Heterocyclic compounds and their uses

Abstract

This disclosure relates to compounds of formula (I): [Formula 1] This invention relates to TIFF2026509176000504.tif33165, as well as its prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods of preparation thereof. The compounds disclosed herein are useful for modulating PARP1 activity and may be used in the treatment of disorders such as cancer in which PARP1 activity is involved.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority and interest to U.S. Provisional Patent Application No. 63 / 583,602, filed September 19, 2023, and U.S. Provisional Patent Application No. 63 / 486,236, filed February 21, 2023, both of which are incorporated herein by reference for all purposes. [Background technology]

[0002] The poly(ADP-ribose) polymerase (PARP) family of enzymes comprises 17 members, among which PARP1 plays a crucial role in the repair of damaged DNA. PARP1 functions by binding to single-strand breaks (SSBs) and catalyzing the formation of large branched chains of poly(ADP-ribose) (PAR) in an NAD+-dependent manner. This process, known as PARylation, recruits different DNA repair enzymes and promotes the release of PARP from DNA. All PARP inhibitors approved to date are NAD+ competitive inhibitors that compete with NAD+ for the PARP catalytic site. They are thought to function by blocking the enzymatic activity of PARP and preventing the release of PARP from damaged DNA (an effect known as PARP trapping). Inhibition of PARP leads to the accumulation of DNA SSBs and double-strand breaks (DSBs), as well as increased apoptosis.

[0003] Currently, there are four PARP inhibitors marketed in the United States that are approved for the treatment of BRCA-mutated breast and ovarian cancer. These inhibitors differ in their PARP scavenging efficiency. Homologous recombination (HR)-deficient tumor cells with harmful BRCA1 or BRCA2 mutations are particularly sensitive to PARP inhibitors.

[0004] Approved PARP inhibitors inhibit both the PARP1 and PARP2 enzymes. All of these first-generation PARP1 / 2 inhibitors have associated hematological toxicities, including neutropenia, anemia, and thrombocytopenia. These toxicities are thought to be largely mediated by PARP2 inhibition.

[0005] PARP inhibitors are being tested in combination with immunotherapies, chemotherapy drugs, and different targeted agents. Because the various toxicities associated with these drugs can be compounded when used in combination with PARP1 / 2 inhibitors, PARP inhibitors that minimize additional toxicity are desirable. Therefore, highly selective PARP1 inhibitors may be useful not only as monotherapy for certain cancers but also as part of combination therapy, fulfilling an unmet need for effective and more tolerable treatment for patients with cancer. [Overview of the project]

[0006] In some aspects, this disclosure relates to small-molecule, potent poly[ADP-ribose] polymerase 1 (PARP1) inhibitors designed for the treatment of cancer. It is hypothesized that PARP1-selective inhibitors offer improved therapeutic index and reduced toxicity compared to first-generation PARP inhibitors.

[0007] In some embodiments, this disclosure relates to compounds of formula (I):

[0008] [ka] or provide a pharmaceutically acceptable salt thereof, in the formula,

[0009] [ka] C 3-10 Cycloalkylene, C 6-10 These are arylenes, 3-10 member heterocycloalkylenes, or 5-10 member heteroarylenes. m is 0, 1, 2, 3, 4, or 5, each R a is independently halogen, -CN, -OH, -NH2, -O-(C 1-6 alkyl), -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, or two Rs a are combined to form oxo, wherein -O-(C 1-6 alkyl), -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, or -C 1-6 alkyl is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 haloalkyl, -O-C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)2, C 3-10 cycloalkyl, or 3- to 10-membered heterocycloalkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, and C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)2, C 3-10 cycloalkyl, or 3- to 10-membered heterocycloalkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, or two Rs aC 3-10 Cycloalkyl, C 6-10 Forms an aryl, a 3-10 membered heterocycloalkyl, or a 5-10 membered heteroaryl, in which C 3-10 Cycloalkyl, C 6-10 An aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. X is -C(=O)-, -S(=O)²-, Y represents a bond, -O-, -S-, -NH-, or C 1-6 It is alkylene, C 1-6 Alkylenes are one or more oxo, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, or the atom(s) to which they are bonded, is combined with C 3-10 Two C atoms form a cycloalkyl group. 1-6 Optionally substituted with alkyl groups, R 1 H, halogen, -CN, -OH, -NH2, -C 1-6 Alkyl, -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 2-6 Alkyl), C 3-10 Cycloalkyl, C 6-10 The aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, where -C 1-6 Alkyl, -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), or -N(C 1-6 Alkyl)2 is one or more oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Optionally substituted with a cycloalkyl group, or a 3-10 member heterocycloalkyl group, or a 5-10 member heteroaryl group, C 3-10Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may contain one or more oxo, deuterium, halogen, -CN, -OH, -NH2, or C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl, or 3-10 member heterocycloalkyl, C 6-10 Optionally substituted with aryl or 5-10 member heteroaryl, L is a bond, -O-, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, -N(C3-6 heterocycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C3-6 cycloalkylene, or C3-6 heterocycloalkylene, where -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, -N(C3-6 heterocycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylenes, C3-6 cycloalkylenes, or C3-6 heterocycloalkylenes are optionally substituted with one or more oxo, deuterium, halogens, -CN, -OH, or -NH2 groups. R 2 C 3-10 Cycloalkylene, C 6-10 Arylene, 3-10 member heterocycloalkylene, or 5-10 member heteroarylene, where C 3-10 Cycloalkylene, C 6-10 Arylene, 3-10 member heterocycloalkylene, or 5-10 member heteroarylene contains one or more R b It is arbitrarily replaced with, Each R b These are independently halogen, -CN, -OH, -NH2, -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C1-6 (alkyl)2, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 is aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, or two Rs b combine to form oxo, wherein, -O-(C 1-6 alkyl), -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, C 1-6 alkyl is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 haloalkyl, -O-C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)2, C 3-10 cycloalkyl, or 3- to 10-membered heterocycloalkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, optionally substituted, and C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-6 alkyl, -NH-C 1-6 alkyl, -N(C 1-6 alkyl)2, C 3-10 cycloalkyl, or 3- to 10-membered heterocycloalkyl, C 6-10 aryl, or 5- to 10-membered heteroaryl, optionally substituted, or two Rs b [[ID=5)9]]together with the intervening atom to which they are attached, form C 3-10 cycloalkyl, C 6-10 aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl, wherein, C 3-10 cycloalkyl, C 6-10An aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. L 1 The bonds are -O-, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, -N(C3-6 heterocycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C3-6 cycloalkylene, or C3-6 heterocycloalkylene, where -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, -N(C3-6 heterocycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C3-6 cycloalkylene, or C3-6 heterocycloalkylene may be optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2 groups. R 3 C 3-10 Cycloalkyl, C 6-10 The aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, where C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may have one or more R c It is arbitrarily replaced with, Each R c These are independently halogen, -CN, -OH, -NH2, -C(=O)-H, -C(=O)-NH2, -NH-C(=O)-H, -NH-(C=O)-NH2, -C(=O)-CN, -NH-C(=O)-CN, -C(=O)-NH-CN, -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -C(=O)-(C 1-6 Alkyl), -C(=O)-NH-(C 1-6 Alkyl), -NH-C(=O)-(C 1-6 Alkyl), -NH-(C=O)-NH-(C1-6 Alkyl), -NH-(C=O)-O-(C 1-6 Alkyl), -C(=O)-NH-(C 3-10 Cycloalkyl), -C(=O)-NH-(3-10 member heterocycloalkyl), C 1-6 Alkyl, C 2-6 Alkenil, C 、2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 It is either an aryl, a 3-10 member heterocycloalkyl, or a 5-10 member heteroaryl, or two R c These combine to form an oxo, in the formula -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2,-C(=O)-(C 1-6 Alkyl),-C(=O)-NH-(C 1-6 Alkyl),-NH-C(=O)-(C 1-6 Alkyl),-NH-(C=O)-NH-(C 1-6 Alkyl), or -NH-(C=O)-O-(C 1-6 Alkyl) is one or more oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl or 3-10 member heterocycloalkyl, C 6-10 It can be optionally substituted with an aryl or a 5- to 10-membered heteroaryl, and -C(=O)-NH-(C 3-10 Cycloalkyl), -C(=O)-NH-(3-10 member heterocycloalkyl), C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 An aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl is one or more oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl, or 3-10 member heterocycloalkyl, C 6-10 Optionally substituted with an aryl or 5-10 member heteroaryl, or two R's c C 3-10 Cycloalkyl, C 6-10 Forms an aryl, a 3-10 membered heterocycloalkyl, or a 5-10 membered heteroaryl, in which C 3-10 Cycloalkyl, C 6-10 An aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. or one R b and one R c C 3-10 Cycloalkyl, C 6-10 Forms an aryl, a 3-10 membered heterocycloalkyl, or a 5-10 membered heteroaryl, in which C 3-10 Cycloalkyl, C 6-10 One or more aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl compounds are present in R bc It is arbitrarily replaced with, Each R bc These are independently oxo, deuterium, halogen, -CN, -OH, -NH2, -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 The aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, where -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 An aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2 groups.

[0010] In some embodiments, the present disclosure provides compounds that can be obtained by, or are obtained by, methods for preparing such compounds as described herein (e.g., methods comprising one or more steps described in schemes 1 to 12).

[0011] In some embodiments, the Disclosure provides a pharmaceutical composition comprising a compound of the Disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0012] In some embodiments, the present disclosure provides intermediates described herein that are suitable for use in methods for preparing the compounds described herein (for example, the intermediate is selected from the intermediates described in Examples 1 to 55).

[0013] In some embodiments, the Disclosure provides a method for modulating PARP1 activity (e.g., in vitro or in vivo) by contacting cells with an effective amount of the compound of the Disclosure or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the Disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject for which treatment or prevention of the disease or disorder disclosed herein is required, the method comprising administering to the subject a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0015] In some embodiments, the Disclosure provides a method for treating a disease or disorder in a subject requiring treatment of a disease or disorder as disclosed herein, comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as disclosed herein.

[0016] In some embodiments, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in the modulation of PARP1 activity (e.g., in vitro or in vivo).

[0017] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment or prevention of diseases or disorders disclosed herein.

[0018] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment of diseases or disorders disclosed herein.

[0019] In some embodiments, the present disclosure provides the use of the compounds of the present disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for modulating PARP1 activity (e.g., in vitro or in vivo).

[0020] In some embodiments, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0021] In some embodiments, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0022] In some embodiments, the Disclosure provides a method for preparing the compounds of the Disclosure.

[0023] In some embodiments, the present disclosure provides a method for preparing a compound, comprising one or more steps described herein.

[0024] In some embodiments, the present disclosure provides compounds having any one of the structures shown in Table 1, or pharmaceutically acceptable salts thereof.

[0025] In some embodiments, the present disclosure provides pharmaceutical compositions comprising compounds of formulas I to XLIV and pharmaceutically acceptable excipients.

[0026] In some embodiments, this disclosure relates to a method for treating cancer in a person requiring cancer treatment using a pharmaceutical composition comprising formulas I to XLIV or the compounds in Table 1, or a pharmaceutical composition comprising formulas I to XLIV or the compounds in Table 1.

[0027] In some embodiments, this disclosure relates to a method for treating cancer with a BRCAness phenotype, comprising administering to a subject requiring treatment for cancer with a BRCAness phenotype a compound of formula I to XLIV or one of the compounds in Table 1.

[0028] In some embodiments, the present disclosure relates to a method for treating breast cancer, ovarian cancer, prostate cancer, or pancreatic cancer in subjects requiring treatment for breast cancer, ovarian cancer, prostate cancer, or pancreatic cancer, and includes administering formulas I to XLIV or compounds listed in Table 1 to the subjects.

[0029] In some embodiments, the present disclosure relates to a method for treating HR-deficient cancer in subjects requiring treatment for HR-deficient cancer, which includes administering formulas I to XLIV or compounds listed in Table 1 to the subjects.

[0030] In some embodiments, the present disclosure relates to a method for treating BRCA1 or BRCA2 mutated cancer in subjects requiring treatment for BRCA1 or BRCA2 mutated cancer, comprising administering to the subjects formulas I to XLIV or compounds listed in Table 1.

[0031] In some embodiments, the present disclosure provides a method for treating HR-deficient cancer, BRCA1-mutated cancer, or BRCA2-mutated cancer, or cancer having a BRCAness phenotype in a subject, the method comprising administering an effective amount of formulas I to XLIV or the compounds in Table 1, or a pharmaceutical composition thereof, to a subject in need.

[0032] In some embodiments, the cancer having the BRCAness phenotype is selected from breast cancer, ovarian cancer, prostate cancer, or pancreatic cancer.

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in which this disclosure pertains. In this specification, singular nouns also include plural nouns unless the context explicitly indicates otherwise. When performing or testing the disclosures, methods and materials similar to or equivalent to those described herein may be used, but preferred methods and materials are described below. All publications, patent applications, patents, and other references referenced herein are incorporated by reference. References cited herein are not considered prior art to the claimed inventions. In case of any conflict, this specification shall prevail, including definitions. Furthermore, materials, methods, and examples are illustrative and not intended to limit the scope. In case of any conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure shall prevail.

[0034] Other features and advantages of this disclosure will become apparent from the following "Modes for Carrying Out the Invention" and "Claims". [Modes for carrying out the invention]

[0035] This disclosure relates to heterocyclic derivatives, prodrugs, and pharmaceutically acceptable salts thereof, which can modulate PARP1 activity and are therefore useful in methods of treating human or animal bodies. This disclosure also relates to processes for the preparation of these compounds, pharmaceutical compositions containing them, and their use in the treatment of disorders involving PARP1.

[0036] definition Unless otherwise specified, the following terms used in this specification and in the claims shall have the meanings set forth below.

[0037] While we do not wish to be limited by this statement, various options for the variables are described herein, but it should be understood that this disclosure is intended to encompass operable embodiments having combinations of options. This disclosure may be interpreted as excluding non-operable embodiments resulting from specific combinations of options. For example, variables L, R 2 , and L 1 Various options are described herein, but this disclosure is limited to the variables L, R 2 , and L 1 This may be interpreted as excluding structures for unmanipulable compounds caused by specific combinations of (e.g., L, R) 2 , and L 1 (If each of them is -O-).

[0038] As used herein, “alkyl,” “C1, C2, C3, C4, C5 or C6 alkyl,” or “C1-C6 alkyl” is intended to include a linear saturated aliphatic hydrocarbon group of C1, C2, C3, C4, C5, or C6 and a branched saturated aliphatic hydrocarbon group of C3, C4, C5, or C6. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyls include, but are not limited to, moieties having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, the linear or branched alkyl has 6 or fewer carbon atoms (e.g., C1-C6 for linear, C3-C6 for branched), and in other embodiments, the linear or branched alkyl has 4 or fewer carbon atoms.

[0039] As used herein, the term “optionally substituted alkyl” refers to an unsubstituted alkyl or an alkyl having a specified substituent that replaces one or more hydrogen atoms on one or more carbons of a hydrocarbon skeleton. Examples of such substituents include alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0040] As used herein, the term “alkylene” refers to an alkyl group in which two hydrogens are removed to form a divalent radical. When a range or number of carbons is given to a particular “alkylene” group, the range or number is understood to refer to the range or number of carbons contained in a divalent carbon linear chain. The “alkylene” group may or may not be substituted with one or more substituents as described herein. Examples of unsubstituted divalent alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (CH2CH2CH2CH2CH2CH2-).

[0041] As used herein, the term "alkenyl" includes unsubstituted aliphatic groups that are similar in length to the alkyl groups and contain at least one double bond, although substitution is possible. For example, the term "alkenyl" includes linear alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In certain embodiments, linear or branched alkyl groups have six or fewer carbon atoms in their skeleton (e.g., C2-C6 for linear groups, C3-C6 for branched groups). The term "C2-C6" includes alkenyl groups containing two to six carbon atoms. The term "C3-C6" includes alkenyl groups containing three to six carbon atoms.

[0042] As used herein, the term “optionally substituted alkenyl” refers to an unsubstituted alkenyl or an alkenyl having a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of a hydrocarbon main chain. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0043] As used herein, the term “alkenylene” refers to an alkyl group in which two hydrogens are removed to form a divalent radical. When a range or number of carbons is given to a particular “alkylene” group, the range or number is understood to refer to the range or number of carbons contained in a divalent carbon linear chain. The “alkenylene” group may or may not be substituted with one or more substituents as described herein. Examples of unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-).

[0044] As used herein, the term "alkynyl" includes unsubstituted aliphatic groups that are similar in length to the alkyl groups and contain at least one triple bond, although substitution is possible. For example, "alkynyl" includes linear alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, noninyl, desynyl) and branched alkynyl groups. In certain embodiments, linear or branched alkynyl groups have six or fewer carbon atoms in their skeleton (e.g., C2-C6 for linear groups, C3-C6 for branched groups). The term "C2-C6" includes alkynyl groups containing two to six carbon atoms. The term "C3-C6" includes alkynyl groups containing three to six carbon atoms. As used herein, "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to include a C2, C3, C4, C5, or C6 chain (linear or branched) diunsaturated aliphatic hydrocarbon group. For example, a C2-C6 alkenylene linker is intended to include C2, C3, C4, C5, and C6 alkenylene linker groups.

[0045] As used herein, the term “alkynylene” refers to an alkyl group in which two hydrogens are removed to form a divalent radical. When a range or number of carbons is given to a particular “alkynylene” group, the range or number is understood to refer to the range or number of carbons contained in a divalent carbon linear chain. The “alkynylene” group may be substituted or unsubstituted with one or more substituents as described herein. Examples of divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene and substituted or unsubstituted propynylene.

[0046] As used herein, the term “optionally substituted alkynyl” refers to an unsubstituted alkynyl or an alkynyl having specified substituents that replace one or more hydrogen atoms on carbons of one or more hydrocarbon main chains. Examples of such substituents include alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0047] Other optionally substituted moieties (such as optionally substituted cycloalkyl, haloalkoxy, heterocycloalkyl, aryl, heterocyclyl, or heteroaryl moieties) include both unsubstituted moieties and moieties having one or more specified substituents. For example, substituted heterocycloalkyls include those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0048] As used herein, the term "cycloalkyl" refers to a group of 3 to 30 carbon atoms (e.g., C3-C3-C3). 12 , C3-C 10 This refers to saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused ring, crosslinked ring, or spirocycle) systems having C3-C8 rings. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyls, only one of the cycloalkyl rings must be non-aromatic.

[0049] As used herein, the term "cycloalkylene" refers to a cycloalkyl group from which two hydrogens are removed, resulting in a divalent radical. It is understood that, prior to removal, the two hydrogens may be bonded to the same or different atoms within the cycloalkyl group.

