl]-piperidine Lazin-2-one (Kheirin-1), 4-[4,5-bis(4-trifluoromethylphenyl) Nyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imino 5-[[3-di-[(2- ... Methylamino)propyl]amino]-3,10-dimethylpyrimido[4,5-b]quinolin trans-4- It is administered in combination with iodo-4'-boranyl-chalcone (SC204072).

[0325] In some embodiments, compounds of the present disclosure inhibit mitogen-activated protein kinase ( MEK) inhibitors, such as XL-518 (also known as GDC-0973, CAS number: 1029872-29-4, available from ACC Corp.); selumetinib (5-[ (4-bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethyl) (Iodoxyl)-1-methyl-1H-benzimidazole-6-carboxamide, AZD624 4 or ARRY 142886, PCT Publication No. WO2003 / 07791 4); 2-[(2-chloro-4-iodophenyl)amino]-N-( Cyclopropylmethoxy)-3,4-difluorobenzamide (CI-1040 or P Also known as D184352 and described in PCT Publication No. WO2000 / 035436 N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro 2-[(2-fluoro-4-iodophenyl)amino]-benzamide (PD032 5901, and is described in PCT Publication No. WO2002 / 006213. 2,3-bis[amino[(2-aminophenyl)thio]methylene]butanediol Toryl (also known as U0126 and described in U.S. Pat. No. 2,779,780) N-[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amine [(2R)-2,3-dihydroxypropyl]-6-methoxyphenyl Chlopropanesulfonamide (also known as RDEA119 or BAY869766) and described in PCT Publication No. WO2007 / 014011); (3S, 4R, 5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy -3,4-dimethyl-3,4,9;19-tetrahydro-1H-2-benzoxacyclo tetradecyne-1,7(8H)-dione] (also known as E6201, PCT Publication No. WO2003 / 076424); 2'-amino-3'-methoxyphenyl Labon (also known as PD98059, Biaffin GmbH & Co., KG, (R)-3-(2,3-dihydroxypropyl)-6- Fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyridin [2, 3-d]pyrimidine-4,7(3H,8H)-dione (TAK-733, CAS:103 5555-63-5); Pimasertib (AS-703026, CAS:1204531- 26-9); trametinib dimethyl sulfoxide (GSK-1120212, CAS:1 204531-25-80;2-(2-fluoro-4-iodophenylamino)-N- (2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin 3,4-difluoro-2-[(2-fluoro- (3-(4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-[(3- Oxo-[1,2]oxazinan-2-yl)methyl]benzamide (CH 49876 55 or RO 4987655); and 5-[(4-bromo-2-fluorophenyl) Amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benz It is administered in combination with imidazole-6-carboxamide (MEK162).

[0326] B-RAF inhibitors, such as regorafenib (BAY73-4506, CAS:755 037-03-7); Tivozanib (AV951, CAS: 475108-18-0); Murafenib (ZELBORAF®, PLX-4032, CAS:91850 4-65-1); encorafenib (also known as LGX818); 1-methyl-5-[ [2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl -N-[4-(trifluoromethyl)phenyl]oxy]-N-[4-(trifluoromethyl)phenyl-1H-benzimidazole -2-amine (RAF265, CAS: 927880-90-8); 5-[1-(2-hydroxybenzoyl) hydroxyethyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2, 3-Dihydroinden-1-one oxime (GDC-0879, CAS: 905281- 76-7);5-[2-[4-[2-(dimethylamino)ethoxy]phenyl]-5-( 4-pyridinyl)-1H-imidazol-4-yl]-2,3-dihydro-1H-indole thion-1-one oxime (GSK2118436 or SB590885); (+ / -)- (5-(2-(5-chloro-2-methylphenyl)-1-hydroxy-3-oxo-2, 3-Dihydro-1H-isoindol-1-yl)-1H-benzimidazol-2-yl methyl carbamate (also known as XL-281 and BMS908662); doubler Fenib (TAFINLAR®); and N-(3-(5-chloro-1H-pyrrolidine) (2,3-b)pyridine-3-carbonyl)-2,4-difluorophenyl)propane -1-sulfonamide (also known as PLX4720).

[0327] In some embodiments, compounds of the present disclosure are used in prostate cancer therapy, e.g., for the treatment of multiple myeloma. Loteasome inhibitors, such as bortezomib (VELCADE®), N-5- Benzyloxycarbonyl-Ile-Glu(O-tert-butyl)-Ala-leucine Nal (PSI), carfilzomib and ixazomib, marizomib (NPI-0052 ), delanzomib (CEP-18770), and O-methyl-N-[(2-methyl- 5-thiazolyl)carbonyl]-L-seryl-O-methyl-N-[(1S)-2-[(2 R)-2-methyl-2-oxiranyl]-2-oxo-1-(phenylmethyl)ethyl] -L-serinamide (oprozomib, ONX-0912, PR-047) (e.g., bolus) It is administered in combination with tezomib.

[0328] A number of chemotherapeutic agents may be used in combination with the compounds of the present disclosure. The chemotherapy drugs include mitotic inhibitors (e.g., paclitaxel, nab-paclitaxel), Alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors Toxicants, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and and antiandrogens.

[0329] In some embodiments, compounds of the present disclosure are useful in combination with alkylating agents, such as thiotepa and cyclohexyl benzoate. Rofosfamide (CYTOXAN®); alkyl sulfonates, e.g., Busu sulfan, improsulfan, and piposulfan; aziridines such as benzodopa (benzodopa), carboquone, meturedopa, and urethra Dopa (uredopa); altretamine, triethylenemelamine, triethylenephosphor methylol melamine, triethylene thiophosphoramide, and trimethylol melamine. methylamelamine; nitro mustards, e.g., chlorambucil, chlornaphazine, chlorophosphamide (c holophosphamide), estramustine, ifosfamide, mechlorethamine mechlorethamine oxide hydrochloride, melphalan, nobembrine, phenesterine, propranolol rednimustine, trofosfamide, uracil mustard; nitrosoureas, e.g., cal Mustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; Bioactive substances, such as aclacinomycin, actinomycin, anthramycin, azace bleomycin, cactinomycin, calicheamicin, carabic in), carminomycin, carzinophilin, Casodex®, chromoma Isin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo- L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, maltose Ceromycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, Peplomycin, potfiromycin, puromycin, Querramycin, rhodrubicin, streptonigrin, streptozocin, tubercidin , ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and and 5-fluorouracil (5-FU); folic acid analogs, e.g., denopterin, methotrexate sartan, pteropterin, trimetrexate; purine analogues, e.g., fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues, e.g., an Cytabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxy Lysine, doxifluridine, enocitabine, floxuridine; androgens, e.g., Calsterone, dromostanolone propionate, epithiostanol, mepitiostane, Testolactone; antiadrenergics, such as aminoglutethimide, mitotane, trilos folic acid supplements, e.g., folinic acid; aceglatone; aldophosphamide glycosides ;Aminolevulinic acid;Amsacrine;Bestravsil;Bisantrene;Edatrexate ;Defofamine;Demecolcine;Diaziquone;Eflornithi Elliptinium acetate; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidamine; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentos Tatin; Fenamet; Pirarubicin; Podophyllic acid; 2-ethylhydrazide; Proca Rubadin; PSK (registered trademark); Razoxane; Sizofiran; Spirogermanium; Tenu Azonic acid;Triaziquone;2,2',2''-Trichlorotriethylamine;Urethane ;Vindesine;Dacarbazine;Mannomustine;Mitobronitol;Mitolactol;Pi Pobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes, e.g., paclitaxel (TAXOL ), Bristol-Myers Squibb Oncology, Princeto n, NJ), docetaxel (TAXOTERE®, Rhone-Poultry enc Rorer, Antony, France), and cabazitaxel (JEVTA NA, Sanofi Genzyme); retinoic acid; esperamycin; capecitabine and pharmaceutically acceptable salts, acids, or derivatives of any of the above. In combination with a compound of the present disclosure (e.g., Further non-limiting examples of chemotherapeutic agents used (e.g., in combination therapy, in drug combinations) include: Typical examples include bortezomib, capecitabine (Xeloda®), N4-pepiviral 5-(2-hydroxybenzoyl)-5-deoxy-5-fluorocytidine, carboplatin (Para platin (registered trademark), cisplatin (Platinol (registered trademark), clad Livin (Leustatin®), cyclophosphamide (Cytoxan®), (Registered Trademark) or Neosar®), cytarabine, cytosine arabinoside (Cy tosar-U (registered trademark), cytarabine liposome injection (DepoCyt (registered trademark) doxycycline (DTIC-Dome®), dacarbazine (DTIC-Dome®), doxorubicin hydrochloride (A driamycin (registered trademark), Rubex (registered trademark), erlotinib, phosphate Rudarabine (Fludara®), 5-fluorouracil (Adrucil®), Registered trademark), Efudex (registered trademark), FOLFIRINOX, Gemcitabine (Dif L-aminopropyl deoxycytidine), irinotecan (Camptosar®), L-aminopropyl deoxycytidine sparginase (ELSPAR®), 6-mercaptopurine (Purinet®), hol®), methotrexate (Folex®), nab-paclitaxel Cell, pentostatin, 6-thioguanine, thiotepa, and injectable topotecan hydrochloride (H ycamptin®). Further non-limiting examples of chemotherapeutic agents used (in combination therapy, in drug combinations) include: Typical examples include erlotinib, afatinib, gefitinib, GDC0941, and MLN. 1117, BYL719 (alpelisib), BKM120 (buparlisib), CYT38 7, GLPG0634, baricitinib, restortinib, momelotinib, pacritinib , ruxolitinib, TG101348, crizotinib, tivantinib, AMG337, Bozantinib, foretinib, onartuzumab, NVP-AEW541, dasatinib, Natinib, saracatinib, bosutinib, trametinib, selumetinib, cobimetinib, P D0325901, RO5126766, axitinib, bevacizumab, cetuximab, Fostamatinib, imatinib, lapatinib, lenvatinib, ibrutinib, nilotinib, Panitumumab, pazopanib, pegaptanib, ranibizumab, sorafenib, sunitinib, SU6656, trastuzumab, tofacitinib, vandetanib, vemurafenib, irinotecan These include notecan, taxol, docetaxel, rapamycin, and MLN0128. In combination with compounds of the present disclosure (e.g., in combination therapy, in pharmaceutical combinations), Further non-limiting examples of chemotherapeutic agents that may be used include capecitabine (Xeloda) Registered trademark), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, ruboplatin (Paraplatin®), cisplatin (Platinol (Registered Trademark), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, Cytarabinoside (Cytosar-U®), cytarabine liposome injection ( DepoCyt®), dacarbazine (DTIC-Dome®), xorubicin hydrochloride (Adriamycin®, Rubex®), Fludarabine phosphate (Fludara®), 5-fluorouracil (Adru cil®, Efudex®), gemcitabine (difluorodeoxyglucan cytidine), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), 6-mercaptopurine (Purinethol®), (trademark), methotrexate (Folex®), pentostatin, 6-thioguaiacol These include thiaminamine, thiotepa, and injectable topotecan hydrochloride (Hycamptin®). It can be obtained.