[0050] As used herein, the term "heterocycloalkyl" means a saturated or partially unsaturated 3- to 8-membered monocyclic, 7- to 12-membered bicyclic (condensed, bridged, or spiro-ring), or 11- to 14-membered tricyclic (condensed, bridged, or spiro-ring) ring system having one or more heteroatoms (e.g., O, N, S, P, or Se), for example, 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or for example, 1, 2, 3, 4, 5, or 6 heteroatoms (unless otherwise specified, independently selected from the group consisting of nitrogen, oxygen, and sulfur).Examples of heterocycloalkyl groups, though not limited to them, include piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxyranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, and 1,4-dia Zepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]yl, 7 'H-Spiro[cyclohexane-1,5'-Flo[3,4-b]pyridine]-yl, 3'H-Spiro[cyclohexane-1,1'-Flo[3,4-c]pyridine]-yl, 3-Azabicyclo[3.1.0]hexanyl, 3-Azabicyclo[3.1.0]hexane-3-yl, 1,4,5,6-Tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-Hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-Tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8 Examples include tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxazaspiro[3.4]octanyl, 2-oxazaspiro[3.4]octan-6-yl, and 5,6-dihydro-4H-cyclopenta[b]thiophenyl.In the case of polycyclic heterocycloalkyls, only one of the rings in the heterocycloalkyl must be non-aromatic (for example, 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0051] As used herein, the term “heterocycloalkylene” refers to a cycloalkyl group from which two hydrogens are removed, resulting in a divalent radical. It is understood that, prior to removal, the two hydrogens may be bonded to the same or different atoms within the cycloalkyl group.

[0052] If a variable has two bonds to the remainder of a compound's formula, it is understood that the two bonds can be on the same atom or different atoms of the variable. For example, if a variable (e.g., variable X) is a cycloalkyl or heterocycloalkyl and has two bonds to the remainder of a compound's formula, it is understood that the two bonds can be on the same atom or different atoms of the cycloalkyl or heterocycloalkyl.

[0053] As used herein, the term “aryl” includes aromatic groups containing a “conjugate,” or polycyclic systems having one or more aromatic rings, without heteroatoms in the ring structure. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl. For example, aryl is phenyl.

[0054] As used herein, the term "arylene" refers to an aryl group from which two hydrogen atoms are removed, resulting in a divalent radical.

[0055] As used herein, the term “heteroaryl” is intended to include stable 5-membered, 6-membered, or 7-membered monocyclic rings or 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered bicyclic aromatic heterocyclic rings. It is intended to consist of a carbon atom and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, or to include nitrogen, oxygen, and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR (wherein R is H or another defined substituent)). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N → O and S(O)). p (wherein p=1 or 2). It should be noted that the total number of S and O atoms in the aromatic heterocyclic compound is 1 or less. Examples of heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, and pyrimidine. Heteroaryl groups can also be condensed or crosslinked with non-aromatic alicyclic or heterocyclic rings to form polycyclic systems (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl). In some embodiments, the heteroaryl is thiophenyl or benzothiophenyl. In some embodiments, the heteroaryl is thiophenyl. In some embodiments, the heteroaryl is benzothiophenyl.

[0056] As used herein, the term "heteroarylene" refers to a heteroaryl group in which two hydrogens are removed, resulting in a divalent radical.

[0057] Furthermore, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl groups, such as tricyclic and bicyclic groups, including naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, and indoridine.

[0058] A cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring may have substituents such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, Alkylthiocarbonyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties may be substituted. The aryl and heteroaryl groups may also be condensed or crosslinked with nonaromatic alicyclic or heterocyclic rings to form polycyclic systems (e.g., tetralin, methylenedioxyphenyl, e.g., benzo[d][1,3]dioxol-5-yl).

[0059] As used herein, the term “substituted” means that any one or more hydrogen atoms on a given atom are replaced with one or more of a group selected from the given groups, provided that the substitution does not exceed the normal valence of the given atom and the result is a stable compound. If the substituent is oxo or keto (i.e., =O), two hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. A ring double bond, as used herein, is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). “Stable compound” and “stable structure” mean a compound that is robust enough to be isolated from a reaction mixture to a useful purity and formulated into an effective therapeutic agent.

[0060] If the bond to a substituent is shown to cross a bond connecting two atoms in a ring, such substituent may be bonded to any atom in the ring. If a substituent is enumerated without indicating the atom to which it will be bonded in the rest of the compound of a given formula, such substituent may be bonded via any atom in such formula. A combination of substituents and / or variables is permissible only if such a combination results in a stable compound.

[0061] When any variable (e.g., R) appears multiple times in any component or formula of a compound, its definition in each appearance is independent of its definition in any other appearance. Therefore, for example, if a group is indicated as being substituted with 0 to 2 R moieties, that group may be arbitrarily substituted with up to 2 R moieties, and R is selected independently of the definition of R for each appearance. Furthermore, combinations of substituents and / or variable elements are permitted, but only if such combinations result in a stable compound.

[0062] As used herein, the terms "hydroxy" or "hydroxyl" refer to -OH or -O - It contains a group having a group.

[0063] As used herein, the terms "halo" or "halogen" refer to fluoro, chloro, bromo, and iodine.

[0064] The terms "haloalkyl" or "haloalkoxyl" refer to alkyl or alkoxyl molecules substituted with one or more halogen atoms.

[0065] As used herein, the term “optionally substituted haloalkyl” refers to an unsubstituted haloalkyl having specified substituents that replace one or more hydrogen atoms on carbon atoms of one or more hydrocarbon main chains. Examples of such substituents include alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0066] As used herein, the terms "alkoxy" or "alkoxyl" include substituted and unsubstituted alkyl groups, alkenyl groups, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy group may be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphoric acid, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0067] As used herein, "one or more of A, B, or C," "one or more A, B, or C," "one or more of A, B, and C," "one or more A, B, and C," "selected from the group consisting of A, B, and C," and "selected from A, B, and C" are used interchangeably and all refer to a selection from the group consisting of A, B, and / or C, i.e., one or more A's, one or more B's, one or more C's, or any combination thereof, unless otherwise indicated.

[0068] It should be understood that this disclosure provides methods for synthesizing any of the compounds of the formulas described herein. This disclosure also provides detailed methods for synthesizing various disclosed compounds of this disclosure according to the schemes shown in the following schemes and examples.

[0069] Throughout this specification, where a composition is described as having, containing, or containing certain components, it should be understood that the composition is also intended to be essentially composed of or consisting of the listed components. Similarly, where a method or process is described as having, containing, or containing certain process steps, this process is also intended to be essentially composed of or consisting of the listed processing steps. Furthermore, it should be understood that the order of steps for performing a particular action is not important, as long as the invention is operable. Moreover, two or more steps or actions may be performed simultaneously.

[0070] It should be understood that the synthetic processes described herein are accommodating a wide variety of functional groups, and therefore, a variety of substituted starting materials can be used. These processes generally provide the desired final compound at or near the end of the overall process, but in certain cases, it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

[0071] It should be understood that the compounds of this disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or readily prepared intermediates, using standard synthetic methods and procedures that are known to those skilled in the art or will become apparent to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and the transformation and manipulation of functional groups can be obtained from relevant scientific literature or standard textbooks in the art. Without limiting itself to any one or more of these sources, Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) (incorporated herein by reference) are useful and well-known reference textbooks for organic synthesis known to those skilled in the art.

[0072] Those skilled in the art will note that the order of certain steps, such as the introduction and removal of protecting groups, may be altered during the reaction procedures and synthetic schemes described herein. Those skilled in the art will recognize that certain groups may require protection from reaction conditions through the use of protecting groups. Protecting groups may also be used to distinguish similar functional groups within a molecule. A list of protecting groups, as well as methods for introducing and removing them, can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999.

[0073] Unless otherwise stated, any description of a method of treatment or prevention should be understood to include the use of compounds to provide treatment or prevention as described herein. Unless otherwise stated, any description of a method of treatment or prevention should be understood to include the use of compounds to prepare agents for treating or preventing such conditions. Treatment or prevention includes treatment or prevention of human or non-human animals, e.g., rodents and other disease models.

[0074] Unless otherwise stated, any description of a treatment method should be understood to include the use of compounds to provide treatment as described herein. Unless otherwise stated, any description of a treatment method should be understood to include the use of compounds to prepare drugs for treating such conditions. Treatments include the treatment of human or non-human animals, e.g., rodents and other disease models.

[0075] As used herein, the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is a mammal. Mammals may be, for example, humans or suitable non-human mammals, such as primates, mice, rats, dogs, cats, cattle, horses, goats, camels, sheep, or pigs. The subject may also be birds or poultry. In some embodiments, the subject is a human.

[0076] As used herein, the term “subjects in need of treatment” refers to subjects having a disease or subjects at high risk of developing a disease. Subjects in need may be subjects who have been previously diagnosed or identified as having one of the diseases or disorders disclosed herein. Subjects in need may also be subjects suffering from one of the diseases or disorders disclosed herein. Alternatively, subjects in need may be subjects at high risk of developing such a disease or disorder compared to the general population (i.e., subjects more likely to develop such a disorder compared to the general population). Subjects in need may have refractory or resistant diseases or disorders disclosed herein (i.e., diseases or disorders disclosed herein that do not respond to or have not yet responded to treatment). Subjects may exhibit resistance at the start of treatment or may develop resistance during treatment. In some embodiments, subjects in need have undergone and failed all known effective treatments for the diseases or disorders disclosed herein. In some embodiments, subjects in need have received at least one prior therapy.

[0077] As used herein, the terms “to treat, to treat” or “to treat, to treat” refer to the management and care of a patient aimed at combating a disease, condition, or disorder, and include the administration of the compounds disclosed herein, or their pharmaceutically acceptable salts, polymorphs, or solvates, to alleviate the symptoms or complications of a disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term “to treat” may also include the treatment of in vitro cell or animal models. It should be understood that references to “to treat, to treat” or “treatment, treatment” include the relief of established symptoms of a condition. Therefore, “treating” or “treating” a stage, disorder, or condition includes: (1) preventing or delaying the onset of the clinical symptoms of a stage, disorder, or condition in a person who is susceptible to or prone to the stage, disorder, or condition but has not yet experienced or exhibited any clinical or paraclinical symptoms of that stage, disorder, or condition; (2) inhibiting the stage, disorder, or condition, i.e., stopping, reducing, or delaying the onset or recurrence of the disease, or at least one of its clinical or paraclinical symptoms (in the case of conservative treatment); or (3) alleviating or reducing the disease, i.e., regressing the stage, disorder, or condition, or at least one of its clinical or paraclinical symptoms.

[0078] It should be understood that the compounds disclosed herein, or any pharmaceutically acceptable salts, polymorphs, or solvates thereof, may be used to prevent related diseases, conditions, or disorders, or to identify suitable candidates for such purposes.

[0079] As used herein, the terms “prevent,” “prevent,” or “protect against” mean reducing or eliminating the onset of symptoms or complications of such disease, condition, or disorder.

[0080] Those skilled in the art will understand that for a detailed description of the known or equivalent technologies discussed herein, general references may be found. These texts include Ausubel et al., *Current Protocols in Molecular Biology*, John Wiley and Sons, Inc. (2005); Sambrook et al., *Molecular Cloning*, A Laboratory Manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., *Current Protocols in Immunology*, John Wiley & Sons, NY; Enna et al., *Current Protocols in Pharmacology*, John Wiley & Sons, NY; and Fingl et al., *The Pharmacological Basis of Therapeutics* (1975), *Remington's Pharmaceutical Sciences*, Mack Publishing Co., Easton, PA, 18th edition (1990). Naturally, these texts may also be referenced when creating or using aspects of this disclosure.

[0081] It should be understood that this disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0082] As used herein, the term “pharmaceutical composition” refers to a formulation containing the compounds of the Disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is a bulk or unit dosage form. A unit dosage form is any variety of form, including, for example, capsules, IV bags, tablets, single pumps of aerosol inhalers, or vials. The amount of the active ingredient (e.g., formulations of the disclosed compound or its salts, hydrates, solvates, or isomers) in a unit dose of the composition is an effective amount and varies according to the specific treatment involved. Those skilled in the art will understand that it is sometimes necessary to modify the dosage depending on the patient’s age and condition. The dosage also depends on the route of administration. Various routes are intended, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrathoracic, intrathecal, and intranasal. Dosage forms for topical or transdermal administration of the compounds of the Disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or sprays.

[0083] As used herein, the term “pharmaceutically acceptable” means a compound, anion, cation, material, composition, carrier and / or dosage form that is suitable for use in contact with human and animal tissues, within reasonable medical judgment, and commensurate with a reasonable benefit / risk ratio, without excessive toxicity, irritation, allergic reaction, or other problems or complications.

[0084] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is generally safe, non-toxic, and useful in the preparation of a pharmaceutical composition that is not biologically or otherwise harmful, and includes excipients acceptable for veterinary and human pharmaceutical uses. As used herein and in the claims, “pharmaceutically acceptable excipient” includes both one and two or more such excipients.

[0085] It should be understood that the pharmaceutical compositions of this disclosure are formulated to suit their intended route of administration. Examples of routes of administration include parenteral administration, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may contain the following components: sterile diluents such as water for injection, physiological saline, non-volatile oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antimicrobial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates; and osmotic adjusters such as sodium chloride or dextrose. pH can be adjusted with an acid or base such as hydrochloric acid or sodium hydroxide. Parenteral preparations may be sealed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0086] It should be understood that the compounds or pharmaceutical compositions of this disclosure can be administered to subjects by many of the well-known methods currently used in chemotherapy. For example, the compounds of this disclosure may be injected into the bloodstream or body cavities, taken orally, or applied to the skin using a patch. The selected dose should be sufficient to constitute an effective treatment but should not be so high as to cause unacceptable side effects. The stage of the medical condition (e.g., the disease or disorder disclosed herein) and the patient's health condition should preferably be carefully monitored for a reasonable period during and after the treatment.

[0087] As used herein, the term "therapeutically effective dose" refers to the amount of an agent that treats, relieves, or prevents a confirmed disease or condition, or that exhibits a detectable therapeutic or inhibitory effect. This effect can be detected by any assay known in the art. The exact effective dose for a subject depends on the subject's weight, size, and health status, the nature and severity of the condition, and the therapeutic agent or combination of therapeutic agents selected for administration. A therapeutically effective dose for a given situation can be determined by experimentation within the scope of the clinician's skill and judgment.

[0088] As used herein, the term "therapeutic dose" refers to the amount of an agent that treats or induces remission of a confirmed disease or condition, or that exhibits a detectable therapeutic or inhibitory effect. This effect can be detected by any assay known in the art. The exact effective dose for a subject depends on the subject's weight, size, and health status, the nature and severity of the condition, and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutic dose for a given situation can be determined by experiment within the scope of the clinician's skill and judgment.

[0089] It should be understood that for any compound, the therapeutically effective dose can first be estimated, for example, in a cell culture assay of newly formed cells, or usually in animal models such as rats, mice, rabbits, dogs, or pigs. Furthermore, appropriate concentration ranges and routes of administration can be determined using animal models. Such information may then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity, e.g., ED 50 (Therapeutic dose effective for 50% of the population) and LD 50 The lethal dose (for 50% of the population) can be determined by standard pharmaceutical procedures for cell cultures or experimental animals. The dose-to-toxicity ratio is the therapeutic index, which is the LD50. 50 / ED 50This can be expressed as a ratio. Pharmaceutical compositions exhibiting a large therapeutic index are preferred. The dose may vary within this range depending on the dosage form used, the patient's sensitivity, and the route of administration.

[0090] Dosage and administration are adjusted to obtain a sufficient level of activator(s) or to maintain the desired effect. Factors to consider include the severity of the disease stage, the overall health status of the subject, the subject's age, weight, and sex, diet, time and frequency of administration, drug combination(s), response sensitivity, and tolerance / response to treatment. Long-acting pharmaceutical compositions may be administered every 3-4 days, weekly, or every 2 weeks, depending on the half-life and clearance rate of the particular formulation.

[0091] Pharmaceutical compositions containing the active compounds of this disclosure may be manufactured in a manner generally known, for example, by conventional mixing, dissolution, granulation, sugar-coated tablet manufacturing, polishing, emulsification, encapsulation, encapsulation, or lyophilization processes. The pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants, that facilitate the processing of the active compounds into pharmaceutically usable preparations. Naturally, the appropriate formulation depends on the chosen route of administration.

[0092] Suitable pharmaceutical compositions for injectable use include sterile aqueous solutions (if water-soluble) or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL® (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid enough to be easily injected. The composition must be stable under manufacturing and storage conditions and protected from contamination by microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), cyclodextrin, and suitable warming agents thereof. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, it is preferable to include isotonic agents, such as sugars, polyhydric alcohols, such as mannitol and sorbitol, and / or sodium chloride, in the composition. Sustained absorption of the injectable composition can be achieved by including absorption-delaying agents, such as aluminum monostearate and gelatin, in the composition.

[0093] Sterile injectable solutions can be prepared by incorporating the required amount of the active compound, along with one or a combination of the raw materials listed above as needed, into a suitable solvent, followed by filtration sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and other required components from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation methods are vacuum drying and freeze-drying, which yield a powder in which the active ingredient is combined with any additional desired components from its pre-sterile filtered solution.

[0094] Oral compositions generally contain an inert diluent or a pharmaceutically acceptable food-grade carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral administration, the active compound is formulated with excipients and used in the form of tablets, lozenges, capsules, or pouches. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which the compound in the fluid carrier is applied orally, rinsed, spat out, or swallowed. Pharmacologically compatible binders and / or auxiliary materials may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds of similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or stellite; fluidizers such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavoring.

[0095] When administered by inhalation, the compound is delivered in the form of an aerosol spray from a pressurized container or dispenser, including a suitable nebulizer, such as a gas like carbon dioxide, or a nebulizer.

[0096] Systemic administration may also be by mucosal or transdermal means. For mucosal or transdermal administration, a suitable penetrating agent is used in the formulation for the barrier to which penetration is to occur. Such penetrating agents are generally known in the art and include, for example, surfactants, bile salts, and fusidic acid derivatives for mucosal administration. Mucosal administration can be achieved through the use of nasal sprays, powders, or suppositories. For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams, as is generally known in the art.

[0097] The active compound can be prepared with a pharmaceutically acceptable carrier that protects the body from the rapid release of the compound, such as a sustained-release formulation including implants and microcapsule-encapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid may be used. The methods for preparing such formulations will be apparent to those skilled in the art. The materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (containing liposomes targeted to infected cells with monoclonal antibodies against viral antigens) may also be used as pharmaceutically acceptable carriers. These may be prepared by methods known to those skilled in the art, such as those taught in, for example, U.S. Patent No. 4,522,811.

[0098] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate oral or parenteral compositions into unit dosage forms. As used herein, unit dosage forms refer to physically separate units suitable as unitary dosages for treating a target, each unit containing a predetermined amount of the active compound calculated to produce the desired therapeutic effect in relation to the required pharmaceutical carrier. The specifications of the unit dosage forms in this disclosure are required by and directly depend on the characteristics inherent to the active compound and the specific therapeutic effect to be achieved.

[0099] In therapeutic use, the dosage of a pharmaceutical composition used in accordance with this disclosure will vary depending on the drug, the age, weight, and clinical condition of the recipient patient, as well as the experience and judgment of the clinician or physician administering the treatment, among other factors that may influence the selected dosage. Generally, the dosage should be sufficient to delay, preferably regress, and preferably result in a complete regression of the symptoms of the disease or disorder disclosed herein. The dosage may range from about 0.01 mg / kg per day to about 5000 mg / kg per day. An effective dose of a drug is the amount that produces an objectively identifiable improvement as observed by a clinician or other qualified observer. Improvement in survival and proliferation indicates regression. As used herein, the term “effective dosage” refers to the amount of the active compound that produces the desired biological effect in the subject or cells.

[0100] Please understand that the pharmaceutical composition may be included in the container, pack, or dispenser along with the instructions for administration.

[0101] Furthermore, with respect to the compounds of this disclosure that can form salts, it should be understood that all of these forms are also intended within the scope of the claimed disclosure.

[0102] As used herein, the term “pharmaceutically acceptable salt” means a derivative of a compound of the disclosed compound that is modified by producing an acidic or basic salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral inorganic salts of basic residues such as amines, and alkali organic salts of acidic residues such as carboxylic acids. Examples of pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic organic acids. For example, such conventional non-toxic salts include, but are not limited to, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonate, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolarsanic acid, hexylresorcinol, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, and isethioic acid. Examples include nic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinous acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and salts derived from inorganic and organic acids selected from commonly existing amino acids, such as glycine, alanine, phenylalanine, and arginine.

[0103] In some embodiments, pharmaceutically acceptable salts include sodium salts, potassium salts, calcium salts, magnesium salts, diethylamine salts, choline salts, meglumine salts, benzathine salts, trometamic acid salts, ammonia salts, arginine salts, or lysine salts.

[0104] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvate, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-octo-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, and muconic acid. The disclosure also includes salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when it coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, or N-methylglucamine. In salt form, it is understood that the ratio of the compound to the cation or anion of the salt may be 1:1, or any other ratio, such as 3:1, 2:1, 1:2, or 1:3.

[0105] All references to pharmaceutically acceptable salts should be understood to include the solubilated form (solvate) or crystalline form (polymorph) of the same salt as defined herein.

[0106] This compound, or a pharmaceutically acceptable salt thereof, may be administered orally, nasally, percutaneously, pulmonaryly, by inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrathoracically, intrathecally, and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of a particular route of administration.

[0107] The administration regimen utilizing the compound is selected according to various factors, including the patient's type, breed, age, weight, sex, and medical condition, the severity of the condition being treated, the route of administration, the patient's renal and hepatic function, and the specific compound or salt used. A physician or veterinarian with ordinary skill can easily determine and prescribe the effective dose of the drug needed to prevent, counteract, or halt the progression of the condition. A physician or veterinarian with ordinary skill can easily determine and prescribe the effective dose of the drug needed to counteract or halt the progression of the condition.

[0108] Techniques for formulation and administration of the compounds disclosed herein can be found in Remington: The Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and their pharmaceutically acceptable salts are used in combination with a pharmaceutically acceptable carrier or diluent in a pharmaceutical preparation. Suitable pharmaceutically acceptable carriers include inert solid extenders or diluents and sterile aqueous organic solutions. The compounds are present in such pharmaceutical compositions in an amount sufficient to provide a desired dose within the range described herein.

[0109] Unless otherwise indicated, all percentages and ratios used herein are in weight (w / w). Other features and advantages of this disclosure are evident from the various examples. The provided examples illustrate different components and methodologies useful for carrying out this disclosure. The examples do not limit the claimed disclosure. Based on this disclosure, those skilled in the art can identify and adopt other components and methodologies useful for practicing this disclosure.

[0110] In the synthetic schemes described herein, compounds may be depicted in one particular configuration for simplification. Such a particular configuration should not be construed as limiting this disclosure to one or another isomer, tautomer, positional isomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, positional isomers, or stereoisomers. However, it is understood that a given isomer, tautomer, positional isomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, positional isomer, or stereoisomer.

[0111] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document were specifically and individually indicated to be incorporated herein by reference. The references to publications and patent documents are not intended to acknowledge the relevant prior art and do not constitute any endorsement of their content or date. While the present invention has been described in writing, those skilled in the art will recognize that the invention can be implemented in various embodiments, and that the foregoing description and the following examples are illustrative and not intended to limit the scope of the following claims.

[0112] As used herein, the phrase "compounds of the disclosure" refers, both generally and specifically, to the compounds disclosed herein. Compounds of the Disclosure

[0113] In some embodiments, this disclosure relates to compounds of formula (I):

[0114] [ka] or provide a pharmaceutically acceptable salt thereof, in the formula,

[0115] [ka] C 3-10 Cycloalkylene, C 6-10These are arylenes, 3-10 member heterocycloalkylenes, or 5-10 member heteroarylenes. m is 0, 1, 2, 3, 4, or 5. Each R a These are independently halogen, -CN, -OH, -NH2, -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 It is either an aryl, a 3-10 member heterocycloalkyl, or a 5-10 member heteroaryl, or two R a These combine to form an oxo, in the formula -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, or -C 1-6 Alkyl is one or more oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl, or 3-10 member heterocycloalkyl, C 6-10 Optionally substituted with aryl or 5-10 member heteroaryl, and C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 An aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl is one or more oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl, or 3-10 member heterocycloalkyl, C 6-10Optionally substituted with an aryl or 5-10 member heteroaryl, or two R's a C 3-10 Cycloalkyl, C 6-10 Forms an aryl, a 3-10 membered heterocycloalkyl, or a 5-10 membered heteroaryl, in which C 3-10 Cycloalkyl, C 6-10 An aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. X is -C(=O)-, -S(=O)²-, Y represents a bond, -O-, -S-, -NH-, or C 1-6 It is alkylene, C 1-6 Alkylenes are one or more oxo, halogen, -CN, -OH, -NH2, C 1-6 Alkyl atoms, or the atom(s) to which they are bonded, together form C 3-10 Two C atoms form a cycloalkyl group. 1-6 Optionally substituted with alkyl groups, R 1 H, halogen, -CN, -OH, -NH2, -C 1-6 Alkyl, -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 2-6 Alkyl), C 3-10 Cycloalkyl, C 6-10 The aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, where -C 1-6 Alkyl, -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), or -N(C 1-6 Alkyl)2 is one or more oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10Optionally substituted with a cycloalkyl group, or a 3-10 member heterocycloalkyl group, or a 5-10 member heteroaryl group, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may contain one or more oxo, deuterium, halogen, -CN, -OH, -NH2, or C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl, or 3-10 member heterocycloalkyl, C 6-10 Optionally substituted with aryl or 5-10 member heteroaryl, L is a bond, -O-, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, -N(C3-6 heterocycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C3-6 cycloalkylene, or C3-6 heterocycloalkylene, where -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, -N(C3-6 heterocycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylenes, C3-6 cycloalkylenes, or C3-6 heterocycloalkylenes are optionally substituted with one or more oxo, deuterium, halogens, -CN, -OH, or -NH2 groups. R 2 C 3-10 Cycloalkylene, C 6-10 Arylene, 3-10 member heterocycloalkylene, or 5-10 member heteroarylene, where C 3-10 Cycloalkylene, C 6-10 Arylene, 3-10 member heterocycloalkylene, or 5-10 member heteroarylene contains one or more R b It is arbitrarily replaced with, Each R bThese are independently halogen, -CN, -OH, -NH2, -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 It is either an aryl, a 3-10 member heterocycloalkyl, or a 5-10 member heteroaryl, or two R b These combine to form an oxo, in the formula -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl is one or more oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl, or 3-10 member heterocycloalkyl, C 6-10 Optionally substituted with aryl or 5-10 member heteroaryl, and C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 An aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl is one or more oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl, or 3-10 member heterocycloalkyl, C 6-10 Optionally substituted with an aryl or 5-10 member heteroaryl, or two R's b C 3-10 Cycloalkyl, C 6-10Forms an aryl, a 3-10 membered heterocycloalkyl, or a 5-10 membered heteroaryl, in which C 3-10 Cycloalkyl, C 6-10 An aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. L 1 The bonds are -O-, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, -N(C3-6 heterocycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C3-6 cycloalkylene, or C3-6 heterocycloalkylene, where -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, -N(C3-6 heterocycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C3-6 cycloalkylene, or C3-6 heterocycloalkylene may be optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2 groups. R 3 C 3-10 Cycloalkyl, C 6-10 The aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, where C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may have one or more R c It is arbitrarily replaced with, Each R c These are independently halogen, -CN, -OH, -NH2, -C(=O)-H, -C(=O)-NH2, -NH-C(=O)-H, -NH-(C=O)-NH2, -C(=O)-CN, -NH-C(=O)-CN, -C(=O)-NH-CN, -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -C(=O)-(C 1-6Alkyl), -C(=O)-NH-(C 1-6 Alkyl), -NH-C(=O)-(C 1-6 Alkyl), -NH-(C=O)-NH-(C 1-6 Alkyl), -NH-(C=O)-O-(C 1-6 Alkyl), -C(=O)-NH-(C 3-10 Cycloalkyl), -C(=O)-NH-(3-10 member heterocycloalkyl), C 1-6 Alkyl, C 2-6 Alkenil, C 、2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 It is either an aryl, a 3-10 member heterocycloalkyl, or a 5-10 member heteroaryl, or two R c These combine to form an oxo, in the formula -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2,-C(=O)-(C 1-6 Alkyl),-C(=O)-NH-(C 1-6 Alkyl),-NH-C(=O)-(C 1-6 Alkyl),-NH-(C=O)-NH-(C 1-6 Alkyl), or -NH-(C=O)-O-(C 1-6 Alkyl) is one or more oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl or 3-10 member heterocycloalkyl, C 6-10 It can be optionally substituted with an aryl or a 5- to 10-membered heteroaryl, and -C(=O)-NH-(C 3-10 Cycloalkyl), -C(=O)-NH-(3-10 member heterocycloalkyl), C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10An aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl is one or more oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl, or 3-10 member heterocycloalkyl, C 6-10 Optionally substituted with an aryl or 5-10 member heteroaryl, or two R's c C 3-10 Cycloalkyl, C 6-10 Forms an aryl, a 3-10 membered heterocycloalkyl, or a 5-10 membered heteroaryl, in which C 3-10 Cycloalkyl, C 6-10 An aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. or one R b and one R c C 3-10 Cycloalkyl, C 6-10 Forms an aryl, a 3-10 membered heterocycloalkyl, or a 5-10 membered heteroaryl, in which C 3-10 Cycloalkyl, C 6-10 One or more aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl compounds are present in R bc It is arbitrarily replaced with, Each R bc These are independently oxo, deuterium, halogen, -CN, -OH, -NH2, -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10The aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, where -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 An aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2 groups.

[0116] In some embodiments, this disclosure relates to compounds of formula (I):

[0117] [ka] or provide a pharmaceutically acceptable salt thereof, in the formula,

[0118] [ka] C 3-10 Cycloalkylene, C 6-10 These are arylenes, 3-10 member heterocycloalkylenes, or 5-10 member heteroarylenes. m is 0, 1, 2, 3, 4, or 5. Each R a These are independently halogen, -CN, -OH, -NH2, -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 It is either an aryl, a 3-10 member heterocycloalkyl, or a 5-10 member heteroaryl, or two R a These combine to form an oxo, in the formula -O-(C 1-6Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, or -C 1-6 Alkyl is one or more oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl, or 3-10 member heterocycloalkyl, C 6-10 Optionally substituted with aryl or 5-10 member heteroaryl, and C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 An aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl is one or more oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl, or 3-10 member heterocycloalkyl, C 6-10 Optionally substituted with an aryl or 5-10 member heteroaryl, or two R's a C 3-10 Cycloalkyl, C 6-10 Forms an aryl, a 3-10 membered heterocycloalkyl, or a 5-10 membered heteroaryl, in which C 3-10 Cycloalkyl, C 6-10 An aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. X is -C(=O)-, -S(=O)²-, Y represents a bond, -O-, -S-, -NH-, or C 1-6 It is an alkylene, and in the formula, C 1-6Alkylenes are one or more oxo, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, or the atom(s) to which they are bonded, is combined with C 3-10 Two C atoms form a cycloalkyl group. 1-6 Optionally substituted with alkyl groups, R 1 H is a halogen, -CN, -OH, -NH2, -C 1-6 Alkyl, -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)(C 2-6 Alkyl), C 3-10 Cycloalkyl, C 6-10 The aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, where -C 1-6 Alkyl, -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), or -N(C 1-6 Alkyl)2 is one or more oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Optionally substituted with cycloalkyl, or 3-10 member heterocycloalkyl, or 5-10 member heteroaryl, and C 3-10 Cycloalkyl, C 6-10 One or more aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl, or 3-10 member heterocycloalkyl, C 6-10 Optionally substituted with an aryl or 5-10 member heteroaryl, L is a bond, -O-, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, -N(C3-6 heterocycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C3-6 cycloalkylene, or C3-6 heterocycloalkylene, where -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, -N(C3-6 heterocycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylenes, C3-6 cycloalkylenes, or C3-6 heterocycloalkylenes are optionally substituted with one or more oxo, deuterium, halogens, -CN, -OH, or -NH2 groups. R 2 C 3-10 Cycloalkylene, C 6-10 Arylene, 3-10 member heterocycloalkylene, or 5-10 member heteroarylene, where C 3-10 Cycloalkylene, C 6-10 Arylene, 3-10 member heterocycloalkylene, or 5-10 member heteroarylene contains one or more R b It is arbitrarily replaced with, Each R b These are independently halogen, -CN, -OH, -NH2, -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 It is either an aryl, a 3-10 member heterocycloalkyl, or a 5-10 member heteroaryl, or two R b These combine to form an oxo, in the formula -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6Alkyl is one or more oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl, or 3-10 member heterocycloalkyl, C 6-10 Optionally substituted with aryl or 5-10 member heteroaryl, and C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 An aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl is one or more oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl, or 3-10 member heterocycloalkyl, C 6-10 Optionally substituted with an aryl or 5-10 member heteroaryl, or two R's b C 3-10 Cycloalkyl, C 6-10 Forms an aryl, a 3-10 membered heterocycloalkyl, or a 5-10 membered heteroaryl, in which C 3-10 Cycloalkyl, C 6-10 An aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. L 1 The bonds are -O-, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, -N(C3-6 heterocycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6Alkynylene, C3-6 cycloalkylene, or C3-6 heterocycloalkylene, where -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, -N(C3-6 heterocycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C3-6 cycloalkylene, or C3-6 heterocycloalkylene may be optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2 groups. R 3 C 3-10 Cycloalkyl, C 6-10 The aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, where C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may have one or more R c It is arbitrarily replaced with, Each R c These are independently halogen, -CN, -OH, -NH2, -C(=O)-H, -C(=O)-NH2, -NH-C(=O)-H, -NH-(C=O)-NH2, -C(=O)-CN, -NH-C(=O)-CN, -C(=O)-NH-CN, -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -C(=O)-(C 1-6 Alkyl), -C(=O)-NH-(C 1-6 Alkyl), -NH-C(=O)-(C 1-6 Alkyl), -NH-(C=O)-NH-(C 1-6 Alkyl), -NH-(C=O)-O-(C 1-6 Alkyl), -C(=O)-NH-(C 3-10 Cycloalkyl), -C(=O)-NH-(3-10 member heterocycloalkyl), C 1-6 Alkyl, C 2-6 Alkenil, C 、2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10It is either an aryl, a 3-10 member heterocycloalkyl, or a 5-10 member heteroaryl, or two R c These combine to form an oxo, in the formula -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2,-C(=O)-(C 1-6 Alkyl),-C(=O)-NH-(C 1-6 Alkyl),-NH-C(=O)-(C 1-6 Alkyl),-NH-(C=O)-NH-(C 1-6 Alkyl), or -NH-(C=O)-O-(C 1-6 Alkyl) is one or more oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl or 3-10 member heterocycloalkyl, C 6-10 It can be optionally substituted with an aryl or a 5- to 10-membered heteroaryl, and -C(=O)-NH-(C 3-10 Cycloalkyl), -C(=O)-NH-(3-10 member heterocycloalkyl), C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 An aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl is one or more oxo, deuterium, halogen, -CN, -OH, -NH2, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 3-10 Cycloalkyl, or 3-10 member heterocycloalkyl, C 6-10 Optionally substituted with an aryl or 5-10 member heteroaryl, or two R's c C 3-10Cycloalkyl, C 6-10 Forms an aryl, a 3-10 membered heterocycloalkyl, or a 5-10 membered heteroaryl, in which C 3-10 Cycloalkyl, C 6-10 An aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. or one R b and one R c C 3-10 Cycloalkyl, C 6-10 Forms an aryl, a 3-10 membered heterocycloalkyl, or a 5-10 membered heteroaryl, in which C 3-10 Cycloalkyl, C 6-10 One or more aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl compounds are present in R bc It is arbitrarily replaced with, Each R bc These are independently oxo, deuterium, halogen, -CN, -OH, -NH2, -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 The aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, where -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 An aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2 groups.

[0119] Exemplary formula of a compound In some embodiments, the compound is the compound of formula (II),

[0120] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0121] [ka] R 1 , R 2 , R 3 , Y, R a , m, L and L 1 This is as detailed herein.

[0122] In some embodiments, the compound is a compound of formula (III),

[0123] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0124] [ka] R 1 , R 2 , R 3 , Y, R a , m, L and L 1 This is as detailed herein.

[0125] In some embodiments, the compound is a compound of formulas (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (II-i), (II-j), (II-k), (II-l), (II-m), (II-n), (II-o), (II-p), (II-q), (II-r), (II-s), (II-t), (II-u) ), (II-v), (II-w), (II-x), (II-y), (II-z), (II-aa), (II-ab), (II-ac), (II-ad), (II-ae), (II-af), (II-ag), (II-ah), (II-ai), (II-aj), (II-ak), or (II-al), or pharmaceutically acceptable salts thereof, where R 1 , R 2 , R 3 , Y, R a , m, L and L 1 This is as detailed herein.

[0126] [Table 1-1] [Table 1-2] [Table 1-3]

[0127] In some embodiments, the compound is of formula (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i), (III-j), (III-k), (III-l), (III-m), (III-n), (III-o), (III-p), (III-q), (III-r), (III-s), (III-t), (III -u), (III-v), (III-w), (III-x), (III-y), (III-z), (III-aa), (III-ab), (III-ac), (III-ad), (III-ae), (III-af), (III-ag), (III-ah), (III-ai), (III-aj), (III-ak), or (III-al), or pharmaceutically acceptable salts thereof, where R 1 , R 2 , R 3 , Y, R a , m, L and L 1 This is as detailed herein.

[0128] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0129] In some embodiments, the compound is the compound of formula (IV'),

[0130] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0131] [ka] R 1 , R 2 X, Y, R a , R c , m, L and L 1 This is as detailed herein, m-iv is between 0 and 5.

[0132] In some embodiments, the compound is the compound of formula (IV'),

[0133] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0134] [ka] R 1 , R 2 X, Y, R a , R c , m, L and L 1 This is as detailed herein.

[0135] In some embodiments, the compound is the compound of formula (V'),

[0136] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0137] [ka] R 1 , R 2 X, Y, R a , R c , m, L and L 1 This is as detailed herein, mv is between 0 and 4.