[0330] Commonly prescribed anti-cancer drugs may also be used in combination with the compounds of the present disclosure. Non-limiting examples of anti-cancer drugs include Herceptin®, Avast®, in®, Erbitux®, Rituxan®, Taxol Dol (registered trademark), Arimidex (registered trademark), Taxotere (registered trademark), ABV D, AVICINE, abagovomab, acridine carboxamide, adecatumumab, 17 -N-allylamino-17-demethoxygeldanamycin, Alfaradin, Albosin Dib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide , anthracenedione, anti-CD22 immunotoxin, anti-cancer drug, anti-tumor herb, Apajikuo , atiprimod, azathioprine, belotecan, bendamustine, BIBW 2992 , biricodal, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, cell cycle non-specific antitumor agent, dichloroacetic acid, discodermo Lyde, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, Xatecan, Exisulind, Ferruginol, Holodesin, Fosfestrol, IC E chemotherapy, IT-101, Imexon, Imiquimod, Indolocarbazole, Iroflu Ben, laniquidar, larotaxel, lenalidomide, lucanton, raltotecan, mahosufu Amido, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, P AC-1, pawpaw, pixantrone, proteasome inhibitor, rebeccamycin, resin Quimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar , tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxasidine Tabine, uramustine, vadimezan, vinflunine, ZD6126, or zosuquidar Examples include:

[0331] Chemotherapy cell modulating agents may also be used in combination with the compounds of the present disclosure. Non-limiting examples of agents include those that act to regulate or inhibit hormone action on tumors. antihormonal agents, such as antiestrogens, e.g., tamoxifen (Nolvad ex(trademark), raloxifene, aromatase inhibitor 4(5)-imidazole, 4-hydroxybenzoates Droxitamoxifen, Trioxifen, Keoxifen, LY 117018, O napristone, and toremifene (Fareston); and antiandrogens, e.g. , flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil Sil; Gemcitabine; 6-Thioguanine; Mercaptopurine; Methotrexate; Platinum analogs, e.g., cisplatin and carboplatin; vinblastine; platinum; etoposide ( VP-16); Ifosfamide; Mitomycin C; Mitoxantrone; Vincristine ;Vinorelbine;Navelbine;Novantrone;Teniposide;Daunomycin;Aminoptera Phosphorus; Xeloda; Ibandronate; Camptothecin-11 (CPT-11); Topoisomerase The enzyme inhibitor RFS2000 and difluoromethylornithine (DMFO) are It can be obtained.

[0332] mTOR inhibitors may also be used in combination with the compounds of the present disclosure. Typical examples include temsirolimus; ridafolimus (officially known as deforolimus); Dimethylphosphinic acid (1R,2R,4S)-4-[(2R)-2[ (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,2 6E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethyl Toxic-15,17,21,23,29,35-hexamethyl-2,3,10,14,2 0-Pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0 4, 9]Hexatriaconta-16,24,26,28-tetraen-12-yl]propyl ]-2-methylcyclohexyl, also known as AP23573 and MK8669, described in PCT Publication No. WO03 / 064383); everolimus (Afini rapamycin (AY22989, Sirol imus®; simapimod (CAS: 164301- 51-3); Temsirolimus, (5-{2,4-bis[(3S)-3-methylmorpholine -4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methyl ethanol (AZD8055); 2-amino-8-[trans-(2-hydroxyethoxy) cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methylpyrido[2 ,3-d]pyrimidin-7(8H)-one (PF04691502, CAS:10131 01-36-4); and N 2 -[1,4-dioxo-4-[[4-(4-oxo-8 -phenyl-4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy ]butyl]-L-arginylglycyl-L-α-aspartyl L-serine inner salt (sequence No. 1482) (SF1126, CAS: 936487-67-1), and XL765 Examples include:

[0333] Some patients may experience a worsening of their condition after treatment with a compound of the present disclosure and / or other therapeutic agent(s) (e.g., an anti-cancer agent) Allergic reactions to the allergen(s) may occur during or after administration. To minimize the risk of allergic reactions, an anti-allergic drug may be administered in combination with the compounds of the present disclosure and / or It may be administered in combination with other therapeutic agent(s) (e.g., anti-cancer agent(s)). Suitable antiallergic drugs include corticosteroids (Knutson, S., et al. .,PLoS One,DOI:10.1371 / journal.pone.0111 840 (2014)), e.g., dexamethasone (e.g., DECADRON® )), beclomethasone (e.g., BECLOVENT®), hydrocortisone (Cortisone, Hydrocortisone Sodium Succinate, Hydrocortisone Sodium Phosphate Also known as ALA-CORT®, hydrocortisone phosphate, SOLU- CORTEF®, HYDROCORT ACETATE®, and L ANACORT®), prednisolone (DELTA -CORTEL®, ORAPRED®, PEDIAPRED® (trademark), and PRELONE®), prednisone ( DELTASONE®, LIQUID RED®, METICOR (sold under the trade names TEN® and ORASONE®), Tilprednisolone (6-methylprednisolone, methylprednisolone acetate, methylprednisolone succinate) Also known as tilprednisolone sodium, DURALONE®, MEDR ALONE®, MEDROL®, M-PREDNISOL® (sold under the trade names SOLU-MEDROL® and SOLU-MEDROL®); antihistamine antihistamines, such as diphenhydramine (e.g., BENADRYL®), roxyzine, and cyproheptadine; and bronchodilators, such as beta-adrenergic agonist, albuterol (e.g., PROVENTIL®) and terbutaline (BRETHINE®).