[0138] In some embodiments, the compound of formula (V') is the compound of formula (V),

[0139] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0140] [ka] R 1 , R 2 X, Y, R a , R c , m, L and L 1 This is as detailed herein.

[0141] In some embodiments, the compound is the compound of formula (VI'),

[0142] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0143] [ka] R 1 X, Y, R a , R b , R c m and L are as detailed herein, m-vi is 0-8, n-vi is between 0 and 5.

[0144] In some embodiments, the compound of formula (VI') is the compound of formula (VI),

[0145] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0146] [ka] R 1 X, Y, R a , R b , R c m and L are as described in detail herein.

[0147] In some embodiments, the compound is the compound of formula (VII'),

[0148] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0149] [ka] R 1 X, Y, R a , R b , R c m and L are as detailed herein, m-vii is 0-8, n-vii is between 0 and 4.

[0150] In some embodiments, the compound of formula (VII') is the same as the compound of formula (VII),

[0151] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0152] [ka] R 1 X, Y, R a , R b , R c m and L are as described in detail herein.

[0153] In some embodiments, the compound is a compound of formula (VIII'),

[0154] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0155] [ka] R 1 X, Y, R a , R b , R c m and L are as detailed herein, m-viii are 0-9, n-viii ranges from 0 to 5.

[0156] In some embodiments, the compound of formula (VIII') is the compound of formula (VIII),

[0157] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0158] [ka] R 1 X, Y, R a , R b , R c m and L are as described in detail herein.

[0159] In some embodiments, the compound is the compound of formula (IX'),

[0160] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0161] [ka] R1 X, Y, R a , R b , R c m and L are as detailed herein, m-ix is ​​0-9, n-ix is ​​between 0 and 4.

[0162] In some embodiments, the compound of formula (IX') is the compound of formula (IX),

[0163] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0164] [ka] R 1 X, Y, R a , R b , R c m and L are as described in detail herein.

[0165] In some embodiments, the compound is the compound of formula (X'),

[0166] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0167] [ka] R 1 X, Y, R a , R b , R c m and L are as detailed herein, mx is between 0 and 9, nx is between 0 and 5.

[0168] In some embodiments, the compound of formula (X') is the compound of formula (X),

[0169] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0170] [ka] R 1 X, Y, R a , R b , R c m and L are as described in detail herein.

[0171] In some embodiments, the compound is the compound of formula (XI'),

[0172] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0173] [ka] R 1 X, Y, R a , R b , R c m and L are as detailed herein, m-xi is between 0 and 9. n-xi is between 0 and 4.

[0174] In some embodiments, the compound of formula (XI') is the compound of formula (XI),

[0175] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0176] [ka] R 1 X, Y, R a , R b , R c m and L are as described in detail herein.

[0177] In some embodiments, the compound is a compound of formula (XII),

[0178] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0179] [ka] R 1 X, Y, R a , R c m and L are as detailed herein,

[0180] In some embodiments, the compound is a compound of formula (XIII),

[0181] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0182] [ka] R 1 X, Y, R a m and L are as described in detail herein.

[0183] In some embodiments, the compound is a compound of formula (XIV),

[0184] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0185] [ka] R 1 X, Y, R a m and L are as described in detail herein.

[0186] In some embodiments, the compound is a compound of formula (XV),

[0187] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0188] [ka] R 1 X, Y, R a m and L are as described in detail herein.

[0189] In some embodiments, the compound is compound (XVI),

[0190] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0191] [ka] R 1 X, Y, R a m and L are as described in detail herein.

[0192] In some embodiments, the compound is a compound of formula (XVII),

[0193] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0194] [ka] R 1 X, Y, R a m and L are as described in detail herein.

[0195] In some embodiments, the compound is of formula (XVIII),

[0196] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0197] [ka] R 1 X, Y, R a , R c m and L are as described in detail herein.

[0198] In some embodiments, the compound is a compound of formula (XIX),

[0199] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0200] [ka] R 1 X, Y, R a , R c m and L are as described in detail herein.

[0201] In some embodiments, the compound is a compound of formula (XX),

[0202] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0203] [ka] R 1 X, Y, R a , R c m and L are as described in detail herein.

[0204] In some embodiments, the compound is a compound of formula (XXI),

[0205] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0206] [ka] R 1 X, Y, R a m and L are as described in detail herein.

[0207] In some embodiments, the compound is a compound of formula (XXII),

[0208] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0209] [ka] R 1 , R 2 X, Y, R a , R c , m, L and L 1 This is as detailed herein.

[0210] In some embodiments, the compound is the compound of formula (XXIII'),

[0211] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0212] [ka] R 1 X, Y, R a , R b , R c m and L are as detailed herein, m-xxiii is 0-8, n-xxiii is between 0 and 4.

[0213] In some embodiments, the compound of formula (XXIII') is the compound of formula (XXIII),

[0214] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0215] [ka] R 1 X, Y, R a , R b , R c m and L are as described in detail herein.

[0216] In some embodiments, the compound is a compound of formula (XXIV),

[0217] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0218] [ka] R 1 X, Y, R a m and L are as described in detail herein.

[0219] In some embodiments, the compound is a compound of formula (XXV),

[0220] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0221] [ka] R 1 X, Y, R a , R c m and L are as described in detail herein.

[0222] In some embodiments, the compound is a compound of formula (XXVI),

[0223] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0224] [ka] R 1 X, Y, R a m and L are as described in detail herein.

[0225] In some embodiments, the compound is a compound of formula (XXVII),

[0226] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0227] [ka] R 1 X, Y, R a , R b , R c m and L are as described in detail herein.

[0228] In some embodiments, the compound is a compound of formula (XXVIII),

[0229] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0230] [ka] R 1 X, Y, R a , R c m and L are as described in detail herein.

[0231] In some embodiments, the compound is a compound of formula (XXIX),

[0232] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0233] [ka] R 1 X, Y, R a , R b , R c m and L are as described in detail herein.

[0234] In some embodiments, the compound is a compound of formula (XXX'),

[0235] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0236] [ka] R 1 X, Y, R a , R b , R c , and m are as detailed herein, m-xxx is between 0 and 8. n-xxx is between 0 and 4.

[0237] In some embodiments, the compound of formula (XXX') is the compound of formula (XXX),

[0238] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0239] [ka] R 1 X, Y, R a , R b , R c , and m are as detailed herein.

[0240] In some embodiments, the compound is a compound of formula (XXXI'),

[0241] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0242] [ka] R 1 , R 3 X, Y, R a , R b, m, L and L 1 This is as detailed herein, m-xxxi is between 0 and 8.

[0243] In some embodiments, the compound of formula (XXXI') is the compound of formula (XXXI),

[0244] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0245] [ka] R 1 , R 3 X, Y, R a , R b , m, L and L 1 This is as detailed herein.

[0246] In some embodiments, the compound is the compound of formula (XXXII'),

[0247] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0248] [ka] R 1 , R 3 X, Y, R a , R b , m, L and L 1 This is as detailed herein, m-xxxii is a range from 0 to 9.

[0249] In some embodiments, the compound of formula (XXXII') is the compound of formula (XXXII),

[0250] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0251] [ka] R 1 , R 3 X, Y, R a , R b , m, L and L 1 This is as detailed herein.

[0252] In some embodiments, the compound is the compound of formula (XXXIII'),

[0253] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0254] [ka] R 1 , R 3 X, Y, R a , R b , m, L and L 1 This is as detailed herein, m-xxxiii is between 0 and 9.

[0255] In some embodiments, the compound of formula (XXXIII') is the compound of formula (XXXIII),

[0256] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0257] [ka] R 1 , R3 X, Y, R a , R b , m, L and L 1 This is as detailed herein.

[0258] In some embodiments, the compound is a compound of formula (XXXIV),

[0259] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0260] [ka] R 1 , R 3 X, Y, R a , m, L and L 1 This is as detailed herein.

[0261] In some embodiments, the compound is a compound of formula (XXXV),

[0262] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0263] [ka] R 1 , R 3 X, Y, R a m and L are as described in detail herein.

[0264] In some embodiments, the compound is a compound of formula (XXXVI),

[0265] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0266] [ka] R 1 , R 3 X, Y, R a m and L are as described in detail herein.

[0267] In some embodiments, the compound is a compound of formula (XXXVII),

[0268] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0269] [ka] R 1 , R 3 X, Y, R a m and L are as described in detail herein.

[0270] In some embodiments, the compound is a compound of formula (XXXVIII),

[0271] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0272] [ka] R 1 , R 3 X, Y, R a , m, L and L 1 This is as detailed herein.

[0273] In some embodiments, the compound is a compound of formula (XXXIX),

[0274] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0275] [ka] R 1 , R 3 X, Y, R a m and L are as described in detail herein.

[0276] In some embodiments, the compound is a compound of formula (XL),

[0277] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0278] [ka] R 1 , R 3 X, Y, R a m and L are as described in detail herein.

[0279] In some embodiments, the compound is a compound of formula (XLI),

[0280] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0281] [ka] R 1 , R 3 X, Y, R a m and L are as described in detail herein.

[0282] In some embodiments, the compound is a compound of formula (XLII),

[0283] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0284] [ka] R 1 , R 2 , R 3 , R a , m, L and L 1 This is as detailed herein.

[0285] In some embodiments, the compound is a compound of formula (XLIII),

[0286] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0287] [ka] R 1 , R 2 , R 3 , R a , m, L and L 1 This is as detailed herein.

[0288] In some embodiments, the compound is a compound of formula (XLIV),

[0289] [ka] or a pharmaceutically acceptable salt thereof, in the formula,

[0290] [ka] R 1 , R b , R c This is as detailed herein, m-xliv is between 0 and 8. n-xliv is between 0 and 4.

[0291] The newspaper in the box (I) has been updated. (II)(II-a)、(II-a)、(II- b)、(II-c)、(II-d)、(II-e)、(II-f)、(II-g)、(II-h)、(II-i)、(II-j)、(II -k)、(II-l)、(II-m)、(II-n)、(II-o)、(II-p)、(II-q)、(II-r)、(II-s)、(I I-t)、(II-u)、(II-v)、(II-w)、(II-x)、(II-y)、(II-z)、(II-aa)、(II-ab) 、(II-ac)、(II-ad)、(II-ae)、(II-af)、(II-ag)、(II-ah)、(II-ai)、(II- aj)、(II-ak)、(II-al)、(III-a)、(III-b)、(III-c)、(III-d)、(III-e)、(I II-f)、(III-g)、(III-h)、(III-i)、(III-j)、(III-k)、(III-l)、(III-m)、 (III-n)、(III-o)、(III-p)、(III-q)、(III-r)、(III-s)、(III-t)、(III-u )、(III-v)、(III-w)、(III-x)、(III-y)、(III-z)、(III-aa)、(III-ab)、( III-ac)、(III-ad)、(III-ae)、(III-af)、(III-ag)、(III-ah)、(III-ai)、 (III-ang)、(III-ak)、(III-al)、(IV’)、(IV)、(V’)、(V)、(VI’)、(VI)、(VII ') (VII)、(VIII')、(VIII)、(IX')、(IX)、(X') XIII. (XXIII')(XXIII)、(XXIV)、(XXV)、(XXVI)、(XXVII)、(XXVIII)、(XXIX)、(X XX') (XXXIV)、(XXXV)、(XXXVI)、(XXXVII)、(XXXVIII)、(XXXIX)、(XL)、(XLI)、It is understood that these are the values ​​of (XLII), (XLIII), and (XLIV), and in the formula,

[0292] [ka] R 1 , R 2 , R 3 X, Y, R a , R b , R c , m, L and L 1 This is detailed herein. It should be understood that two or more values ​​can be combined. Any of the groups listed above for any variable can be combined with any of the other groups listed above for any of the formulas described herein, where applicable. Therefore, any variable for a compound of formula (I) or any related formula can be combined with any other variable for a compound of formula (I) or any related formula, as the variables have been specifically and individually described.

[0293] variable

[0294] [ka] , m, and R a In some embodiments,

[0295] [ka] C 3-10 It is a cycloalkylene.

[0296] In some embodiments,

[0297] [ka] This is cyclopentylene or cyclohexylene.

[0298] In some embodiments,

[0299] [ka] C 6-10 It is arrine.

[0300] In some embodiments,

[0301] [ka] It is phenylene.

[0302] In some embodiments,

[0303] [ka] These are 3- to 10-membered heterocycloalkylenes.

[0304] In some embodiments,

[0305] [ka] These are pyrrolidinylene, imidazolidinylene, pyrazolidinylene, oazolidinylene, isoxazolidinylene, piperidinylene, oxaniylene, diazinaniylene, or morpholinylene.

[0306] In some embodiments,

[0307] [ka] It is pyrrolidinylene.

[0308] In some embodiments,

[0309] [ka] It is piperidinylene.

[0310] In some embodiments,

[0311] [ka] It is diazinanirene.

[0312] In some embodiments,

[0313] [ka] These are 5-10 member heteroarylenes.

[0314] In some embodiments,

[0315] [ka] These are pyrrolylene, furanylene, imidazolene, pyrazolylene, oxazolylene, thiazolene, and isothiazolene.

[0316] In some embodiments,

[0317] [ka] It is pyridinylene or diazinylene.

[0318] In some embodiments,

[0319] [ka] These are pyridinylene, pimidinylene, pyridadinylene, or triazinylene.

[0320] In some embodiments, m is 0.

[0321] In some embodiments, m is 1, 2, 3, 4, or 5.

[0322] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5.

[0323] In some embodiments, at least one R a These are oxo, halogen, -CN, -OH, or -NH2.

[0324] In some embodiments, at least one R a is an oxo. In some embodiments, at least one R a is a halogen (e.g., F, Cl, or Br). In some embodiments, at least one R a is -CN. In some embodiments, at least one R a is -OH. In some embodiments, at least one R a It is -NH2.

[0325] In some embodiments, at least one R a is -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 The aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, where -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl can be optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2 groups.

[0326] In some embodiments, at least one R a -O-(C) is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 1-6 It is alkyl.

[0327] In some embodiments, at least one R a -NH(C) is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 1-6 It is alkyl.

[0328] In some embodiments, at least one R a -N(C) is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 1-6 It is alkyl(2).

[0329] In some embodiments, at least one R a C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 1-6 It is an alkyl group (for example, methyl, ethyl, propyl, butyl, pentyl, or hexyl).

[0330] In some embodiments, at least one R a C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 2-6 It is Alkenil.

[0331] In some embodiments, at least one R a C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 2-6 It is alkinyl.

[0332] In some embodiments, at least one R a C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 3-10It is a cycloalkyl group.

[0333] In some embodiments, at least one R a C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 6-10 It is Ariel.

[0334] In some embodiments, at least one R a It is a 3- to 10-membered heterocycloalkyl group optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2 groups.

[0335] In some embodiments, at least one R a It is a 5- to 10-membered heteroaryl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2.

[0336] In some embodiments,

[0337] [ka] teeth,

[0338] [ka] That is the case.

[0339] In some embodiments,

[0340] [ka] teeth,

[0341] [ka] That is the case.

[0342] Variables X, Y, and R 1 In some embodiments, X is -C(=O)-.

[0343] In some embodiments, X is S(=O)²⁻.

[0344] In some embodiments, Y is a bond.

[0345] In some embodiments, Y is -O-, -S-, -NH-, or C 1-6 It is an alkylene, and in the formula, C 1-6 Alkylenes are optionally substituted with one or more oxo, halogen, -CN, -OH, or -NH2 groups.

[0346] In some embodiments, Y is a bond, -O-, -S-, or -NH-.

[0347] In some embodiments, Y is -O-. In some embodiments, Y is -S-. In some embodiments, Y is -NH-.

[0348] In some embodiments, Y is a C atom optionally substituted with one or more oxo, halogen, -CN, -OH, or -NH2 atoms. 1-6 These are alkylenes (for example, methylene, ethylene, propylene, butylene, pentylene, or hexylene).

[0349] In some embodiments, Y is C 1-6 These are alkylenes (for example, methylene, ethylene, propylene, butylene, pentylene, or hexylene).

[0350] In some embodiments, Y is methylene, ethylene, or propylene.

[0351] In some embodiments, Y is methylene (e.g., -CH2-). In some embodiments, L is ethylene (e.g., -CH2CH2-). In some embodiments, L is propylene (e.g., -CH2CH2CH2-).

[0352] In some embodiments, Y is C substituted with one or more oxo, halogen, -CN, -OH, or -NH2 1-6 alkylene (e.g., methylene, ethylene, propylene, butylene, pentylene or hexylene).

[0353] In some embodiments, R 1 is H.

[0354] In some embodiments, R 1 is halogen, -CN, -OH, -NH2, -O-(C 1-6 alkyl), -NH(C 1-6 alkyl), or -N(C 1-6 alkyl)2.

[0355] In some embodiments, R 1 is halogen (e.g., F, Cl, or Br).

[0356] In some embodiments, R 1 is -CN.

[0357] In some embodiments, R 1 is -OH.

[0358] In some embodiments, R 1 is NH2.

[0359] In some embodiments, R 1 is -O-(C 1-6 alkyl).

[0360] In some embodiments, R 1 is -NH(C 1-6 alkyl).

[0361] In some embodiments, R 1 is -N(C 1-6 alkyl)2.

[0362] In some embodiments, R 1 is -N(C 1-6 Alkyl)(C 2-6 It is alkyl.

[0363] In some embodiments, R 1 C 1-6 It is alkyl.

[0364] In some embodiments, R 1 C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 3-10 These are cycloalkyl compounds (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).

[0365] In some embodiments, R 1 is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2.

[0366] In some embodiments, R 1 This is a cyclopropyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2 groups.

[0367] In some embodiments, R 1 It is cyclopropyl.

[0368] In some embodiments, R 1 This is cyclobutyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2.

[0369] In some embodiments, R 1 It is cyclobutyl.

[0370] In some embodiments, R 1 C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 6-10It is Ariel.

[0371] In some embodiments, at least one R 1 It is a 3- to 10-membered heterocycloalkyl group optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2 groups.

[0372] In some embodiments, R 1 It is a 5- to 10-membered heteroaryl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2.

[0373] In some embodiments, R 1 C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 1-6 It is alkyl.

[0374] Variables L, R 2 , R b , L 1 , R 3 , R c , and R bc In some embodiments, L is a bond.

[0375] In some embodiments, L is a bond, -O-, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, -N(C3-6 heterocycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C3-6 cycloalkylene, or C3-6 heterocycloalkylene, where -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, -N(C3-6 heterocycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C3-6 cycloalkylene, or C3-6 heterocycloalkylene is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2.

[0376] In some embodiments, L is -O-, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, or C 2-6 It is an alkylylene, in the formula -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, or C 2-6 The alkynylene is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2 groups.

[0377] In some embodiments, L is -O-, -S-, -S(=O)2-, or -NH-.

[0378] In some embodiments, L is -O-. In some embodiments, L is -S-. In some embodiments, L is -S(O)-. In some embodiments, L is S(=O)2. In some embodiments, L is -NH-.

[0379] In some embodiments, L is -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, or C 2-6 It is an alkylylene, in the formula -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, or C 2-6 The alkynylene is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2 groups.

[0380] In some embodiments, L is a -N(C1-6 alkyl) optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2.

[0381] In some embodiments, L is a -N(C3-6 cycloalkyl)- optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2.

[0382] In some embodiments, L is a -N (3-6 member heterocycloalkyl) optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2.

[0383] In some embodiments, L is C, which is optionally substituted with one or more oxo, halogen, -CN, -OH, or -NH2. 1-6 These are alkylenes (for example, methylene, ethylene, propylene, butylene, pentylene, or hexylene).

[0384] In some embodiments, L is C 1-6 These are alkylenes (for example, methylene, ethylene, propylene, butylene, pentylene, or hexylene).

[0385] In some embodiments, L is methylene, ethylene, or propylene.

[0386] In some embodiments, L is methylene (e.g., -CH2-). In some embodiments, L is ethylene (e.g., -CH2CH2-). In some embodiments, L is propylene (e.g., -CH2CH2CH2-).

[0387] In some embodiments, L is a C substituted with one or more oxo, halogen, -CN, -OH, or -NH2. 1-6 These are alkylenes (for example, methylene, ethylene, propylene, butylene, pentylene, or hexylene).

[0388] In some embodiments, L is C, which is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 2-6 It is alkyl.

[0389] In some embodiments, L is C, which is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 2-6 It is alkynylene.

[0390] In some embodiments, L is a C that is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 3-6 It is a cycloalkylene.

[0391] In some embodiments, L is a C that is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 3-6 It is a heterocycloalkylene.

[0392] In some embodiments, L is a bond, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -C(O)-, -O-, -S-, -NH-, -N(CH3)-,

[0393] [ka] That is the case.

[0394] In some embodiments, L is -N(CH3)-

[0395] [ka] That is the case.

[0396] In some embodiments, L is a C1 or C2 alkylene optionally substituted with an oxo.

[0397] In some embodiments, L is

[0398] [ka] That is the case.

[0399] In some embodiments, L is

[0400]

Chem.

[0401] In some embodiments, R 2 is C b cycloalkylene optionally substituted with one or more R 3-10 .

[0402] In some embodiments, R 2 is

[0403]

Chem.

[0404] In some embodiments, R 2 is arylene C b optionally substituted with one or more R 6-10 .

[0405] In some embodiments, R 2 is C3-10 member heterocycloalkylene optionally substituted with one or more R b .

[0406] In some embodiments, R 2 is 3-10 member heterocycloalkylene containing at least one N atom (e.g., aziridinylene, azetidinylene, pyrrolidinylene, or piperidinylene), and the 3-10 member heterocycloalkylene is optionally substituted with one or more R b .

[0407] In some embodiments, R 2 is aziridinylene, azetidinylene, pyrrolidinylene, or piperidinylene, wherein the aziridinylene, azetidinylene, pyrrolidinylene, or piperidinylene is optionally substituted with one or more R b .

[0408] In some embodiments, R 2 is one or more R b This is aziridinylene that has been arbitrarily substituted.

[0409] In some embodiments, R 2 It is aziridinylene.

[0410] In some embodiments, R 2 is one or more R b This is azetidinylene that has been arbitrarily substituted with [another compound].

[0411] In some embodiments, R 2 It is azetidinylene.

[0412] In some embodiments, R 2 is one or more R b It is pyrrolidinylene that has been arbitrarily substituted with (for example,

[0413] [ka]

[0414] In some embodiments, R 2 Pyrrolidinylene (for example,

[0415] [ka] That is the case.

[0416] In some embodiments, R 2 is one or more R b This is piperidinylene with arbitrary substitution.

[0417] In some embodiments, R 2 It is piperidinylene.

[0418] In some embodiments, R 2is a 3- to 10-membered heterocycloalkylene (e.g., diazinaniylene) containing at least two N atoms, and the 3- to 10-membered heterocycloalkylene contains one or more R b It can be arbitrarily replaced with.

[0419] In some embodiments, R 2 is one or more R b Diazinanilenes that are arbitrarily substituted with (for example,

[0420] [ka] That is the case.

[0421] In some embodiments, R 2 is diazinanirene (for example,

[0422] [ka] That is the case.

[0423] In some embodiments, R 2 is one or more R b Diazinanilen 3,6-diazabicyclo[3.1.1]heptanylene (for example,

[0424] [ka] In the formula, * indicates bonding to L.

[0425] In some embodiments, R 2 This is diazinanirene 3,6-diabicyclo[3.1.1]heptanirene (for example,

[0426] [ka] In the formula, * indicates bonding to L.

[0427] In some embodiments, R2 is one or more R b It is a C5-10 member heteroarylene that has been arbitrarily substituted.

[0428] In some embodiments, R 2 teeth,

[0429] [ka] (Each of these is one or more R b It can be arbitrarily substituted with, in the expression, * and

[0430] [ka] However, L and L 1 This represents a connection point to [a specific location].

[0431] In some embodiments, R 2 teeth,

[0432] [ka] That is the case.

[0433] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0434] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0435] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0436] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0437] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0438] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0439] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0440] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0441] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0442] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0443] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0444] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0445] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0446] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0447] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0448] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0449] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0450] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0451] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0452] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0453] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0454] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0455] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0456] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0457] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0458] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0459] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0460] [ka] In some embodiments, R 2 is one or more R b Replaced arbitrarily

[0461] [ka] In some embodiments, R 2is one or more R b Replaced arbitrarily

[0462] [ka] That is the case.

[0463] In some embodiments, at least one R b These are oxo, halogen, -CN, -OH, or -NH2.

[0464] In some embodiments, at least one R b is an oxo. In some embodiments, at least one R b is a halogen (e.g., F, Cl, or Br). In some embodiments, at least one R b is -CN. In some embodiments, at least one R b is -OH. In some embodiments, at least one R b It is -NH2.

[0465] In some embodiments, at least one R b is -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 The aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, where -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10Aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl can be optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2 groups.

[0466] In some embodiments, at least one R b -O-(C) is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 1-6 It is alkyl.

[0467] In some embodiments, at least one R b -NH(C) is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 1-6 It is alkyl.

[0468] In some embodiments, at least one R b -N(C) is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 1-6 It is alkyl(2).

[0469] In some embodiments, at least one R b C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 1-6 It is alkyl.

[0470] In some embodiments, at least one R b C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 2-6 It is Alkenil.

[0471] In some embodiments, at least one R b C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 2-6 It is alkinyl.

[0472] In some embodiments, at least one R bC is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 3-10 It is a cycloalkyl group.

[0473] In some embodiments, at least one R b C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 6-10 It is Ariel.

[0474] In some embodiments, at least one R b It is a 3- to 10-membered heterocycloalkyl group optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2 groups.

[0475] In some embodiments, at least one R b It is a 5- to 10-membered heteroaryl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2.

[0476] In some embodiments, L 1 It is a combination.

[0477] In some embodiments, L 1 These are -O-, -S-, -S(=O)-, -S(=O)2-, -NH-, -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, or C 2-6 It is an alkylylene, in the formula -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, or C 2-6 The alkynylene is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2 groups.

[0478] In some embodiments, L 1 These are -O-, -S-, -S(=O)-, -S(=O)2-, or -NH-.

[0479] In some embodiments, L 1 is -O-. In some embodiments, L 1 is -S-. In some embodiments, L 1 In some embodiments, L 1 is -S(=O)2-. In some embodiments, L 1 It is -NH-.

[0480] In some embodiments, L 1 These are -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, or C 2-6 It is an alkylylene, in the formula -N(C1-6 alkyl)-, -N(C3-6 cycloalkyl)-, C 1-6 Alkylene, C 2-6 Alkenylene, or C 2-6 The alkynylene is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2 groups.

[0481] In some embodiments, L 1 is a -N(C1-6 alkyl)- which is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2.

[0482] In some embodiments, L 1 is a -N(C3-6 cycloalkyl)- which is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2.

[0483] In some embodiments, L 1 is a -N(3-6 member heterocycloalkyl)- which is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2.

[0484] In some embodiments, L 1C is optionally substituted with one or more oxo, halogen, -CN, -OH, or -NH2 groups. 1-6 These are alkylenes (for example, methylene, ethylene, propylene, butylene, pentylene, or hexylene).

[0485] In some embodiments, L 1 C 1-6 These are alkylenes (for example, methylene, ethylene, propylene, butylene, pentylene, or hexylene).

[0486] In some embodiments, L 1 These are methylene, ethylene, or propylene.

[0487] In some embodiments, L 1 is methylene (e.g., -CH2-). In some embodiments, L 1 L is ethylene (e.g., -CH2CH2-). In some embodiments, L 1 This is propylene (for example, -CH2CH2CH2-).

[0488] In some embodiments, L 1 C is a C substituted with one or more oxo, halogen, -CN, -OH, or -NH2. 1-6 These are alkylenes (for example, methylene, ethylene, propylene, butylene, pentylene, or hexylene).

[0489] In some embodiments, L 1 C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 2-6 It is alkenylene.

[0490] In some embodiments, L 1 C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 2-6 It is alkynylene.

[0491] In some embodiments, L 1C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 3-6 It is a cycloalkylene.

[0492] In some embodiments, L 1 C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 3-6 It is a heterocycloalkylene.

[0493] In some embodiments, L 1 is -N(CH3)-,

[0494] [ka] That is the case.

[0495] In some embodiments, L 1 teeth,

[0496] [ka] That is the case.

[0497] In some embodiments, L 1 It is -O-.

[0498] In some embodiments, L 1 teeth,

[0499] [ka] That is the case.

[0500] In some embodiments, R 3 is one or more R c C arbitrarily replaced by 3-10 It is a cycloalkyl group.

[0501] In some embodiments, R 3This refers to one or more halogens, -C(=O)-H, -C(=O)-NH2, -NH-C(=O)-H, -NH-(C=O)-NH2, -C(=O)-CN, -NH-C(=O)-CN, -C(=O)-NH-CN, -C(=O)-(C 1-6 Alkyl), -C(=O)-NH-(C 1-6 Alkyl), -NH-C(=O)-(C 1-6 Alkyl), -NH-(C=O)-NH-(C 1-6 Alkyl), or C 1-6 C substituted with alkyl 3-10 It is a cycloalkyl group.

[0502] In some embodiments, R 3 This refers to one or more halogens, -C(=O)-NH2, -C(=O)-NH-CN, -C(=O)-NH-(C 1-6 Alkyl), or C 1-6 C substituted with alkyl 3-10 It is a cycloalkyl group.

[0503] In some embodiments, R 3 This is one or more -C(=O)-NH2, -C(=O)-NH-CN, or -C(=O)-NH-(C 1-6 C substituted with alkyl 3-10 It is a cycloalkyl group.

[0504] In some embodiments, R 3 is one or more R c C arbitrarily replaced by 6-10 It is Ariel.

[0505] In some embodiments, R 3 C 6-10 These are aryl groups (for example, phenyl groups).

[0506] In some embodiments, R 3 is one or more R c C replaced by 6-10 These are aryl groups (for example, phenyl groups).

[0507] In some embodiments, R 3 This refers to one or more halogens, -C(=O)-H, -C(=O)-NH2, -NH-C(=O)-H, NH-(C=O)-NH2, -C(=O)-CN, -NH-C(=O)-CN, -C(=O)-NH-CN, -C(=O)-(C 1-6 Alkyl), -C(=O)-NH-(C 1-6 Alkyl), -NH-C(=O)-(C 1-6 Alkyl), -NH-(C=O)-NH-(C 1-6 Alkyl), or C 1-6 C substituted with alkyl 6-10 It is Ariel.

[0508] In some embodiments, R 3 This refers to one or more halogens, -C(=O)-NH2, -C(=O)-NH-CN, -C(=O)-NH-(C 1-6 Alkyl), or C 1-6 C substituted with alkyl 6-10 These are aryl groups (for example, phenyl groups).

[0509] In some embodiments, R 3 This is one or more -C(=O)-NH2, -C(=O)-NH-CN, or -C(=O)-NH-(C 1-6 C substituted with alkyl 6-10 These are aryl groups (for example, phenyl groups).

[0510] In some embodiments, R 3 is one or more R c It is a C3-10 member heterocycloalkyl group that is arbitrarily substituted.

[0511] In some embodiments, R 3 is one or more R c These are C5-10 member heteroaryls (e.g., pyridinyl) that are arbitrarily substituted.

[0512] In some embodiments, R 3 is one or more R c Pyridinyl arbitrarily substituted (for example,

[0513] [ka] That is the case.

[0514] In some embodiments, R 3 These are 5-10 member heteroaryl compounds.

[0515] In some embodiments, R 3 Pyridinyl (for example,

[0516] [ka] That is the case.

[0517] In some embodiments, R 3 is one or more R c It is a C5-10 member heteroaryl (e.g., pyridinyl) substituted with .

[0518] In some embodiments, R 3 is one or more R c It is a C5-10 member heteroaryl (e.g., pyridinyl) containing at least one N atom that is optionally substituted.

[0519] In some embodiments, R 3 is a 5-10 member heteroaryl (e.g., pyridinyl) containing at least one N atom, where the heteroaryl is one or more halogens, CN, -C(=O)-H, -C(=O)-NH2, -NH-C(=O)-H, -NH-(C=O)-NH2, -C(=O)-CN, -NH-C(=O)-CN, -C(=O)-NH-CN, -C(=O)-(C 1-6 Alkyl), -C(=O)-NH-(C 1-6 Alkyl), -NH-C(=O)-(C 1-6 Alkyl), -NH-(C=O)-NH-(C 1-6 Alkyl)-NH-(C=O)-O-(C 1-6 Alkyl) or C 1-6It is substituted with an alkyl group.

[0520] In some embodiments, R 3 is a 5-10 member heteroaryl (e.g., pyridinyl) containing at least one N atom, where the heteroaryl is one or more halogens, -C(=O)-NH2, -C(=O)-NH-CN, -C(=O)-NH-(C 1-6 Alkyl) or C 1-6 It is substituted with an alkyl group.

[0521] In some embodiments, R 3 is one or more R c Pyridinyl substituted with (for example,

[0522] [ka] That is the case.

[0523] In some embodiments, R 3 teeth,

[0524] [ka] (Each of these is one or more R c It is arbitrarily replaced, and * is L 1 (Represents the connection point to R). In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0525] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0526] [ka] In some embodiments, R3 is one or more R c Replaced arbitrarily

[0527] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0528] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0529] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0530] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0531] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0532] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0533] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0534] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0535] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0536] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0537] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0538] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0539] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0540] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0541] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0542] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0543] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0544] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0545] [ka] In some embodiments, R 3 is one or more Rc Replaced arbitrarily

[0546] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0547] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0548] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0549] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0550] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0551] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0552] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0553] [ka] In some embodiments, R 3 is one or more R c Replaced arbitrarily

[0554] [ka] That is the case.

[0555] In some embodiments, R 3 teeth,

[0556] [ka] [ka] And in the formula, * is L 1 This represents a connection point to [a specific location].

[0557] In some embodiments, R 3 teeth,

[0558] [ka] That is the case.

[0559] In some embodiments, R 3 teeth,

[0560] [ka] That is the case.

[0561] In some embodiments, R 3 teeth,

[0562] [ka] That is the case.

[0563] In some embodiments, at least one R c These are oxo, halogen, -CN, -OH, -NH2, -C(=O)-H, -C(=O)-NH2, -NH-C(=O)-H, -NH-(C=O)-NH2, -C(=O)-CN, -NH-C(=O)-CN, or -C(=O)-NH-CN.

[0564] In some embodiments, at least one R c It is oxo.

[0565] In some embodiments, at least one R c This is a halogen (for example, F, Cl, or Br).

[0566] In some embodiments, at least one R c is -CN. In some embodiments, at least one R c is -OH. In some embodiments, at least one R c is -NH2. In some embodiments, at least one R c is -C(=O)-H. In some embodiments, at least one R c is -C(=O)-NH2. In some embodiments, at least one R c is -NH-C(=O)-H. In some embodiments, at least one R c It is -NH-(C=O)-NH2. In some embodiments, at least one R c is -C(=O)-CN. In some embodiments, at least one R c is -NH-C(=O)-CN. In some embodiments, at least one R c The compound is -C(=O)-NH-CN.

[0567] In some embodiments, at least one R c is -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -C(=O)-(C 1-6 Alkyl), -C(=O)-NH-(C 1-6 Alkyl), -NH-C(=O)-(C 1-6 Alkyl), -NH-(C=O)-NH-(C 1-6 Alkyl), -NH-(C=O)-O-(C 1-6 Alkyl), -C(=O)-NH-(C 3-10 Cycloalkylalkyl), -C(=O)-NH-(3-10 member heterocycloalkyl), C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 The aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, where -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -C(=O)-(C 1-6 Alkyl), -C(=O)-NH-(C 1-6 Alkyl), -NH-C(=O)-(C 1-6 Alkyl), -NH-(C=O)-NH-(C 1-6 Alkyl), -NH-(C=O)-O-(C 1-6 Alkyl), -C(=O)-NH-(C 3-10 Cycloalkyl), -C(=O)-NH-(3-10 member heterocycloalkyl), C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 An aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2 groups.

[0568] In some embodiments, at least one R c -O-(C) is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 1-6 It is alkyl. In some embodiments, at least one R c -NH(C) is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 1-6 Alkyl) In some embodiments, at least one R c -N(C) is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 1-6 It is alkyl(2).

[0569] In some embodiments, at least one R c -C(=O)-(C) is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 1-6 Alkyl groups are (for example, -C(=O)-CH3).

[0570] In some embodiments, at least one R c is -C(=O)-(C 1-6 Alkyl groups are (for example, -C(=O)-CH3).

[0571] In some embodiments, at least one R c This is -C(=O)-CH3.

[0572] In some embodiments, at least one R c -C(=O)-NH-(C) is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 1-6 Alkyl groups are (for example, -C(=O)-NH-CH3).

[0573] In some embodiments, at least one R c is -C(=O)-NH-(C 1-6 Alkyl groups are (for example, -C(=O)-NH-CH3).

[0574] In some embodiments, at least one R c It is -C(=O)-NH-CH3.

[0575] In some embodiments, at least one R c -NH-C(=O)-(C) is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 1-6 Alkyl groups are (for example, -NH-C(=O)-CH3).

[0576] In some embodiments, at least one R c is -NH-C(=O)-(C 1-6 Alkyl groups are (for example, -NH-C(=O)-CH3).

[0577] In some embodiments, at least one R c It is -NH-C(=O)-CH3.

[0578] In some embodiments, at least one R c -NH-C(=O)-(C) is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 1-6 Alkyl groups are (for example, -NH-C(=O)-CH3).

[0579] In some embodiments, at least one R c is -NH-C(=O)-(C 1-6 Alkyl groups are (for example, -NH-C(=O)-CH3).

[0580] In some embodiments, at least one R c It is -NH-C(=O)-CH3.

[0581] In some embodiments, at least one R c -NH-(C=O)-NH-(C 1-6Alkyl groups are (for example, -NH-(C=O)-NH-CH3).