[0334] Some patients may experience a worsening of their condition after treatment with the compounds described herein and / or other therapeutic agent(s) (e.g., For example, nausea may occur during and after administration of anticancer drug(s). and antiemetics may be administered in combination with compounds of the present disclosure and / or other therapeutic agents to prevent emesis. Suitable antiemetics include, for example, anticancer drugs (multiple drugs). These include aprepitant (EMEND®), ondansetron (ZOFRAN®), (Trademark), granisetron HCl (KYTRIL®), lorazepam (ATI VAN®), dexamethasone (DECADRON®), prochlor Perazine (COMPAZINE®), casopitant (REZONIC®) and ZUNRISA®, and combinations thereof.

[0335] Medications to reduce pain experienced during the procedure to make the patient more comfortable Common over-the-counter pain relievers, such as TYLENOL®, are also used in this study. in combination with the indicated compounds and / or other therapeutic agent(s) (e.g., anti-cancer agent(s)). Opioid analgesics, e.g. hydrocodone / paracetamol or Hydrocodone / acetaminophen (e.g., VICODIN®), morphine (e.g., ASTRAMORPH® or AVINZA®), Cycodone (e.g., OXYCONTIN® or PERCOCET®) )), oxymorphone hydrochloride (OPANA®), and fentanyl (e.g., DURAGESIC® may be useful for moderate or severe pain, and the present disclosure and / or other therapeutic agent(s) (e.g., anti-cancer agent(s)). It can be used in combination.

[0336] To protect normal cells from treatment toxicity and to reduce organ toxicity, cytoprotective agents (e.g., For example, neuroprotectants, free radical scavengers, cardioprotectants, anthracycline vasopressins, Extravasation reversal agents, nutrients, etc., may be used in combination with the compounds of the present disclosure as adjunctive therapy. Suitable cytoprotective agents include amifostine (ETHYOL®), glutamic acid (Gluconamide), and cyclosporine. Tammin, Dimesna (TAVOCEPT®), Mesna (MESNEX®) )), dexrazoxane (ZINECARD® or TOTECT® )), xaliproden (XAPRILA®), and leucovorin (leucovorin These include glutamic acid (also known as calcium carbonate, citrovorum factor, and folinic acid).

[0337] To protect normal cells from treatment toxicity and to reduce organ toxicity, cytoprotective agents (e.g., For example, neuroprotectants, free radical scavengers, cardioprotectants, anthracycline vasopressins, Extravasation reversal agents, nutrients, etc., may be used in combination with the compounds of the present disclosure as adjunctive therapy. Suitable cytoprotective agents include amifostine (ETHYOL®), glutamic acid (Gluconamide), and cyclosporine. Tammin, Dimesna (TAVOCEPT®), Mesna (MESNEX®) )), dexrazoxane (ZINECARD® or TOTECT® )), xaliproden (XAPRILA®), and leucovorin (leucovorin These include glutamic acid (also known as calcium carbonate, citrovorum factor, and folinic acid).

[0338] In the combination therapy of the present disclosure, the compound of the present disclosure and the other therapeutic agent may be of the same or different composition. Additionally, the compounds of the present invention and other therapeutic agents may be manufactured and / or formulated by the manufacturer. (i) Before delivering a combination product to a physician (e.g., a combination product containing a compound of the present disclosure and another therapeutic agent), (ii) by a physician (or under the guidance of a physician) immediately before administration; (iii) ) The patient may be taking other medications, such as during sequential administration of a compound of the invention and another therapeutic agent, to achieve a combination therapy. It can be considered.

[0339] Pharmaceutical Composition In certain embodiments, the present disclosure provides a compound as described above (e.g., a compound of the present disclosure, e.g., , a compound of formula (I) or (II) or (III)), and one or more pharmaceutical and providing pharmaceutical formulations suitable for use in human patients, comprising a physiologically acceptable excipient. In certain embodiments, the pharmaceutical preparations are for the treatment or prevention of a condition or disease described herein. Any of the compounds of the present disclosure may be for use in the The compounds may be used in the manufacture of a medicament for the treatment of any disease or condition that is

[0340] The compositions and methods of the present disclosure can be utilized to treat a subject in need of treatment. In certain embodiments, the subject is a mammal, eg, a human or non-human mammal. When administered to a subject, e.g., a human, the composition or compound preferably It is administered as a pharmaceutical composition comprising a compound of the disclosure and a pharmaceutically acceptable carrier. Acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or is a physiologically buffered saline solution or other solvent or vehicle, e.g., glycol, glycerol , oils such as olive oil, or injectable organic esters. In some embodiments, such pharmaceutical compositions are suitable for administration to humans, particularly those intended for administration via invasive routes (i.e., If the route is for a route that avoids transport or diffusion through a skin barrier (e.g., injection or implantation), In this case, the aqueous solution is pyrogen-free or substantially pyrogen-free. For example, to provide a delayed release of a drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition may be in unit dosage form, e.g., a tablet, capsule, or the like. capsules (including sprinkle capsules and gelatin capsules), granules, lyophilized powders for reconstitution Lyophile, suspension, cream, gel, ointment, aerosol injection, powder, solution The composition may be in the form of a transdermal delivery system, e.g., a skin patch. The composition may also be present in a solution suitable for topical administration, for example, eye drops.

[0341] Pharmaceutically acceptable carriers may be used, for example, to stabilize compounds such as those of the present disclosure. to increase its solubility, or to increase its absorption, or to The composition may contain physiologically acceptable agents that act to enable the synthesis of such compounds. Suitable therapeutically acceptable agents include, for example, carbohydrates, e.g., glucose, sucrose, or dextran, antioxidants, e.g., ascorbic acid or glutathione, chelates These include stabilizers, low molecular weight proteins, or other stabilizers or excipients. The choice of pharmaceutically acceptable carrier, including the agent to be administered, will depend, for example, on the route of administration of the composition. The formulation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying The pharmaceutical composition (formulation) can be, for example, a drug delivery system incorporating a compound of the present disclosure. The liposome may be a liposome or other polymer matrix, which may be, for example, a phospholipid. or other lipid-containing liposomes are non-toxic, physiologically acceptable, and metabolizable. It is a carrier and is relatively easy to prepare and administer.

[0342] The phrase "pharmaceutically acceptable" means, within the scope of sound medical judgment, a substance that is not excessively toxic, irritating, or irritating. be used in contact with the tissue of interest without allergic responses or other problems or complications. compounds, substances, compositions, and / or compounds suitable for use in the treatment of cancer and for which a reasonable benefit / risk ratio is met Used herein to refer to dosage forms.

[0343] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a material that is pharmaceutically acceptable. materials, compositions, or vehicles, such as liquid or solid fillers, diluents, excipients, solvents, Each carrier must be compatible with the other ingredients of the formulation and not harmful to the subject. It must be "acceptable" in the sense that it does not function as a pharmaceutically acceptable carrier. Some examples of materials that may be used include: (1) sugars, e.g., lactose; , glucose, and sucrose; (2) starches, such as corn starch and disaccharides; potato starch, (3) cellulose and its derivatives, such as carboxymethyl cellulose sodium cellulose, ethyl cellulose, and cellulose acetate, (4) powdered tragacanth, (5) Malt, (6) gelatin, (7) talc, (8) excipients, such as cocoa butter and suppository wax. (9) Oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil, (10) glycols, such as propylene glycol, (1 1) Polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycols, (12) esters such as ethyl oleate and ethyl laurate, (1 3) agar, (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide, (1 5) Alginic acid, (16) Pyrogen-free water, (17) Isotonic saline, (18) Ringer's (19) ethyl alcohol, (20) phosphate buffer solution, and (21) pharmaceutical preparations Other non-toxic compatible materials may be used.

[0344] The pharmaceutical composition (formulation) can be administered, for example, orally (e.g., in an aqueous or non-aqueous solution or suspension). such as liquid medicines, tablets, capsules (including sprinkle capsules and gelatin capsules) ), boluses, powders, granules, pastes for application to the tongue), absorption through the oral mucosa (e.g. sublingually), anally, rectally, or vaginally (e.g., with a pessary, cream, or foam) as a sterile solution or parenterally (intramuscular, intravenous, subcutaneous, or intrathecal), as a suspension), intranasal, intraperitoneal, subcutaneous, transdermal (e.g., as a patch applied to the skin) , as well as topical (e.g., creams, ointments, or sprays applied to the skin, or The compound may be administered to a subject by any of a number of routes of administration, including as eye drops. The compound may be formulated for inhalation. In certain embodiments, the compound may be simply dissolved in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found, for example, in , U.S. Patent Nos. 6,110,973, 5,763,493, and 5,731,00 No. 0, No. 5,541,231, No. 5,427,798, No. 5,358,970 and 4,172,896, and the patents cited therein. do.

[0345] The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form can be The dosage form will vary depending on the subject being treated and the particular mode of administration. The amount of active ingredient that can be combined with a carrier material generally will be that amount that produces a therapeutically effective compound of the invention. Generally, this amount will be between about 1 percent and about 99 percent of 100 percent. of active ingredient, preferably from about 5 percent to about 70 percent active ingredient, most preferably Generally, it is in the range of about 10 percent to about 30 percent.

[0346] Methods for preparing these formulations or compositions include incorporating an active compound, such as a compound of the present disclosure, into a carrier. In general, the formulations include any of the methods described herein. The compound is uniformly and intimately mixed with a liquid carrier or a finely divided solid carrier, or both. The ingredients are mixed together and then, if necessary, shaping the product.

[0347] Formulations of the present disclosure suitable for oral administration each contain a predetermined amount of a compound of the present disclosure as the active ingredient. capsules (including sprinkle capsules and gelatin capsules), cachets, pills tablets, lozenges (flavored base, usually sucrose and acacia or tragacanth) Use a can (lyophile), powder, granules, or aqueous or is a solution or suspension in a non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion or elixirs or syrups or pastilles (gelatin and glycerin, or or inert bases such as sucrose and acacia), and / or mouthwashes The composition or compound may also be administered as a bolus, electuary, or paste. It can be done.

[0348] Solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules) To prepare pharmaceutical preparations (such as tablets, pills, dragees, powders, granules, etc.), the active compound is The above pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate , and / or mixed with any of the following: (1) a filler or extender, e.g. , starch, lactose, sucrose, glucose, mannitol, and / or silicic acid (2) Binders, such as carboxymethylcellulose, alginate, gelatin, poly vinylpyrrolidone, sucrose, and / or acacia; (3) humectants, e.g., glycerin; roll, (4) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch Oka starch, alginic acid, certain silicates, and sodium carbonate, (5) slow dissolution (6) absorption promoters, such as quaternary ammonium compounds; 7) humectants, such as cetyl alcohol and glycerol monostearate; (8) absorption (9) lubricants, such as talc, stearic acid, Calcium phosphate, magnesium stearate, solid polyethylene glycol, lauryl sulfate sodium phosphates, and mixtures thereof; (10) complexing agents, such as modified cyclodextrins and unmodified cyclodextrin, and (11) coloring agent. Capsules (sprinkle capsules) In the case of pharmaceutical formulations (including gelatin capsules and gelatin capsules), tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also include lactose or milk sugar and high molecular weight polyethylene. Filling of soft gelatin capsules and hard gelatin capsules using excipients such as ethylene glycol It can also be used as a filler.

[0349] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may contain binders (e.g., gelatin or hydroxypropyl methylcellulose). ), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants or dispersants are not used. Molded tablets may be prepared by mixing the powdered compound moistened with an inert liquid diluent. , can be produced by molding in a suitable machine.

[0350] Tablets and other solid dosage forms of pharmaceutical compositions, e.g., dragees, capsules (sprinkle capsules) and gelatin capsules), pills, and granules may optionally be marked, and coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may also be prepared with other coatings, e.g., to provide a desired release profile. Hydroxypropyl methylcellulose, other polymer matrices, and Active ingredients contained therein using liposomes, liposomes, and / or microspheres They may be formulated to give slow or controlled release of, for example, bacteria-catching agents. by filtering through a collection filter or by adding sterile water or other sterile injection solution immediately before use. Sterilization is achieved by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in the pharmaceutical vehicle. These compositions may optionally contain opacifying agents, and may be used to relieve discomfort in certain parts of the gastrointestinal tract. only or preferentially in certain parts of the digestive tract, optionally in a delayed manner, the active ingredient(s) Examples of embedding compositions that can be used include polymeric substances. and waxes. The active ingredient may, where appropriate, be mixed with one or more of the above excipients. It may also be in a microencapsulated form containing the compound.

[0351] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, frozen solutions for reconstitution, and the like. Lyophile, microemulsion, solution, suspension, syrup, and Liquid dosage forms include, for example, water or other solvents in addition to the active ingredient. solvents, cyclodextrin and its derivatives, solubilizers and emulsifiers, such as ethyl alcohol , isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoate benzyl, propylene glycol, 1,3-butylene glycol, oil (specifically cottonseed oil) , peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan Commonly used in the art, such as fatty acid esters, and mixtures thereof An inert diluent may be included.

[0352] Besides inert diluents, the oral compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, or the like. Flavorings, flavorings, coloring agents, perfumes, and preservatives may be included.

[0353] Suspensions may contain, in addition to the active compound, suspending agents, for example ethoxylated isostearyl alcohol. Polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, Aluminum metahydroxide, bentonite, agar and tragacanth, and their It may contain mixtures.

[0354] Formulations of pharmaceutical compositions for rectal, vaginal, or urethral administration may contain one or more active compounds, e.g. , cocoa butter, polyethylene glycol, suppository wax, or salicylate It can be prepared by mixing with one or more suitable non-irritating excipients or carriers, and at room temperature Although solid, it is liquid at body temperature and melts in the rectum or vaginal cavity, releasing the active compound. It may be provided as a suppository.

[0355] The formulation of the pharmaceutical composition for oral administration may be as a mouthwash, oral spray, or oral ointment. It can be provided as follows.

[0356] Alternatively or additionally, the composition may be applied to a catheter, stent, wire, or other tube. The drug may be formulated for delivery via an intraluminal device. Delivery via such a device may involve the bladder, It may be particularly useful for delivery to the urethra, ureter, rectum, or intestine.

[0357] Formulations suitable for vaginal administration may contain carriers known in the art to be appropriate. Diaphragms, tampons, creams, gels, pastes, foams, or sprays containing Also included are formulations.

[0358] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, These include lotions, gels, solutions, patches, and inhalants. under sterile conditions with an acceptable carrier, and any preservatives, buffers, or propellants which may be required. They may be mixed.

[0359] Ointments, pastes, creams, and gels may contain, in addition to the active compound, excipients, e.g., animal Natural and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives Conductor, polyethylene glycol, silicone, bentonite, silica, talc, and zinc oxide lead, or mixtures thereof.

[0360] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, or cellulose gum. acid, aluminum hydroxide, calcium silicate, and polyamide powder, or Sprays can contain conventional propellants, such as chlorofluorohydrocarbons. and may additionally contain volatile unsubstituted hydrocarbons such as butane and propane.

[0361] Transdermal patches have the added advantage of providing controlled delivery of the compounds of the present disclosure to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dissolving the compound in a polymer matrix or gel. The amount of the ion can be controlled by either dispersing it into a solution or by dispersing it into a solution.

[0362] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this disclosure. Exemplary ophthalmic formulations are described in U.S. Patent Application Publication Nos. 2005 / 0080056, 2005 / 0080057, and 2005 / 0080059. 0059744, 2005 / 0031697, and 2005 / 004074 No. 6,583,124, the contents of each of which are incorporated herein by reference. Optionally, the ophthalmic liquid formulation may contain tears, aqueous humor, or have properties similar to the vitreous humor or are compatible with such humor. The route of administration may be local administration (e.g., administration by eye drops or implants) )

[0363] As used herein, the phrases "parenteral administration" and "parenterally administered" refer to enteral administration. This refers to modes of administration other than topical administration, usually by injection, including but not limited to: Intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal These include subcutaneous, subcuticular, intra-articular, subcapsular, intrathecal, intrathecal, intraspinal, and intrasternal injection and infusion. can be.