[0582] In some embodiments, at least one R c is -NH-(C=O)-NH-(C 1-6 Alkyl groups are (for example, -NH-(C=O)-NH-CH3).

[0583] In some embodiments, at least one R c -NH-(C=O)-O-(C 1-6 Alkyl groups are (for example, -NH-(C=O)-O-CH3).

[0584] In some embodiments, at least one R c is -NH-(C=O)-O-(C 1-6 Alkyl groups are (for example, -NH-(C=O)-O-CH3).

[0585] In some embodiments, at least one R c It is -NH-(C=O)-O-CH3.

[0586] In some embodiments, at least one R c It is -NH-(C=O)-NH-CH3.

[0587] In some embodiments, at least one R c -C(=O)-NH-(C) is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 3-10 It is a cycloalkyl (cycloalkyl) compound.

[0588] In some embodiments, at least one R c is --C(=O)-NH-(C 3-10 It is a cycloalkyl (cycloalkyl) compound.

[0589] In some embodiments, at least one R cIt is a -C(=O)-NH-(3-10 member heterocycloalkyl) optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2.

[0590] In some embodiments, at least one R c It is a -C(=O)-NH- (3-10 member heterocycloalkyl) group.

[0591] In some embodiments, at least one R c C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 1-6 It is alkyl. In some embodiments, at least one R c C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 2-6 It is an alkenyl. In some embodiments, at least one R c C 2-6 It is alkinyl.

[0592] In some embodiments, at least one R c C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 3-10 It is cycloalkyl. In some embodiments, at least one R c C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 6-10 It is an arrow. In some embodiments, at least one R c is a 3- to 10-membered heterocycloalkyl group optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2 groups. In some embodiments, at least one R c is a 5- to 10-membered heteroaryl (e.g., imidazolyl) optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2 groups.

[0593] In some embodiments, one R b and one R cC 3-10 Cycloalkyl, C 6-10 Forms an aryl, a 3-10 membered heterocycloalkyl, or a 5-10 membered heteroaryl, in which C 3-10 Cycloalkyl, C 6-10 One or more aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl compounds are present in R bc It can be arbitrarily replaced with.

[0594] In some embodiments, R b and R c Along with the atoms to which they are bonded, one or more R bc C arbitrarily replaced by 3-10 It forms a cycloalkyl group.

[0595] In some embodiments, one R b and one R c Along with the atoms to which they are bonded, one or more R bc C arbitrarily replaced by 6-10 Form an aryl group.

[0596] In some embodiments, one R b and one R c Along with the atoms to which they are bonded, one or more R bc This forms a 3- to 10-membered heterocycloalkyl group with arbitrary substitutions.

[0597] In some embodiments, one R b and one R c Along with the atoms to which they are bonded, one or more R bc It forms a 5-10 member heteroaryl with arbitrary substitutions.

[0598] In some embodiments, at least one R bc These are oxo, halogen, -CN, -OH, or -NH2.

[0599] In some embodiments, at least one R bcis an oxo. In some embodiments, at least one R bc is deuterium. In some embodiments, at least one R bc is a halogen (e.g., F, Cl, or Br). In some embodiments, at least one R bc is -CN. In some embodiments, at least one R bc is -OH. In some embodiments, at least one R bc It is -NH2.

[0600] In some embodiments, at least one R bc is -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 The aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, where -O-(C 1-6 Alkyl), -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl can be optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2 groups.

[0601] In some embodiments, at least one R bc -O-(C) is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 1-6 It is alkyl.

[0602] In some embodiments, at least one R bc-NH(C) is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 1-6 It is alkyl.

[0603] In some embodiments, at least one R bc -N(C) is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 1-6 It is alkyl(2).

[0604] In some embodiments, at least one R bc C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 1-6 These are alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, or hexyl).

[0605] In some embodiments, at least one R bc C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 2-6 It is Alkenil.

[0606] In some embodiments, at least one R bc C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 2-6 It is alkinyl.

[0607] In some embodiments, at least one R bc C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 3-10 It is a cycloalkyl group.

[0608] In some embodiments, at least one R bc C is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2. 6-10 It is Ariel.

[0609] In some embodiments, at least one Rbc It is a 3- to 10-membered heterocycloalkyl group optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2 groups.

[0610] In some embodiments, at least one R bc It is a 5- to 10-membered heteroaryl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH2.

[0611] Exemplary Compounds In some embodiments, the compounds are selected from the compounds listed in Table 1, as well as their prodrugs and pharmaceutically acceptable salts.

[0612] In some embodiments, the compounds are selected from the compounds listed in Table 1 and their pharmaceutically acceptable salts.

[0613] In some embodiments, the compound is selected from the compounds listed in Table 1.

[0614] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] Table 3-9 Table 3-10 Table 3-11 Table 3-12 Table 3-13 Table 3-14 Table 3-15 Table 3-16 Table 3-17 Table 3-18 Table 3-19 Table 3-20 Table 3-21 Table 3-22 Table 3-23 Table 3-24 Table 3-25 Table 3-26 Table 3-27 Table 3-28 Table 3-29 Table 3-30 Table 3-31 Table 3-32 Table 3-33 Table 3-34 Table 3-35 Table 3-36 Table 3-37 Table 3-38 Table 3-39 Table 3-40 Table 3-41 Table 3-42 Table 3-43 Table 3-44 Table 3-45 Table 3-46 Table 3-47 Table 3-48 Table 3-49 Table 3-50 Table 3-51 Table 3-52 Table 3-53 Table 3-54 Table 3-55 Table 3-56 Table 3-57 Table 3-58 Table 3-59 Table 3-60 Table 3-61 Table 3-62 Table 3-63 Table 3-64 Table 3-65 Table 3-66 Table 3-67 Table 3-68 Table 3-69 Table 3-70 Table 3-71 Table 3-72 Table 3-73 Table 3-74 Table 3-75 Table 3-76 Table 3-77 Table 3-78 Table 3-79 Table 3-80 Table 3-81 Table 3-82 Table 3-83 Table 3-84 Table 3-85 Table 3-86 Table 3-87 Table 3-88 Table 3-89 Table 3-90 Table 3-91 Table 3-92 Table 3-93 [Table 3-94] [Table 3-95] [Table 3-96] [Table 3-97] [Table 3-98] [Table 3-99] [Table 3-100] [Table 3-101] [Table 3-102] [Table 3-103] [Table 3-104]

[0615] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds listed in Table 1.

[0616] The neutral compound of formula (I) can be converted to a pharmaceutically acceptable salt of the corresponding compound using the techniques of the art (for example, by saponification of the ester to a carboxylate, or by hydrolysis of the amide to form the corresponding carboxylic acid, and then by converting the carboxylic acid to a carboxylate).

[0617] In some embodiments, the Disclosure provides compounds that are isotopic derivatives (e.g., isotopically labeled compounds) of any one of the compounds of the formulas disclosed herein.

[0618] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1, as well as its prodrug and pharmaceutically acceptable salt.

[0619] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1 and a pharmaceutically acceptable salt thereof.

[0620] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds listed in Table 1 and a pharmaceutically acceptable salt thereof.

[0621] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1.

[0622] It is understood that isotopic derivatives can be prepared using any variety of techniques known in the art. For example, isotopic derivatives can generally be prepared by replacing non-isotopic labeling reagents with isotopic labeling reagents, as disclosed in the schemes and / or examples described herein.

[0623] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0624] In some embodiments, the isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulas disclosed herein.

[0625] As used herein, the term “isotope derivative” refers to a derivative of a compound in which one or more atoms are isotope-enriched or labeled. For example, an isotope derivative of compound (I) is isotope-enriched with respect to one or more isotopes or labeled with one or more isotopes compared to the corresponding compound (I). In some embodiments, the isotope derivative is 2 H, 13 C, 14 C, 15 N, 18 O, 29 Si, 31 P, and 34 The isotopic derivative is enriched with respect to one or more atoms selected from S, or labeled with those atoms. In some embodiments, the isotopic derivative is a deuterium-labeled compound (i.e., with respect to one or more atoms thereof). 2 (H is concentrated) In some embodiments, the compound is 18 It is a fluorine-labeled compound. In some embodiments, this compound is 123 I-labeled compound, 124 I-labeled compound, 125 I-labeled compound, 129 I-labeled compound, 131 I-labeled compound, 135 I-labeled compounds, or any combination thereof. In some embodiments, this compound is 33 S-labeled compound, 34 S-labeled compound, 35 S-labeled compound, 36 This is an S-labeled compound, or any combination thereof.

[0626] 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S and / or 36 It is understood that S-labeled compounds can be prepared using any various techniques recognized in the art. For example, deuterium-labeled compounds are generally prepared using18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S and / or 36 The reagents can be prepared by replacing the S-labeled reagent with a non-isotope-labeled reagent, and by following the procedures disclosed in the schemes and / or examples described herein.

[0627] As mentioned above 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and 36 Compounds of the present invention, or pharmaceutically acceptable salts or solvates thereof, containing one or more S atoms, are within the scope of the present invention. Furthermore, isotopes (e.g., 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 S, 34 S, 35 S and / or 36 Substitution with S) may result in certain therapeutic benefits arising from greater metabolic stability, such as an increased half-life in vivo or a reduction in the required dosage.

[0628] To avoid misunderstanding, when a group is described herein as “as described herein,” it should be understood that this group encompasses the broadest definition that first arises, as well as each and all of the specific definitions of that group.

[0629] The various functional groups and substituents constituting the compound of formula (I) are typically selected so that the molecular weight of the compound does not exceed 1000 daltons. In some embodiments, the molecular weight of the compound is less than 900, for example, less than 800 daltons, or less than 750 daltons, or less than 700 daltons, or less than 650 daltons. For example, the molecular weight is less than 600 daltons, for example, 550 daltons or less.

[0630] Suitable pharmaceutically acceptable salts of the compounds of this disclosure are, for example, acid addition salts of the compounds of this disclosure with sufficiently basic inorganic organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, methanesulfonate citrate, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of the compounds of this disclosure that are sufficiently acidic are salts with alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or organic bases that give pharmaceutically acceptable cations, such as methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris(2-hydroxyethyl)amine.

[0631] Any compound of any of the formulas disclosed herein and any pharmaceutically acceptable salt thereof will be understood to include stereoisomers of the compound, mixtures of stereoisomers, and polymorphs of all isomeric forms of the compound.

[0632] It will be understood that the compounds disclosed herein may be presented in one particular configuration. Such a particular configuration should not be construed as limiting this disclosure to one or another isomer, tautomer, regioisomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers, or stereoisomers. In some embodiments, the presentation of a compound herein in a particular configuration is intended to encompass and refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof, while this presentation is further intended to refer to a particular configuration of the compound.

[0633] It will be understood that the compounds disclosed herein may be presented without a specific configuration (e.g., without a specific stereochemistry). Such presentations are intended to encompass all available isomers, tautomers, regioisomers, and stereoisomers of the compound. In some embodiments, presentations of compounds herein without a specific configuration are intended to encompass each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof.

[0634] As used herein, the term "isomer" refers to compounds that have the same molecular formula but differ in the arrangement of their atomic bonds or the spatial configuration of their atoms. Isomers that differ in spatial configuration of their atoms are called "stereoisomers." Stereoiomers that are not mirror images of each other are called "diastereoisomers," and stereoisomers that are mirror images of each other but cannot be superimposed are sometimes called "enantiomers" or optical isomers. A mixture containing equal amounts of individual enantiomer forms with opposite chiralities is called a "racemic mixture."

[0635] As used herein, the term “chiral center” refers to a carbon atom bonded to four non-identical substituents.

[0636] As used herein, the term “chiral isomer” means a compound having at least one chiral center. Compounds having two or more chiral centers may exist as individual diastereomers or as a mixture of diastereomers referred to as a “diastereomer mixture.” Where a single chiral center is present, the stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of substituents attached to the chiral center. Substituents attached to the chiral center under consideration are ranked according to the sequence rules of Kahn, Ingold, and Prelog. (Cahn et al.,Angew. Chem.Inter. Edit.1966,5,385;errata 511;Cahn et al.,Angew. Chem.1966,78,413;Cahn and Ingold,J.Chem.Soc.1951(London),612;Cahn et al.,Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0637] As used herein, the term “geometric isomer” means a diastereomer that is hindered from rotating around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These arrangements are distinguished in their names by the prefixes cis and trans, or Z and E, indicating that the group is on the same side or opposite side of the double bond within the molecule, according to the Kahn-Ingold-Prelogue rule.

[0638] It should be understood that the compounds of this disclosure may be illustrated as different chiral or geometric isomers. Where a compound has chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of this disclosure, and the name of the compound does not exclude any of the isomeric forms. It should be understood that not all isomers have the same level of activity.

[0639] It should be understood that the structures and other compounds discussed in this disclosure include all of their atropisomers. It should also be understood that not all atropisomers have the same level of activity.

[0640] As used herein, the term “atropisomer” refers to a type of stereoisomer in which the atoms of two isomers are spatially distinct. The existence of atropisomers is due to rotational constraints resulting from the obstruction of rotation of the larger group around a central bond. Such atropisomers typically exist as a mixture, but recent advances in chromatography techniques have made it possible, in some cases, to separate a mixture of two atropisomers.

[0641] As used herein, the term “tautomer” refers to one of two or more structural isomers that exist in equilibrium and into which one isomeric form is readily converted. This conversion results in a formal transfer of hydrogen atoms, involving the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of sets of tautomers in solution. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can be interconverted by tautomerization is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. Keto-enol tautomerism involves a simultaneous shift of electrons and hydrogen atoms. Ring-chain tautomerism occurs as a result of an aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxyl groups (-OH) in the same molecule to produce a cyclic (ring-shaped) form, as represented by glucose.

[0642] It should be understood that the compounds in this disclosure may be described as different tautomers. If a compound has tautomer forms, all tautomer forms are intended to be included within the scope of this disclosure, and the name of the compound does not exclude tautomer forms. It should also be understood that certain tautomers may have higher activity levels than others.

[0643] Compounds having the same molecular formula but differing in the nature or order of atomic bonding, or in the spatial arrangement of atoms, are called "isomers." Isomers with different spatial arrangements of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are mirror images of each other but cannot be superimposed are called "enantiomers." If a compound has an asymmetric center, for example, if it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their chiral center and are described by being dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively) according to the Kahn-Prelogue RS order rule or by the way the molecule rotates its plane of polarization. Chiral compounds may exist as any individual enantiomer or as a mixture thereof. A mixture containing enantiomers in equal proportions is called a "racemic mixture."

[0644] The compounds of this disclosure may have one or more chiral centers. Therefore, such compounds may be produced as individual (R) or (S) stereoisomers, or as mixtures thereof. Unless otherwise indicated, the descriptions or nomenclature of specific compounds in this specification and the claims are intended to include both individual enantiomers and their racemates or other mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or by separation of racemic forms (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001). Some of the compounds of this disclosure may have geometric isomer centers (E and Z isomers). It should be understood that this disclosure encompasses all optical, diastereoisomers, and geometric isomers, as well as mixtures thereof, that have (1) PARP and / or (2) PARP inhibitory activity.

[0645] This disclosure also includes compounds of the disclosure as defined herein, which involve one or more isotopic substitutions.

[0646] It should be understood that any compound of any formula described herein includes, where applicable, the compound itself, as well as its salts and solvates. For example, salts may be formed between an anion on a substituted compound disclosed herein and a positively charged group (e.g., amino). Suitable anions include chlorides, bromides, iodides, sulfates, bisulfates, sulfamates, nitrates, phosphates, citrates, methanesulfons, trifluoroacetates, glutamates, glucurons, glutarates, malates, maleates, succinates, fumarates, tartrates, tosylates, salicylates, lactates, naphthalenesulfons, and acetates (e.g., trifluoroacetates).

[0647] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts may be formed between a cation on a substituted compound disclosed herein and a negatively charged group (e.g., a carboxylate). Suitable cations include sodium, potassium, magnesium, and calcium ions, and ammonium cations such as tetramethylammonium or diethylamine ions. The substituted compounds disclosed herein also include salts containing a quaternary nitrogen atom.

[0648] It should be understood that the compounds of this disclosure, for example, salts of the compounds, may exist in the form of hydrates or unhydrated (anhydrous) compounds, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates and dihydrates. Non-limiting examples of solvates include ethanol solvate and acetone solvate.

[0649] As used herein, the term “solvate” means a solubilated form containing either a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to capture solvent molecules in a fixed molar ratio in their crystalline solid state and thus form solvates. When the solvent is water, the solvate formed is a hydrate; when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the bonding of one or more water molecules with one molecule of a substance in which water retains its molecular state as H2O.

[0650] As used herein, the term “analog” refers to a compound that is structurally similar to another but has a slightly different composition (for example, by replacing one atom with an atom of a different element, or by the presence of a particular functional group, or by replacing one functional group with another). Thus, an analog is a compound that is similar or equivalent to a reference compound in function and appearance, but does not have a similar or equivalent structural origin.

[0651] As used herein, the term “derivative” refers to a compound having a common core structure and substituted with any of the groups described herein.

[0652] As used herein, the term “biological equivalent” refers to a compound resulting from the exchange of an atom or group of atoms with another broadly similar atom or group of atoms. The purpose of biological equivalent substitution is to create a new compound with similar biological properties to the parent compound. Biological equivalent substitution can be physicochemical or topological. Examples of biological equivalents of carboxylic acids include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0653] It should be understood that any particular compound of any one of the formulas disclosed herein may exist in solvated form as well as in non-solvated form, such as hydrated form. Preferred pharmaceutically acceptable solvates are hydrates such as hemihydrate, monohydrate, dihydrate, or trihydrate. It should be understood that this disclosure encompasses all such solvated forms having (1) PARP and / or (2) PARP inhibitory activity.

[0654] It should also be understood that any particular compound of any one of the formulas disclosed herein may exhibit polymorphism, and that this disclosure encompasses all such forms, or mixtures thereof, having (1) PARP and / or (2) PARP inhibitory activity. In general, crystalline materials are known to be analyzed using the prior art, e.g., X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared conversion (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis.

[0655] Any compound of any of the formulas disclosed herein may exist in several different tautomerized forms, and a reference to a compound in formula (I) is to encompass all such forms. To avoid misunderstanding, even if a compound may exist in one of several tautomerized forms and only one is specifically described or shown, all others are encompassed in formula (I). Examples of tautomerized forms include, for example, the keto form, the enol form, and the enol form, as in the following tautomer pairs: keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enthiol, and nitro / acy-nitro.

[0656] [ka]

[0657] Any compound of any of the formulas disclosed herein that contains amine functionalities may also form N-oxides. References herein to compounds of formula (I) containing amine functionalities also include N-oxides. If a compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines, or nitrogen atoms of nitrogen-containing heterocycles. N-oxides may be formed by treating the corresponding amine with an oxidizing agent, such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid). See, for example, Advanced Organic Chemistry, by Jerry March 4th Edition, Wiley Interscience. More specifically, N-oxides were prepared by LW Deady (Syn. Comm. 1977, 7, 509-514) by reacting an amine compound with meta-chloroperoxybenzoic acid (mCPBA) in an inert solvent, such as dichloromethane.