[0364] Pharmaceutical compositions suitable for parenteral administration contain one or more active compounds in one or more pharmaceutically acceptable salts of hydroxybenzoates. sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, is a combination of sterile powders that can be reconstituted into sterile solutions or dispersions for injection immediately before use. The pharmaceutical composition may further comprise an antioxidant, a buffer, a bacteriostat, a formulation suitable for the intended recipient. The solution may contain solutes which render the solution isotonic with blood, or suspending or thickening agents.

[0365] Examples of suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions of the present disclosure include water, ethanol, and the like. alcohols, polyols (e.g., glycerin, propylene glycol, polyethylene glycol) oils such as olive oil, and oleic acid; Injectable organic esters such as ethyl esters are also available. For example, coatings such as lecithin are also available. By using a coating material and, in the case of dispersions, by maintaining the required particle size. Furthermore, the use of surfactants helps maintain adequate fluidity.

[0366] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. The activity of microorganisms can be inhibited by various antibacterial and antifungal agents, e.g., parabens, chlorobutanol. This can be reliably prevented by including phenol sorbic acid or the like in the composition of the present invention. It may be desirable to include, for example, sugars, sodium chloride, etc. Prolonged absorption of the formulation is ensured by the use of aluminum monostearate and gelatin. This can be caused by the inclusion of a retarding agent.

[0367] In some cases, the drug is administered by subcutaneous or intramuscular injection to prolong its effect. This is desirable in liquid suspensions of crystalline or amorphous substances that are poorly water soluble. This can be achieved by using a suspension, in which case the rate of absorption of the drug depends on its rate of dissolution. The dissolution rate, in turn, may depend upon crystal size and crystalline form. Delayed absorption of an administered drug form can be accomplished by dissolving or suspending the drug in an oil vehicle. It is achieved.

[0368] Injectable depot forms can be formulated as pharmaceutical compositions containing the active ingredient in biodegradable polymers such as polylactide-polyglycolide. They are made by forming a microencapsulated matrix of the compound. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Other examples of biodegradable polymers include poly(orthoesters) and poly(non-orthoesters). Injectable depot formulations include liposomal or steroid formulations that are compatible with body tissue. They can also be prepared by encapsulating drugs in microemulsions.

[0369] When used in the methods of the present disclosure, the active compound can be administered per se or, e.g., 0.1 to 99.5% (more preferably, 0.5 to 90%) of the active ingredient is pharmaceutically acceptable The compound may be administered as a pharmaceutical composition comprising the compound in combination with a suitable carrier.

[0370] The method of introduction may also be via a rechargeable or biodegradable device. In recent years, various sustained-release polymers have been developed for the controlled delivery of drugs, including protein biopharmaceuticals. Polymer devices have been developed and tested in vivo. Biodegradable and non-degradable polymers A variety of biocompatible polymers (including hydrogels) are available that contain both It can be used to form an implant for sustained release of the compound at a site.

[0371] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention will vary depending on the particular patient, composition, and dosage regimen. The mode of administration should be one that is effective in achieving the desired therapeutic response without being toxic to the patient. The amount of the active ingredient may be varied to obtain the desired results.

[0372] The dosage level selected will depend on the particular compound or combination of compounds used, or or their esters, salts, or amides, and the activity of the particular compound(s) used. route of administration, time of administration, rate of excretion, duration of treatment, and combination with the specific compound(s) used Other drugs, compounds, and / or materials used in combination, the age and sex of the subject being treated These factors include weight, condition, health status, and medical history, as well as similar factors well known in the medical arts. The amount of time that the blood pressure is measured depends on a variety of factors.

[0373] A physician or veterinarian having ordinary skill in the art will be able to administer the required pharmaceutical composition. For example, a physician or veterinarian can readily determine and prescribe a therapeutically effective amount of the pharmaceutical composition. or administering the compound at a level lower than that required to achieve the desired therapeutic effect. Therapeutic doses may be initiated at low levels and gradually increased until the desired effect is achieved. "Effective amount" means the concentration of a compound sufficient to induce the desired therapeutic effect. It is generally understood that the effective amount will vary depending on the weight, sex, age, and medical history of the subject. Other factors that affect efficacy include, but are not limited to, the severity of the subject's condition. The disorder being treated, the stability of the compound, and, if necessary, the compound being administered with the disclosed compound will determine the severity of the disorder. Other types of therapeutic agents may be used, such as steroids, which may be administered in multiple doses, where a larger total dose is delivered by multiple administrations of the drug. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbach, er et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882 (reference incorporated herein).

[0374] Generally, a suitable daily dose of the active compounds used in the compositions and methods of the present disclosure will be Such an effective dose is typically the amount of compound that is the lowest dose effective to produce Depends on the factors mentioned above.

[0375] If desired, the effective daily dose of the active compound is administered in units of 100mg of ethanol at appropriate intervals throughout the day. For one, two, three, four, five, six or more separate doses administered separately in a dosage form In certain embodiments of the present disclosure, activation The combination may be administered two or three times daily. In certain embodiments, the active compound is administered in a single dose. It is administered once daily.

[0376] In certain embodiments, the compounds of the present disclosure may be used alone or in combination with other compounds. As used herein, the phrase "co-administered" refers to a therapeutic agent that is administered in combination with a previously administered therapeutic agent. While the first therapeutic compound is still active in the body, a second compound is administered (e.g., two The compounds are simultaneously effective in a subject, which includes a synergistic effect of the two compounds. It refers to any administration form of two or more different therapeutic compounds, such as those that can be administered in combination with different therapeutic agents. The therapeutic compounds may be administered in the same formulation or simultaneously or in separate formulations. In certain embodiments, the different therapeutic compounds may be administered within one hour of each other. may be administered within 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or 1 week. Thus, subjects undergoing such treatment may benefit from the combined effects of different therapeutic compounds. obtain.

[0377] In certain embodiments, a compound of the present disclosure and one or more additional therapeutic agent(s) (e.g., For example, co-administration of a compound of the present disclosure (e.g., For example, a compound of Formula (I) or (II) or (III)) or one or more additional therapeutic agents. This results in improved efficacy compared to the individual administration of one or more of the following: In embodiments, co-administration results in an additive effect, wherein the additive effect is a combination of the compounds of the present disclosure. and the sum of the effects of each of the individual administrations of one or more additional therapeutic agents.

[0378] The present disclosure provides for the use of pharmaceutically acceptable salts of the compounds of the present disclosure in the compositions and methods of the present disclosure. In certain embodiments, contemplated salts of the present disclosure include, but are not limited to: However, alkyl, dialkyl, trialkyl, or tetraalkylammonium salts are not In certain embodiments, contemplated salts of the present disclosure include those having the following limitations: Although not recommended, L-arginine salts, benenthamine Salt, Benzathine Salt, Betaine Salt, Calcium Hydroxide Salt, Choline Salt, Deanol Salt, Dietha diethylamine salt, diethylamine salt, 2-(diethylamino)ethanol salt, ethanol Amine salts, ethylenediamine salts, N-methylglucamine salts, hydrabamine salts, 1H-imino Dazole salt, lithium salt, L-lysine salt, magnesium salt, 4-(2-hydroxyethyl ) Morpholine salt, piperazine salt, potassium salt, 1-(2-hydroxyethyl)pyrrolidine salts, sodium salts, triethanolamine salts, tromethamine salts, and zinc salts. In certain embodiments, contemplated salts of the present disclosure include, but are not limited to: , Na salts, Ca salts, K salts, Mg salts, Zn salts, or other metal salts.

[0379] Pharmaceutically acceptable acid addition salts include those derived from various solvates, such as water, methanol, ethanol, etc. Mixtures of such solvates may also be prepared. The source of such solvates may be from the solvent of crystallization or may be from the solvent of preparation or crystallization. The solvent may be inherent in the solvent or may be incidental to such solvent.