[0658] Any one of the compounds of the formulas disclosed herein may be administered in the form of a prodrug, which is broken down in the body of a human or animal to release the compound of the disclosure. Prodrugs may be used to alter the physical and / or pharmacokinetic properties of the compound of the disclosure. Prodrugs may be formed when the compound of the disclosure contains a suitable group or substituent to which a characterizing group can be bonded. Examples of prodrugs include derivatives of any one of the formulas disclosed herein that contain an alkyl or acyl substituent in the ester or amide group that is cleavable in vivo.

[0659] Accordingly, this disclosure includes any one compound of any of the formulas disclosed herein as defined earlier herein, when made available by organic synthesis and when made available in the body of a human or animal by cleavage of its prodrug. Accordingly, this disclosure also includes any one compound of any of the formulas disclosed herein produced by organic synthesis means, and also such compounds produced in the body of a human or animal by the metabolism of a precursor compound which is any one of the formulas disclosed herein, and may be synthetically produced or metabolically produced compounds.

[0660] A suitable pharmaceutically acceptable prodrug of any one compound of any of the formulas disclosed herein is a prodrug that is deemed suitable for administration to the human or animal body without undesirable pharmacological activity and without excessive toxicity, based on reasonable medical judgment. Various forms of prodrugs are described in the following literature, for example: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard pp. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al. al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACS Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0661] A suitable pharmaceutically acceptable prodrug of any one of the compounds of the formulas disclosed herein having a hydroxyl group is, for example, its ester or ether which can be cleaved in vivo. An in vivo cleavable ester or ether of any one of the compounds of the formulas disclosed herein containing a hydroxyl group is, for example, a pharmaceutically acceptable ester or ether which cleaves in the human or animal body to produce a parent hydroxyl compound. Suitable pharmaceutically acceptable ester-forming groups for the hydroxyl group include inorganic esters, such as phosphate esters (including phosphoramide cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups as hydroxyl groups include C1-C 10 Alkanoyl groups, for example, acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-C 10 Examples of alkoxycarbonyl groups include ethoxycarbonyl, N,N-(C1-C6 alkyl)2-carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for the hydroxyl group include acetoxymethyl and α-acyloxyalkyl groups such as pivaloyloxymethyl.

[0662] A suitable pharmaceutically acceptable prodrug of any one of the compounds of the formulas disclosed herein having a carboxyl group is, for example, an amide of the compound that is cleavable in vivo, such as an amine such as ammonia, C 1-4Alkylamines, such as methylamine; (C1-C4 alkyl)2-amines, such as dimethylamine, N-ethyl-N-methylamine, or diethylamine; C1-C4 alkoxy-C2-C4 alkylamines, such as phenyl-C1-C4 alkylamines like 2-methoxyethylamine and benzylamine; and amino acids such as glycine or its esters.

[0663] A suitable pharmaceutically acceptable prodrug of any one of the compounds of the formulas disclosed herein having an amino group is, for example, its amide derivative that can be cleaved in vivo. Suitable pharmaceutically acceptable amides from an amino group include, for example, C1-C 10 Examples of alkanoyl groups include acetyl, benzoyl, phenylacetyl, and amides formed with substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl.

[0664] The in vivo effect of any one of the compounds of the formulas disclosed herein may be partially exerted by one or more metabolites formed in the human or animal body after administration of any one of the compounds of the formulas disclosed herein. As previously stated herein, the in vivo effect of any one of the compounds of the formulas disclosed herein may also be exerted by the metabolism of a precursor compound (prodrug).

[0665] Preferably, this disclosure excludes any individual compounds that do not have the biological activity defined herein.

[0666] Synthesis method In some embodiments, the Disclosure provides a method for preparing the compounds of the Disclosure.

[0667] In some embodiments, the present disclosure provides a method for compounding a compound comprising one or more steps described herein.

[0668] In some embodiments, the present disclosure provides compounds that can be obtained by, or are obtained by, or directly obtained by, the methods for preparing the compounds described herein.

[0669] In some embodiments, the present disclosure provides intermediates described herein that are suitable for use in methods for preparing the compounds described herein.

[0670] The compounds of this disclosure can be prepared by any suitable technique known in the art. Specific processes for these compounds are further described in the accompanying examples.

[0671] It should be understood that in the descriptions of the synthesis methods described herein, and in any reference synthesis methods used to prepare the starting materials, all proposed reaction conditions, including the selection of solvent, reaction atmosphere, reaction temperature, experimental duration, and workup procedures, can be selected by those skilled in the art.

[0672] Those skilled in organic synthesis will understand that the functional groups present in various parts of a molecule must be compatible with the reagents and reaction conditions used.

[0673] It will be understood that during the synthesis of the compounds of this disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent undesirable reactions. A skilled chemist will understand when such protection is needed, how such protecting groups are positioned, and how they are subsequently removed. For examples of protecting groups, see one of the many general texts on this subject, e.g., Theodora Green's "Protective Groups in Organic Synthesis" (publisher: John Wiley & Sons). Protecting groups can be removed by any convenient method described in the literature or known to a skilled chemist, suitable for the removal of the protecting group in question, and such method is selected to achieve the removal of the protecting group with minimal impact on other groups in the molecule. Thus, if the reactants contain groups such as amino, carboxy, or hydroxy, it may be desirable to protect those groups in some of the reactions described herein.

[0674] For example, suitable protecting groups for amino groups or alkylamino groups include acyl groups, such as alkanoyl groups like acetyl; alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups; arylmethoxycarbonyl groups, such as benzyloxycarbonyl; or aroyl groups, such as benzoyl. The deprotection conditions for the above protecting groups inevitably change depending on the choice of protecting group. Therefore, for example, acyl groups such as alkanoyl, alkoxycarbonyl groups, or aroyl groups can be removed by hydrolysis with a suitable base such as an alkali metal hydroxide, such as lithium hydroxide or sodium hydroxide. Alternatively, acyl groups such as tert-butoxycarbonyl can be removed by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl can be removed by hydrogenation with a catalyst such as palladium carbon, or by treatment with a Lewis acid such as Tris(boron trifluoroacetate). Suitable alternative protecting groups for primary amino groups include, for example, alkylamines, such as dimethylaminopropylamine, or phthaloyl groups, which can be removed by treatment with hydrazine.

[0675] Suitable protecting groups for hydroxyl groups include, for example, acyl groups, such as alkanoyl groups like acetyl, alloyl groups like benzoyl, or arylmethyl groups like benzyl. The deprotection conditions for the above protecting groups will inevitably vary depending on the choice of protecting group. For example, acyl groups like alkanoyl or alloyl groups can be removed by hydrolysis with a suitable base such as alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups like benzyl can be removed by hydrogenation on a catalyst such as palladium-carbon.

[0676] Suitable protecting groups for the carboxyl group include, for example, esterifying groups such as methyl or ethyl groups that can be removed by hydrolysis with a base such as sodium hydroxide, or tert-butyl groups that can be removed by treatment with an acid such as an organic acid such as trifluoroacetic acid, or benzyl groups that can be removed by hydrogenation on a catalyst such as palladium carbon.

[0677] When a compound of formula (I) is synthesized by any one of the processes defined herein, the process may further include the following additional steps: (i) removing any existing protecting groups; (ii) converting the compound of formula (I) to another compound of formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof.

[0678] The resulting compound of formula (I) can be isolated and purified using techniques well known in the art.

[0679] For example, the reaction of compounds is preferably carried out in the presence of a suitable solvent that is inert under the respective reaction conditions. Examples of suitable solvents include hydrocarbons such as hexane, petroleum ether, benzene, toluene, or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform, or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE), or dioxane; and ethylene. Examples of solvents include, but are not limited to, glycol ethers such as glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones such as acetone, methyl isobutyl ketone (MIBK), or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF), or N-methylpyrrolidinone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or methyl acetate, or mixtures of such solvents or mixtures with water.

[0680] The appropriate reaction temperature is approximately -100°C to 300°C, depending on the reaction steps and the conditions under which they are used.

[0681] Reaction times generally range from a few minutes to several days, depending on the reactivity of each compound and the respective reaction conditions. A suitable reaction time can be easily determined by methods known in the art, such as reaction monitoring. Based on the reaction temperature mentioned above, suitable reaction times generally range from 10 minutes to 48 hours.

[0682] Furthermore, by utilizing the procedures described herein in cooperation with those skilled in the art, further compounds of this disclosure can be easily prepared. Those skilled in the art will readily understand that these compounds can be prepared using known variations of the conditions and processes of the following preparation procedures.

[0683] As those skilled in the art will understand, the compounds of this disclosure are readily available through various synthetic routes, some of which are illustrated in the accompanying examples. Those skilled in the art will readily recognize what kinds of reagents and reaction conditions should be used to obtain the compounds of this disclosure, and how to apply and utilize them in any particular case (whenever necessary or useful). Furthermore, some of the compounds of this disclosure can be readily synthesized by reacting other compounds of this disclosure under appropriate conditions, for example, by applying standard synthetic methods such as reduction, oxidation, addition, and substitution reactions, to convert one particular functional group or a suitable precursor molecule present in the compounds of this disclosure to another, methods well known to those skilled in the art. Similarly, those skilled in the art will apply synthetic protecting (or protecting) groups whenever necessary or useful. Suitable protecting groups, as well as methods for introducing and removing them, are well known to those skilled in the art of chemical synthesis, and are described in detail, for example, PGMWuts, TW Greene, “Greene's Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons).

[0684] A preferred general route for preparing the compounds of this application is described in schemes 1 to 12 of this specification. General Scheme 1

[0685] [ka] General Scheme 2

[0686] [ka] General Scheme 3

[0687] [ka] General Scheme 4

[0688] [ka] General Scheme 5

[0689] [ka] General Scheme 6

[0690] [ka] General Scheme 8

[0691] [ka] General Scheme 9

[0692] [ka] General Scheme 10

[0693] [ka] General Scheme 11

[0694] [ka] General Scheme 12

[0695] [ka]

[0696] Biological assays Compounds designed, selected, and / or optimized by the methods described above, once produced, can be characterized using various assays known to those skilled in the art to determine whether or not they possess biological activity. For example, molecules can be characterized by conventional assays, including but not limited to those listed below, to determine whether or not they possess expected activity, binding activity, and / or binding specificity.

[0697] Furthermore, high-throughput screening can be used to expedite analysis using such assays. As a result, it may be possible to rapidly screen for activity of the molecules described herein using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker, and U.S. Patent No. 5,763,263. One or more different assay techniques, including but not limited to those described below, may be used in high-throughput assays.

[0698] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds of this disclosure. These in vitro or in vivo biological assays may include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein.

[0699] In some embodiments, the biological assay is described in the examples herein. In some embodiments, the biological assay measures PARP-1 binding by fluorescence polarization measurement. In some embodiments, the binding of the test compound to recombinant human PARP-1 reduces the amount of the fluorescent probe bound, and consequently lowers the detection level of fluorescence polarization. The stock solution of some test compounds is prepared in a solvent, for example DMSO, and then sequentially diluted to dilution factors, for example 10-fold, 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4-fold, 3-fold, or 2-fold, in the concentration range of, for example, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, and 5. In some embodiments, serial dilutions, such as 100 nL, 90 nL, 80 nL, 70 nL, 60 nL, 50 nL, 30 nL, 20 nL, or 10 nL, are added to a multi-well plate, such as a 1536-well plate, a 384-well plate, or a 96-well plate. In some embodiments, PARP-1, such as GST-tagged PARP-1, is diluted with assay buffer, such as 50 μL, 40 μL, 30 μL, 20 μL, 10 μL, or 5 μL, and added to the plate. In some embodiments, the plate is incubated, for example by centrifugation at 1000 rpm for 1 minute and incubation at room temperature (RT) for 30 minutes. In some embodiments, a fluorescent probe, such as 10 μL of 6 nM PARPi-FL (TOCRIS, catalog no. 6461), is diluted in assay buffer and added to the plate. In some embodiments, the final concentrations of PARP-1 and the fluorescent probe are 20 nM and 3 nM, respectively, with a total volume of 20 μL. In some embodiments, the plate is centrifuged at, for example, 1000 rpm for 1 minute, and the assay plate is incubated at, for example, room temperature (RT) for 4 hours.In some embodiments, the sample in each well is read out using a plate reader, for example, excitation = 480 nm and emission wavelengths = FITC FP-P pol 535 nm and FITC FP-S pol 535 nm. In some embodiments, the inhibition percentage is given by inhibition (%) = [1 - (mP). c -mP L ) / (mP H -mP L ) × 100% is used to calculate the mP value, in the formula, mP c , mP L , and mP H These are the mP values ​​for the test compound, low control, and high control, respectively. In some embodiments, the coupled IC50 is used. 50 The value was calculated using XLFit (Equation 201: y = A + ((BA) / (1 + ((x / C)^D))) (where A = bottom, B = top, C = IC) 50 For curves, a floating top and bottom are used (and D = slope).

[0700] In some embodiments, this biological assay measures PARP-2 binding through fluorescence polarization measurement. In some embodiments, binding of the test compound to recombinant human PARP-2 reduces the amount of the fluorescent probe bound, resulting in a decrease in the detection level of fluorescence polarization. Stock solutions of some test compounds are prepared in a solvent, for example, DMSO, and then sequentially diluted to concentration ranges of, for example, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, and 5 by dilution factors, for example, 10-fold, 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4-fold, 3-fold, or 2-fold. In some embodiments, serial dilutions, such as 100 nL, 90 nL, 80 nL, 70 nL, 60 nL, 50 nL, 30 nL, 20 nL, or 10 nL, are added to a multiwell plate, such as a 1536-well plate, a 384-well plate, or a 96-well plate. In some embodiments, PARP-2, such as GST-tagged PARP-2, is diluted with assay buffer, such as 50 μL, 40 μL, 30 μL, 20 μL, 10 μL, or 5 μL, and added to the plate. In some embodiments, the plate is incubated, for example by centrifugation at 1000 rpm for 1 minute and incubation at room temperature (RT) for 30 minutes. In some embodiments, a fluorescent probe, such as 10 μL of 6 nM PARPi-FL (TOCRIS, catalog no. 6461), is diluted in assay buffer and added to the plate. In some embodiments, the final concentrations of PARP-2 and the fluorescent probe are 20 nM and 3 nM, respectively, with a total volume of 20 μL. In some embodiments, the plate is centrifuged, for example, at 1000 rpm for 1 minute, and the assay plate is incubated, for example, at room temperature (RT) for 4 hours.In some embodiments, the sample in each well is read out using a plate reader, for example, excitation = 480 nm and emission wavelengths = FITC FP-P pol 535 nm and FITC FP-S pol 535 nm. In some embodiments, the inhibition percentage is given by inhibition (%) = [1 - (mP). c -mP L ) / (mP H -mP L ) × 100% is used to calculate the mP value, in the formula, mP c , mP L , and mP H These are the mP values ​​for the test compound, low control, and high control, respectively. In some embodiments, the coupled IC50 is used. 50 The value was calculated using XLFit (Equation 201: y = A + ((BA) / (1 + ((x / C)^D))) (where A = bottom, B = top, C = IC) 50 For curves, a floating top and bottom are used (and D = slope).

[0701] In some embodiments, biological assays measure the effect that the compounds of the disclosed herein may have on cell viability, for example, cancer cell viability. In some embodiments, DLD-1 wild-type and DLD-1BRCA2(- / -) colorectal adenocarcinoma cells (homogeneous pairs of cell lines, one in the presence and the other in the absence of each BRCA2 allele) are used to measure the effect on cancer cell viability. In some embodiments, cells are harvested and counted during a logarithmic growth period and seeded in specific numbers in the wells of a 96-well or 384-well cell culture plate. In some embodiments, after seeding, the cells are incubated overnight, for example, at 37°C and 5% CO2. In some embodiments, the cells are treated with the compound, for example, a serially diluted test compound at concentrations of 8 to 11 within a desired concentration range, e.g., 1 nM to 10 μM, for the generation of a dose-response curve. In some embodiments, the plates are further incubated for a further 3 to 7 days, for example, in a humidified incubator at 37°C and 5% CO2. In some embodiments, cell viability is assessed by luminescence measurement after adding Cell Titer-Glo reagent (Promega, Madison, Wis.) according to the manufacturer's instructions. In some embodiments, cell viability IC5 is assessed. 50 The value is calculated using XLFit, formula 201: y = A + ((BA) / (1 + ((x / C)^D))) (where A = bottom, B = top, C = IC). 50 , and D = slope). In some embodiments, the effect of the test compound on the viability of other cell lines such as MDA-MB-436, MDA-MB-231, SUM149PT, HCC1395, and UWB1.289 is confirmed in a similar manner.

[0702] Pharmaceutical composition In some embodiments, the Disclosure provides pharmaceutical compositions comprising the compounds of the Disclosure as active ingredients. In some embodiments, the Disclosure provides pharmaceutical compositions comprising at least one compound of each of the formulas described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the Disclosure provides at least one pharmaceutical composition selected from Table 1.

[0703] As used herein, the term “composition” is intended to encompass any product containing a specific amount of a particular component, as well as any product obtained directly or indirectly from a specific combination of a particular component.

[0704] The compounds of this disclosure can be formulated for oral administration in the form of tablets, capsules (each including sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of this disclosure may also be formulated for intravenous (bolus or fusion infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all using forms well known to those skilled in the pharmaceutical art.

[0705] The formulations of this disclosure may be in the form of an aqueous solution containing an aqueous vehicle. The aqueous vehicle component may contain water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, isotonic agents, viscosity enhancers / suspending agents, buffering agents, and pH adjusters, and mixtures thereof.

[0706] Any suitable solubility enhancer may be used. Examples of solubility enhancers include cyclodextrins, selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated-β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, as well as mixtures thereof.

[0707] Any suitable chelating agent may be used. Examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0708] Any suitable preservative may be used. Examples of preservatives include quaternary ammonia salts, such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, melthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, polyaminopropyl biguanide, and butyl p-hydroxybenzoate, as well as preservatives selected from the group consisting of sorbic acid and mixtures thereof.

[0709] The aqueous vehicle may also contain an isotonic agent to adjust the tonicity (osmotic pressure). The isotonic agent may be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, and triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, as well as mixtures thereof.

[0710] The aqueous vehicle may also contain a viscous agent / suspension agent. Suitable viscous agents / suspension agents are selected from the group consisting of cellulose derivatives, e.g., methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol (e.g., polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethylcellulose, and crosslinked acrylic acid polymers (carbomers), e.g., polymers of acrylic acid crosslinked with polyalkenyl ethers or divinyl glycol (Carbopol - e.g., Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0711] To adjust the formulation to an acceptable pH (typically about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjuster is typically an inorganic acid or metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, as well as mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters are added to adjust the formulation to the target acceptable pH range. Therefore, it may not be necessary to use both an acid and a base, and depending on the formulation, adding either an acid or a base may be sufficient to bring the mixture to the desired pH range.