[0380] Pharmaceutically acceptable anionic salts include acetate, aspartate, and benzenesulfonate. Phosphate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate Salt, chloride, citrate, decanoate, edetate, esylate, fumarate, glucept Salts include butyrate, gluconate, glutamate, glycolate, hexanoate, and hydroxybenzoate. Phthoate, iodide, isethionate, lactate, lactobionate, malate, maleate nitrate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate Salt, octanoate, oleate, pamoate, pantothenate, phosphate, polygalactose Ronate, propionate, salicylate, stearate, acetate, succinate, sulfate salts, tartrates, octadecyl salts, and tosyl salts.

[0381] Wetting agents, emulsifying agents and lubricating agents such as sodium lauryl sulfate and magnesium stearate sodium, as well as coloring agents, release agents, coating agents, sweeteners, flavors and fragrances, and preservatives , as well as antioxidants may also be present in the composition.

[0382] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, Acid, Cysteine ​​Hydrochloride, Sodium Bisulfate, Sodium Metabisulfite, Sodium Sulfite (2) Oil-soluble antioxidants, such as ascorbyl palmitate and butylated hydrochloride. BHT, butylated hydroxytoluene (BHA), lecithin, gall propyl acetate, α-tocopherol, etc., and (3) metal chelating agents, e.g., citric acid, Examples include ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid. .

[0383] The present disclosure has been generally described above, but certain specific aspects and embodiments of the disclosure will now be described. See the following examples, which are included for illustrative purposes only and are not intended to limit the disclosure. This will be more easily understood by: [Example]

[0384] General synthetic procedure The starting materials and reagents used in preparing these compounds were obtained from commercial suppliers, e.g. For example, it is available from Aldrich Chemical Co., Bachem, etc. or can be made by methods well known in the art. These steps are merely illustrative of some of the ways in which the compounds disclosed therein may be synthesized. Various modifications of the scheme may be made and will be suggested to those skilled in the art having reference to this disclosure. and intermediates and final products may be purified by, but not limited to, filtration, distillation, crystallization, cracking, etc. isolated and purified as needed using conventional techniques, including chromatography. They may be obtained and characterized using conventional means, including physical constants and spectral data.

[0385] Unless otherwise specified, reactions described herein are carried out in a temperature range of about -78°C to about 150°C. The reaction is carried out at atmospheric pressure. [Table 2] TIFF2025134754000217.tif235165TIFF2025134754000218.tif176165

[0386] The compounds of the present invention can be prepared by a variety of synthetic methods, as further described and exemplified herein. The following general synthetic methods are representative and are not intended to be limiting. It will be understood by those skilled in the art that this is not the case.

[0387] As demonstrated by the following examples, To this end, starting materials and reaction conditions may be varied, the order of reactions may be altered, and additional steps may be added. It will be understood by those skilled in the art that certain reactive functionalities may be used. Protecting groups may be required to achieve some of the above transformations. Generally, such protecting groups The necessity for groups and the conditions necessary to attach and remove such groups are well understood through experience. It will be apparent to the skilled organic chemist. All references in this application, including patents, The disclosures of the articles and references therein are incorporated herein by reference.

[0388] The preparation of the compounds of the present disclosure is further illustrated by the following examples, which are provided to illustrate, but are not to be construed as limiting the scope of the present disclosure. It is not intended to limit the scope or scope of the present invention to the specific procedures and compounds described therein. It shouldn't be.

[0389] Analysis method LCMS data was collected using one of the following methods: [Table 3] TIFF2025134754000220.tif236165TIFF2025134754000221.tif192165TIFF2025134754000222.tif134165

[0390] Exemplary Synthesis The exemplified syntheses, for example, some of the variable moiety variations in the exemplified general synthetic schemes. As used herein, each occurrence of X independently represents, where valency permits, , CR5 or N, R 1a is hydrogen, halogen, or optionally substituted alkyl and R 2a is hydrogen, halogen, optionally substituted alkyl, or optionally substituted and R5 is independently halo, optionally substituted alkyl, or optionally substituted alkyl. and R is an alkoxy substituted with 2b is hydrogen or optionally substituted alkyl , R 1d is hydrogen, halo, or optionally substituted alkyl, and R 3a Ha, Hello, optionally substituted alkyl, or optionally substituted heterocyclyl; R 4a is water hydrogen, halo, or optionally substituted alkoxy; R 5a is hydrogen, optionally substituted alkyl, or heterocyclyl, and R 6a is hydrogen or halo, alkenyl or is alkynyl, each of which may be one or more R a is optionally replaced by occurrences of Ri(R a is as defined in this application), each occurrence of A may be optionally followed by C or is N, and PG is a nitrogen protecting group when attached to nitrogen, or attached to oxygen If present, it is an oxygen protecting group.

[0391] The compounds exemplified in Figures 1 to 17 can be prepared from the corresponding starting materials and commercially available reagents by the following procedure. It can be synthesized using

[0392] Synthesis of intermediates Synthesis of 4-(benzo[d]oxazol-5-yloxy)-3-methylaniline 7 [ka] Step 1: 5-bromobenzo[d]oxazole in dioxane (50.00 mL) 1 (2.00g, 10.10mmol, 1.00 equivalent), Pd(dppf)Cl2(1 .65g, 2.02mmol, 0.20eq), AcOK(2.97g, 30.30mm ol, 3.00 equiv.), and bis(pinacolato)diboron 2 (3.85 g, 15.15 A mixture of 1.50 eq. (1 mmol) was stirred at 100°C under a N2 atmosphere for 6 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography ( Purification by 0-20% MeOH in DCM yielded 5-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)benzo[d]oxazole 3(2.10 g, 85%) as a yellow solid. LCMS (ESI, m / z): 246 [M+H ] + .

[0393] Step 2: 5-(4,4,5,5-tetramethyl-1-methyl-1-methylpropional) in THF (60.00 mL) ,3,2-dioxaborolan-2-yl)benzo[d]oxazole 3 (2.00 g, 8.16 mmol, 1.00 equiv.) and H2O2 (30%, 50.00 mL, 2.00 equiv. The mixture was stirred at 0° C. for 1 hour and then concentrated under reduced pressure to give benzo[d]oxazo[methyl]methylpropional. The ol-5-ol 4 (crude product, 2.30 g) was obtained as a black oil, which was further purified. Used in the next step without further purification. LCMS (ESI, m / z): 136 [M+H] + .

[0394] Step 3: Benzo[d]oxazol-5-ol in DMF (30.00 mL) 4 (1.28 g, 8.16 mmol, 1.00 equiv.), 1-fluoro-2-methyl-4- Nitrobenzene 5 (1.39 g, 8.98 mmol, 1.10 equiv.) and KCO ( A mixture of 3.38 g, 24.48 mmol, 3.00 equiv. was stirred at 50° C. for 16 hours. The resulting mixture was diluted with water and extracted three times with EtOAc. The organic layers were combined and washed with brine. The residue was washed with HCl, dried over Na2SO4, and concentrated under reduced pressure. Purification by chromatography (0-20% MeOH in DCM) gave 5-(2-methyl (4-nitrophenoxy)benzo[d]oxazole 6 (610.0 mg, 28%) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.26 (s, 1H), 8.04 (d, J = 9.2 Hz, 1 H), 7.89 (d, J = 8.8 Hz, 1H), 7.63 (s, 1H), 7 .27 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 9.2 Hz, 1H), 2.43 (s, 3H). LCMS (ESI, m / z): 271 [M+ H] + .

[0395] Step 4: 5-(2-methyl-4-nitrophenoxy)-2-methylpropional in EtOH (5.00 mL) ) Benzo[d]oxazole 6 (250.0 mg, 0.92 mmol, 1.00 equiv) and Pd / C (10% water content, 25.0 mg, 1 / 10 w / w) mixture under H2 atmosphere. Stirred at ambient temperature for 2 hours, then filtered. The filtrate was concentrated under reduced pressure to give 4-(benzo[a]-[(2-methyl-2-propanol)-4-yl]-2-propanol). [d]oxazol-5-yloxy)-3-methylaniline 7 (crude product, 210. 0 mg) as a yellow solid, which was used in the next step without further purification. CMS (ESI, m / z): 241 [M + H] + .

[0396] N-(4-(5-methoxy-[1,2,4]triazolo[1,5-a]pyridine-7-yl) (peroxy)-3-methylphenyl)-6-(1,2,3,6-tetrahydropyridine-4 Synthesis of (-yl)pyrido[3,2-d]pyrimidin-4-amine 14 [ka] Step 1: 4-amino-2-methylphenol 8 (3.2%) in DMSO (50 mL) To a stirred solution of potassium tert-butoxide (7.0 g, 61 After stirring at room temperature for 0.5 hours, 4,6-dichloropyridine- 2-Amine 9 (5.0 g, 30.7 mmol) was added. The reaction was heated to 80 °C under N2. After cooling to room temperature, the reaction mixture was poured into water (150 mL) and stirred for 18 hours. Extraction was performed with EtOAc (50 mL x 3). The combined organic layer was washed with brine (100 mL). The residue was purified by flash chromatography. (0-100% EtOAc in PE) to give 4-(4-amino-2-methyl- (phenoxy)-6-chloropyridin-2-amine 10 (4.9 g, 52.2% yield) was obtained by elution with hexane. Obtained as a colored solid. LCMS (ESI) (m / z): 250 [M+H] + .

[0397] Step 2: 4-(4-amino-2-methylphenoxy)-6 in DCM (20 mL) To a stirred solution of 10 (3.0 g, 12.0 mmol) of 1-chloropyridin-2-amine was added pyridine. 1.4 g, 18.0 mmol) and acetic anhydride (1.2 g, 12.0 mmol) were added to 0 The reaction was stirred at room temperature for 1 hour and then concentrated to dryness. Purification by column chromatography (0-33% EtOAc in PE) gave N-(4-( (2-amino-6-chloropyridin-4-yl)oxy)-3-methylphenyl)aceto Amide 11 (2.5 g, 71.3% yield) was obtained as a yellow oil. LCMS (ESI) m / z: 292 [M+H] + .

[0398] Step 3: N-(4-((2-amino-6-chloropyridine)) in EtOH (20 mL) (4-phenyl)oxy)-3-methylphenyl)acetamide 11 (2.5g, 8.6 To a solution of 1.5 mmol of dimethylformamide (DMF) was added 3.1 g (25.7 mmol). The mixture was degassed with N2 and stirred at 80 °C for 36 h. The reaction was concentrated to dryness. The residue was Purification by column chromatography (0–66% EtOAc in PE) gave (E)-N -(4-((2-chloro-6-(((dimethylamino)methylene)amino)pyridine-4 (-yl)oxy)-3-methylphenyl)acetamide 12 (2.5 g, 84.1% yield) ) was obtained as a yellow solid. LCMS ESI (m / z): 347 [M+H] + .

[0399] Step 4: (E)-N-(4-((2-chloro-6-(( (Dimethylamino)methylene)amino)pyridin-4-yl)oxy)-3-methylphenyl To a stirred solution of 12 (1.0 g, 2.9 mmol) of hydroxyl acetamide was added A mixture of amine-O-sulfonic acid (0.3 g, 3.0 mmol) and pyridine (0.3 g, 4.3 mmol) mol) was added at 0° C. The mixture was degassed with N2 and stirred at room temperature for 18 hours. The residue was dissolved in THF (20 mL) and trifluoroacetic anhydride (0. 7g, 3.5mmol) was added. The reaction was stirred at 40°C overnight and then washed with ice water (0. The mixture was quenched with 5 mL of ethyl acetate and concentrated to dryness. The residue was purified by flash chromatography (PE 0-100% EtOAc) to give N-(4-((5-chloro-[1,2,4 ]triazolo[1,5-a]pyridin-7-yl)oxy)-3-methylphenyl)acetate The amide 13 (150 mg, 12.3% yield) was obtained as a yellow oil. LCMS ESI ( m / z): 317 [M+H] + .

[0400] Step 5: N-(4-((5-chloro-[1,2,4]trimethylsilyl)methyl)-N-(4-((5-chloro-[1,2,4]trimethylsilyl)methyl ...methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl)methyl) Azolo[1,5-a]pyridin-7-yl)oxy)-3-methylphenyl)acetamido To a stirred solution of 13 (150 mg, 0.5 mmol) was added concentrated HCl (0.2 mL, 12 N). was added. The reaction was stirred at 80° C. for 18 hours. The reaction was concentrated and analyzed by preparative TLC (DCM :MeOH=10:1) to give 4-((5-chloro-[1,2,4]triazoline). (1,5-a)pyridin-7-yl)oxy)-3-methylaniline 14 (80 mg, 61.5% yield) was obtained as a yellow solid. LCMS ESI (m / z): 275 [M+ H] + .

[0401] 4-((5-methoxy-[1,2,4]triazolo[1,5-a]pyridin-7-yl) Synthesis of (hydroxy)-3-methylaniline 16 [ka] Step 1: N-[4-({5-chloro-[1,2,4]triazolo[1,5-a]pi Lysin-7-yl}oxy)-3-methylphenyl]acetamide 13 (150 mg, To a solution of 0.5 mmol) in MeOH (5.0 mL), sodium methoxide (256 m g, 1.4 mmol) was added. The reaction was stirred at 70° C. for 4 hours. After cooling to room temperature, The reaction was quenched by the addition of saturated aqueous NH4Cl. The reaction mixture was diluted with EA (2 x 1 The combined extracts were washed with water (5 mL), brine (5 mL), and Water, dried over Na2SO4, filtered and concentrated to give crude N-[4-({5-methoxy-[ 1,2,4]triazolo[1,5-a]pyridin-7-yl}oxy)-3-methylphen The residue was subjected to the following steps: Used directly in step 2. LCMS ESI (m / z): 313 [M+H] + .

[0402] Step 2: N-[4-({5-methoxy-[1,2,4]triazolo[1,5-a] Pyridin-7-yl}oxy)-3-methylphenyl]acetamide 15 (140 mg To a solution of (0.5 mmol) in MeOH (5.0 mL) was added concentrated HCl (1.0 mL). The reaction was stirred at 70 °C overnight. After cooling to 0 °C, the reaction mixture was washed with aqueous NH The residue was neutralized and then concentrated under reduced pressure. This was further purified to give 4-((5-methoxy-[1,2,4]triazolo[1,5-a]pyridin (7-phenyl)oxy)-3-methylaniline 16 (42 mg, 34.7%) was added to a pale yellow Obtained as a solid. LCMS (ESI) m / z: 271 [M + H]+ .

[0403] 3-methyl-4-({5-methyl-[1,2,4]triazolo[1,5-a]pyridine- Synthesis of (7-yl)oxyaniline 26 [ka] Step 1: 2-Methyl-4-nitrophenol 17 (2. To a stirred solution of NaH (0.71 g, 17.7 mmol, mineral (60% in oil) was added under N2 at 0°C. After stirring at 0°C for 30 minutes, 2,6-dibromo Dissolve 4-nitropyridine 18 (5.0 g, 17.7 mmol) in DMF (30 mL). The solution was added at 0° C. The reaction was stirred at 70° C. overnight and then saturated NH4Cl (10 mL The mixture was quenched with ethyl acetate (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic solution was diluted with Na The residue was purified by silica gel chromatography (PE:Et OAc=5:1) to give 2,6-dibromo-4-(2-methyl-4-nitrophenyl)- (Phenoxy)pyridine 19 (4.4 g, 48.6% yield) was obtained as a yellow solid. S (ESI) m / z: 387 / 389 / 391 [M+H] + .

[0404] Step 2: 2,6-dibromo-4-(2-methyl-4-methyl-2-methylpropional) in dioxane (100 mL) -nitrophenoxy)pyridine 19 (4.40 g, 8.66 mmol) and diphenyl To a stirred solution of methanimine 20 (1.5 mL, 8.66 mmol) was added xantphos (1 .0g, 1.73mmol), Pd2(dba)3(0.79g, 0.87mmol), and Cs2CO3 (5.64 g, 17.3 mmol) were added at 25 °C. After stirring at 0°C for 4 hours, LCMS showed that the reaction had progressed well. To the solution was added HCl (26 mL, 1 M) at 25° C. The reaction was stirred at 25° C. for 1 hour. Then, NaHCO3 solution was added to adjust the pH to above 7. The mixture was then The combined organic solution was dried over Na2SO4 and extracted with tOAc (100 mL x 2). The residue was purified by silica gel chromatography (PE: EtOAc = 3:1). It was further purified to give 6-bromo-4-(2-methyl-4-nitrophenoxy)pyridine-2- Amine 21 (1.21 g, 43.1% yield) was obtained as a yellow solid. LCMS (E SI) m / z: 324 / 326 [M+H] + .

[0405] Step 3: 6-Bromo-4-(2-methyl-4-nitrophenyl)-2-(4-bromo-2-methyl-4-nitrophenyl)-2-(2-bromo-4-nitrophenyl)-2-( ... To a stirred solution of (phenoxy)pyridin-2-amine 21 (1.21 g, 3.74 mmol) Then, DMF-DMA (0.58 g, 4.86 mmol) was added at 25° C. The reaction mixture was stirred for 80 The mixture was stirred at °C overnight. LCMS showed that the reaction had proceeded well. The reaction mixture was then Concentration gave the crude product (Z)-N'-[6-bromo-4-(2-methyl-4-nitrophenyl)- N,N-dimethylmethylimidamide 22 (1.42 g, 80.2% yield) as a brown oil. LCMS (ESI) m / z: 379 / 3 81 [M+H] + .

[0406] Step 4: (Z)-N'-[6-bromo-4-(2- Methyl-4-nitrophenoxy)pyridin-2-yl]-N,N-dimethylmethanimide To a stirred solution of amide 22 (1.42 g, 3.75 mmol) was added hydroxylamine HCl. 1 salt (0.29 g, 4.12 mmol) was added at 25°C. After stirring at 80°C for 1 hour, LCMS showed the reaction had proceeded well. The mixture was diluted with DCM (60 mL). The separated organic solution was dried over Na2SO4 and washed with water (20 mL). Concentration gave the crude product (Z)-N'-[6-bromo-4-(2-methyl-4-nitrophenyl)- [N-hydroxy]pyridin-2-yl]-N-hydroxymethanimidamide 23 (1.38g) , 70.5% yield) as a yellow solid. LCMS (ESI) m / z: 367 / 3 69 [M+H] + .

[0407] Step 5: (Z)-N'-[6-bromo-4-(2-methyl)-2-propanol] in THF (20 mL) -4-nitrophenoxy)pyridin-2-yl]-N-hydroxymethanimidamide To a stirred solution of 23 (1.38 g, 3.759 mmol) was added trifluoroacetic anhydride (0. After stirring overnight at 40°C under N2, L CMS showed that the reaction had proceeded well. NaHCO3 solution was added to the reaction mixture, and The pH was adjusted to above 7. The mixture was then extracted with EtOAc (20 mL x 2) and The residue was purified by silica gel chromatography (PE:Et OAc=2:1) ​​to give 5-bromo-7-(2-methyl-4-nitrophenoxy) CI)-[1,2,4]triazolo[1,5-a]pyridine 24 (300 mg, 22.9 % yield) was obtained as a yellow solid. LCMS (ESI) m / z: 349 / 351 [M+ H] + .

[0408] Step 6: 5-Bromo-7-( ... 2-Methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridin 24 (300 mg, 0.86 mmol) and methylboronic acid (61.7 mg, 1.0 To a stirred solution of Pd(dppf)Cl2 (126 mg, 0.17 mmol) and K2CO3 (238 mg, 1.72 mmol) were added at room temperature. The reaction was then cooled to room temperature under a N2 atmosphere. The reaction was degassed under air three times and stirred at 80° C. overnight. The reaction was cooled to room temperature and diluted with EtOAc (25 ml). The organic solution was washed with brine (25 mL) and dried over Na2SO4. The crude product, 5-methyl-7-(2-methyl-4-nitrophenoxy)-[ 1,2,4]Triazolo[1,5-a]pyridine 25 (244 mg, 80.0% yield) was obtained as a black solid. LCMS (ESI) m / z: 285 [M+H] + .

[0409] Step 7: 5-methyl-7-(2-methyl-2-methylpropional) in EtOH (5 mL) and water (1 mL) -4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine 25( A mixture of iron powder (479 mg, 8.58 mmol) and iron powder (244 mg, 0.86 mmol) and NH4Cl (459 mg, 8.58 mmol) were added. The mixture was heated at 80°C for 2 The mixture was then immediately filtered and concentrated. The residue was The product was purified by column chromatography (PE:EA=0:1) to give 3-methyl-4-({5 -methyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl}oxy)aniline Phosphorus 26 (133 mg, 61.0% yield) was obtained as a yellow solid. LCMS (ESI ) m / z: 255 [M+H] + .

[0410] 4-...

Claims

1. below: 【Chemical 1】 1. A compound represented by a formula selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

2. The compound has the formula 【Chemistry 2】 10. The compound of claim 1, wherein the compound is:

3. The compound has the formula 【Chemistry 3】 10. The compound of claim 1, wherein the compound is:

4. The compound has the formula 【Chemistry 4】 10. The compound of claim 1, wherein the compound is:

5. The compound has the formula 【Chemistry 5】 10. The compound of claim 1, wherein the compound is:

6. The compound has the formula 【Chemistry 6】 10. The compound of claim 1, wherein the compound is:

7. The compound has the formula 【Chemistry 7】 10. The compound of claim 1, wherein the compound is:

8. The compound has the formula 【Chemistry 8】 10. The compound of claim 1, wherein the compound is:

9. The compound has the formula 【Chemistry 9】 10. The compound of claim 1, wherein the compound is:

10. The compound has the formula 【Chemistry 10】 10. The compound of claim 1, wherein the compound is:

11. The compound has the formula 【Chemistry 11】 10. The compound of claim 1, wherein the compound is:

12. The compound has the formula 【Chemistry 12】 10. The compound of claim 1, wherein the compound is:

13. The compound has the formula 【Chemistry 13】 2. The compound of claim 1, wherein:

14. The compound has the formula 【Chemistry 14】 2. The compound of claim 1, wherein:

15. The compound has the formula 【Chemistry 15】 2. The compound of claim 1, wherein:

16. The compound has the formula 【Chemistry 16】 2. The compound of claim 1, wherein:

17. The compound has the formula 【Chemistry 17】 2. The compound of claim 1, wherein:

18. The compound has the formula 【Chemistry 18】 2. The compound of claim 1, wherein:

19. The compound has the formula 【Chemistry 19】 2. The compound of claim 1, wherein:

20. The compound has the formula 【Chemistry 20】 2. The compound of claim 1, wherein:

21. The compound has the formula 【Chemical 21】 2. The compound of claim 1, wherein:

22. The compound has the formula 【Chemical 22】 2. The compound of claim 1, wherein:

23. The compound has the formula 【Chemical 23】 2. The compound of claim 1, wherein:

24. 10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

25. 14. A pharmaceutical composition comprising a compound of claim 2 or 13 and a pharmaceutically acceptable excipient.

26. 15. A pharmaceutical composition comprising a compound of claim 3 or 14 and a pharmaceutically acceptable excipient.

27. 16. A pharmaceutical composition comprising a compound of claim 4 or 15 and a pharmaceutically acceptable excipient.

28. 17. A pharmaceutical composition comprising a compound of claim 5 or 16 and a pharmaceutically acceptable excipient.

29. 20. A pharmaceutical composition comprising a compound of claim 6 or 17 and a pharmaceutically acceptable excipient.

30. 20. A pharmaceutical composition comprising a compound of claim 7 or 18 and a pharmaceutically acceptable excipient.

31. 20. A pharmaceutical composition comprising a compound of claim 8 or 19 and a pharmaceutically acceptable excipient.

32. 21. A pharmaceutical composition comprising a compound of claim 9 or 20 and a pharmaceutically acceptable excipient.

33. A pharmaceutical composition comprising a compound of claim 10 or 21 and a pharmaceutically acceptable excipient. 。

34. A pharmaceutical composition comprising a compound of claim 11 or 22 and a pharmaceutically acceptable excipient. 。

35. A pharmaceutical composition comprising a compound of claim 12 or 23 and a pharmaceutically acceptable excipient. 。

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