[0712] The aqueous vehicle may also contain a buffer to stabilize the pH. If used, the buffer is selected from the group consisting of phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffer (such as boric acid or its salts containing disodium tetraborate), citrate buffer (such as citric acid or its salts containing sodium citrate), and ε-aminocaproic acid, as well as mixtures thereof.

[0713] This formulation may further contain a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylene-sorbitan esters (polysorbates), oxyethylated octylphenol (tyroxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polymers of polyoxyethylene fatty acid esters, as well as mixtures thereof.

[0714] Oral compositions generally contain an inert diluent or a pharmaceutically acceptable food-grade carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral administration, the active compound is formulated with excipients and used in the form of tablets, lozenges, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which the compound in the fluid carrier is applied orally, rinsed, spat out, or swallowed. Pharmacologically compatible binders and / or auxiliary materials may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds of similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or stellite; fluidizers such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavoring.

[0715] In a further aspect of this disclosure, a pharmaceutical composition is provided comprising a pharmaceutically acceptable diluent or carrier in combination with a compound of the disclosure as defined prior to this specification, or a pharmaceutically acceptable salt, hydrate, or solvate carrier thereof.

[0716] The compositions of this disclosure may be in preferred forms for oral use (e.g., as tablets, lollipops, hard or flexible capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups, or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as fine powders or liquid aerosols), administration by blown (e.g., as fine powders), or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration, or as suppositories for rectal administration).

[0717] The compositions of this disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Accordingly, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings, and / or preservatives.

[0718] An effective amount of the compounds of this disclosure for therapeutic use is an amount sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with, (1) PARP and / or (2) PARP-1 related conditions as referred herein.

[0719] An effective amount of the compounds of this disclosure for therapeutic use is an amount sufficient to treat, slow the progression of, and / or alleviate the symptoms associated with (1) PARP and / or (2) PARP-1 related conditions as referred herein.

[0720] The size of the doses of the compounds of formula (I) disclosed herein for therapeutic or prophylactic purposes will naturally vary according to well-known pharmacopoeia principles, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0721] How to use Homologous recombination (HR) is a crucial process for repairing DNA double-strand breaks (DSBs), and defects in HR can lead to the accumulation of DNA damage and genomic instability (Mekonnen N, et al. Frontiers in oncology. 2022:2747). HR defects or deficiencies can result from mutations, loss of function, or inactivation of one or more genes involved in HR.

[0722] BRCA1 and BRCA2 are important tumor suppressor genes that play a central role in HR-mediated DNA DSB repair. Adverse mutations in BRCA1 and / or BRCA2 result in HR deficiency and are associated with an increased risk of several cancers, most notably breast and ovarian cancer. Other genes involved in HR-mediated repair, whose mutations, loss of function, or inactivation can contribute to HR deficiency, include members of the FANC gene family, ATM, RAD51, PALB2, MRE11A, RAD50, NBS1, and EMSY.

[0723] Some sporadic cancers do not have BRCA1 or BRCA2 mutations but exhibit the BRCAness phenotype. Cancers with the BRCAness phenotype share the phenotypic features of cancers with germline BRCA1 or BRCA2 mutations, particularly HR deficiency (Turner N, et al. Nature Reviews Cancer. 2004 Oct;4(10):814-9.). HR deficiency can result from inactivation of tumor suppressor genes, including HR repair genes, loss of heterozygosity, or hypermethylation of promoters due to mutations. The phenotypic features of cancers with germline BRCA1 or BRCA2 mutations are generally associated with genomic instability and include both chromosomal and subchromosomal abnormalities such as mutations, structural copy number changes, and / or structural rearrangements (Mekonnen N, et al., 2022).

[0724] PARP inhibition has been shown to be synthetically lethal in both preclinical and clinical settings for cancers with BRCA1 and / or BRCA2 mutations (Lord CJ, et al. Science. 2017 Mar 17;355(6330):1152-8). Cancers with the BRCAness phenotype are also thought to be particularly sensitive to PARP inhibition. PARP inhibitors are part of the standard treatment for cancers with defects in DNA HR repair. These cancers include HR-deficient breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer.

[0725] In some embodiments, the Disclosure provides methods for modulating PARP1 activity (e.g., in vitro or in vivo) by contacting cells with an effective amount of the compound of the Disclosure or a pharmaceutically acceptable salt thereof.

[0726] In some embodiments, the Disclosure provides methods for modulating PARP1 activity (e.g., in vitro or in vivo) by contacting cells with a compound of the Disclosure or a pharmaceutically acceptable salt thereof.

[0727] In some embodiments, the Disclosure provides a method for treating or preventing a disease or disorder in a subject requiring treatment or prevention of the disease or disorder disclosed herein, the method comprising administering a therapeutically effective amount of the compound or a salt thereof to the subject.

[0728] In some embodiments, the Disclosure provides a method for treating a disease or disorder in a subject requiring treatment of the disease or disorder disclosed herein, the method comprising administering a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, to the subject.

[0729] In some embodiments, the Disclosure provides methods for treating or preventing a disease or disorder in a subject requiring treatment or prevention of the disease or disorder disclosed herein, the methods comprising administering the compound of the Disclosure or a pharmaceutically acceptable salt thereof to the subject.

[0730] In some embodiments, the Disclosure provides a method for treating a disease or disorder in a subject requiring treatment of the disease or disorder disclosed herein, the method comprising administering a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to the subject.

[0731] In some embodiments, the disease or disorder is related to the PARP1 activity involved. In some embodiments, the disease or disorder is a disease or disorder in which PARP1 activity is involved.

[0732] In some embodiments, the disease or disorder is cancer.

[0733] In some embodiments, this disease or disorder is HR-deficient cancer.

[0734] In some embodiments, the disease or disorder is a BRCA-1 or BRCA2 mutant cancer.

[0735] In some embodiments, the Disclosure provides a method for treating or preventing cancer in a subject requiring treatment or prevention of cancer, the method comprising administering a therapeutically effective amount of a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to the subject.

[0736] In some embodiments, the Disclosure provides a method for treating or prophylactic HR-deficient cancer in subjects requiring treatment or prophylactic treatment of HR-deficient cancer, the method comprising administering a therapeutically effective amount of a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to a subject.

[0737] In some embodiments, the Disclosure provides a method for treating or prophylactic BRCA1 or BRCA2 mutated cancer in subjects requiring treatment or prophylactic treatment of BRCA1 or BRCA2 mutated cancer, the method comprising administering a therapeutically effective amount of a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to a subject.

[0738] In some embodiments, the Disclosure provides a method for treating cancer in a subject requiring cancer treatment, the method comprising administering a therapeutically effective amount of a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to the subject.

[0739] In some embodiments, the Disclosure provides a method for treating HR-deficient cancer in subjects requiring treatment of HR-deficient cancer, the method comprising administering a therapeutically effective amount of a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to a subject.

[0740] In some embodiments, the Disclosure provides a method for treating BRCA1 or BRCA2 mutated cancer in subjects requiring treatment of BRCA1 or BRCA2 mutated cancer, the method comprising administering a therapeutically effective amount of a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to a subject.

[0741] In some embodiments, the Disclosure provides a method for treating or preventing cancer in a subject requiring treatment or prevention of cancer, the method comprising administering a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to the subject.

[0742] In some embodiments, the Disclosure provides a method for treating or prophylactic HR-deficient cancer in subjects requiring treatment or prophylactic treatment of HR-deficient cancer, the method comprising administering a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to a subject.

[0743] In some embodiments, the Disclosure provides a method for treating or prophylactic BRCA1 or BRCA2 mutant cancer in subjects requiring treatment or prophylactic treatment of BRCA1 or BRCA2 mutant cancer, the method comprising administering a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to a subject.

[0744] In some embodiments, the Disclosure provides a method for treating cancer in a subject requiring cancer treatment, the method comprising administering a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to the subject.

[0745] In some embodiments, the Disclosure provides a method for treating HR-deficient cancer in subjects requiring treatment of HR-deficient cancer, the method comprising administering a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to a subject.

[0746] In some embodiments, the Disclosure provides a method for treating BRCA1 or BRCA2 mutated cancer in subjects requiring treatment of BRCA1 or BRCA2 mutated cancer, the method comprising administering a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to a subject.

[0747] In some embodiments, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in the modulation of PARP1 activity (e.g., in vitro or in vivo).

[0748] In some embodiments, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in the treatment or prevention of diseases or disorders disclosed herein.

[0749] In some embodiments, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in the treatment of diseases or disorders disclosed herein.

[0750] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment or prevention of cancer in subjects requiring treatment or prevention of cancer.

[0751] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment or prevention of HR-deficient cancer in subjects requiring treatment or prevention of HR-deficient cancer.

[0752] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment or prophylaxis of BRCA1 or BRCA2 mutated cancer in subjects requiring treatment or prophylaxis of BRCA1 or BRCA2 mutated cancer.

[0753] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment of cancer in subjects requiring cancer treatment.

[0754] In some embodiments, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in the treatment of HR-deficient cancer in subjects requiring treatment of HR-deficient cancer.

[0755] In some embodiments, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in the treatment of BRCA-1 or BRCA-2 mutated cancer in subjects requiring treatment of BRCA-1 or BRCA-2 mutated cancer.

[0756] In some embodiments, the disclosure provides the use of the compounds of the disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for modulating PARP1 activity (e.g., in vitro or in vivo).

[0757] In some embodiments, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for treating or preventing the diseases or disorders disclosed herein.

[0758] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for treating diseases or disorders disclosed herein.

[0759] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for treating or preventing cancer in subjects requiring treatment or prevention of cancer.

[0760] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for treating or preventing HR-deficient cancer in subjects requiring treatment or prevention of HR-deficient cancer.

[0761] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for treating or prophylactically treating BRCA1 or BRCA2 mutated cancers in subjects requiring treatment or prophylactic treatment of BRCA1 or BRCA2 mutated cancers.

[0762] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for treating cancer in subjects requiring cancer treatment.

[0763] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for treating HR-deficient cancer in subjects requiring treatment of HR-deficient cancer.

[0764] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for treating BRCA1 or BRCA2 mutated cancers in subjects requiring treatment of BRCA1 or BRCA2 mutated cancers.

[0765] This disclosure provides compounds that function as regulators of PARP1 activity.

[0766] In some embodiments, the compounds of this disclosure are PARP1 inhibitors.

[0767] In some embodiments, the regulation of PARP1 is the inhibition of PARP1.

[0768] The efficacy of the compounds disclosed herein can be determined by industry-accepted assays / disease models in accordance with standard practice that describes the same things as described in the art and found in current general knowledge.

[0769] The disclosure also provides a method for treating a disease or disorder in which PARP1 activity is involved in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0770] Route of administration The compounds of this disclosure, or pharmaceutically acceptable salts thereof, may be administered alone as a monotherapy, or in addition to one or more other substances and / or treatments. Such combination therapy may be achieved by simultaneous, sequential, or separate administration of the individual components of the treatment.

[0771] For example, therapeutic effects can be enhanced by the administration of an adjuvant (i.e., an adjuvant may have minimal therapeutic effect on its own, but when combined with another therapeutic agent, it improves the overall therapeutic effect on the individual). Alternatively, as merely an example, the benefits experienced by an individual can be increased by administering the compound of formula (I) together with another therapeutic agent (including a therapeutic regimen) that also has therapeutic effects.

[0772] When the compounds of the disclosed herein are administered in combination with other therapeutic agents, the compounds of the disclosed herein do not need to be administered via the same route as the other therapeutic agents, and may be administered via different routes due to their different physical and chemical properties. For example, the compounds of the disclosed herein may be administered orally to generate and maintain their good blood levels, while the other therapeutic agents may be administered intravenously. The initial dose may be given according to established protocols known in the art, and the dose, mode of administration, and time of administration may then be modified by an experienced clinician based on the observed effects.

[0773] The specific selection of other therapeutic agents is subject to the attending physician's diagnosis and judgment regarding the individual's condition and the appropriate treatment protocol. According to this aspect of the Disclosure, combinations are provided for use in the treatment of diseases involving PARP1 activity, comprising the compounds of the Disclosure as defined above herein, or pharmaceutically acceptable salts thereof, and other suitable agents.

[0774] A further aspect of this disclosure provides a pharmaceutical composition comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof, in appropriate combination with a pharmaceutically acceptable diluent or carrier.

[0775] In addition to their use in therapeutics, the compound of formula (I) and its pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems to evaluate the effects of PARP1 activity regulators in experimental animals such as dogs, rabbits, monkeys, miniature pigs, rats, and mice, as part of the search for new therapeutic drugs.

[0776] Any of the above-described pharmaceutical compositions, processes, methods, uses, agents, and manufacturing characteristics of this disclosure may be applied to any of the alternative embodiments of the compounds of this disclosure described herein.

[0777] The compounds of this disclosure, or pharmaceutical compositions containing such compounds, can be administered to a subject by any convenient route of administration, whether systemic, peripheral, or topical (i.e., at the desired site of action).

[0778] Routes of administration are not limited to, but include: oral (e.g., by oral ingestion), buccal; sublingual; transdermal (e.g., by patches, poultices, etc.); transmucosal (e.g., by patches, poultices, etc.); intranasal (e.g., by nasal spray or powder); ocular (e.g., by eye drops); pulmonary (e.g., via aerosol, e.g., by use via mouth or nose, e.g., by inhalation or inhalation therapy); rectal (e.g., by suppositories or enemas); vaginal (e.g., by pessaries); parenteral, e.g., by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratubular, subcutaneous, intra-articular, subarachnoid, and intrasternal; and implantation of depots or reservoirs, e.g., subcutaneous or intramuscular. [Examples]

[0779] It is understood that the neutral compound of formula (I) can be converted to a salt of the corresponding compound using certain techniques in the art (for example, by saponification of an ester to a carboxylate, or by hydrolysis of an amide to form the corresponding carboxylic acid, and then by converting the carboxylic acid to a carboxylate).

[0780] [Table 4-1] [Table 4-2]

[0781] Example S-1: Synthesis of 5-(4-((2-(3-ethylureido)pyrimidine-4-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide formate (compound 13).

[0782] [ka] Step 1: Synthesis of 1-(4-(chloromethyl)pyridine-2-yl)-3-ethylurea. Ethyl isocyanate (0.08 mL, 1.01 mmol) and Et3N (0.12 mL, 0.84 mmol) were added to a stirred solution of 4-(chloromethyl)pyridine-2-amine hydrochloride (150 mg, 0.84 mmol) in DMF (1 mL). The reaction mixture was stirred at 25°C for 16 hours, then quenched with NH4Cl aqueous solution and extracted with RINKAN (2 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel chromatography yielded the crude title compound (70 mg). LCMS (m / z): 214.1 [M+H] + .

[0783] Step 2: Synthesis of 5-(4-((2-(3-ethylureido)pyrimidine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide formate. To a stirred solution of crude 1-(4-(chloromethyl)pyridine-2-yl)-3-ethylurea (70 mg) in DMF (1 mL), N,6-dimethyl-5-(piperazine-1-yl)picolinamide (77 mg, 0.33 mmol) and K2CO3 (91 mg, 0.66 mmol) were added. The reaction mixture was heated to 100°C and stirred at that temperature for 4 hours. The reaction mixture was quenched with aqueous NH4Cl solution and extracted with ELISA (2 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. Purification by preparative HPLC yielded the title compound (6.4 mg, 1.7%). LCMS(m / z):412.3[M+H] + . 1 H NMR(400MHz,CD3OD)δ8.35(s,1H),8.17(d,J=5.3 Hz,1H),7.88(d,J=8.3 Hz,1H),7.51(d,J=8.3 Hz,1H),7.14(s,1H),7.02(d,J=5.3 Hz,1H),3.62(s,2H),3.38-3.34(m,2H),3.10-3.01(m,4H),2.96(s,3H),2.75-2.65(m,4H),2.56(s,3H),1.23(t,J=7.2 Hz,3H).

[0784] Example S-2: Synthesis of 5-(4-((2-butylamidopyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide (compound 161).

[0785] [ka] Step 1: Synthesis of N-(4-(chloromethyl)pyridine-2-yl)butylamide. Butyl chloride (119 mg, 1.12 mmol) was added to a suspension of 4-(chloromethyl)pyridine-2-amine hydrochloride (200 mg, 1.12 mmol) and pyridine (177 mg, 2.24 mmol) in THF (5 mL) at 0°C. The reaction mixture was stirred at the same temperature for 1 hour. The reaction product was quenched with saturated NaHCO3 aqueous solution and extracted by DCM. The organic layer was concentrated under vacuum. The residue was purified by silica gel chromatography to obtain the title compound (25 mg, 10%). LCMS: m / z 213.2 (M+H) + .

[0786] Step 2: Synthesis of 5-(4-((2-butylamidopyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide. N,6-dimethyl-5-(piperazine-1-yl)picolinamide (28 mg, 0.12 mmol) and potassium carbonate (50 mg, 0.36 mmol) were added to a solution of N-[5-(chloromethyl)pyridine-2-yl]butanamide (25 mg, 0.12 mmol) in DMF (1 mL). The resulting solution was stirred at 60°C for 15 hours and then concentrated. The residue was purified by preparative HPLC to obtain the title compound (9 mg, 18%). LCMS (m / z): 411.3 [M+H] + . 1H NMR(400MHz,CD3OD)δ8.22(d,J=4.7 Hz,1H),8.14(s,1H),7.84(d,J=8.3 Hz,1H),7.47(d,J=8.3 Hz,1H),7.14(d,J=5.0 Hz,1H),3.69(d,J=8.8 Hz,2H),3.08-3.00(m,4H),2.91(s,3H),2.80-2.68(m,4H),2.52(s,3H),2.39(t,J=7.4 Hz,2H),1.77-1.65(m,2H),0.99(t,J=7.4 Hz,3H).

[0787] Example S-3: Synthesis of N-methyl-3-(piperazin-1-yl)-1,7-naphthyridine-8-amine.

[0788] [ka] Step 1: Synthesis of 3-bromo-N-methyl-1,7-naphthyridine-8-amine. Methylamine (33% in methanol, 4 mL) was added to a solution of 3-bromo-8-chloro-1,7-naphthyridine (500 mg, 2.05 mmol) in MeOH (5 mL), and the reaction was stirred at 80°C for 12 hours. The mixture was then concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (450 mg, 92%). LCMS (m / z): 238.1 [M+H] + .

[0789] Step 2: Synthesis of tert-butyl (3-bromo-1,7-naphthyridine-8-yl)(methyl)carbamate. A mixture of 3-bromo-N-methyl-1,7-naphthyridine-8-amine (400 mg, 1.68 mmol), di-tert-butyl dicarbonate (3.67 g, 16.8 mmol), Et3N (340 mg, 3.36 mmol), and DMAP (21 mg, 0.17 mmol) was stirred at 50°C for 48 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound (450 mg, 79%). LCMS (m / z): 338.0 [M+H] + .

[0790] Step 3: Synthesis of 4-(8-((tert-butoxycarbonyl)(methyl)amino)-1,7-naphthiridine-3-yl)piperazine-1-carboxylate tert-butyl. To a solution of (3-bromo-1,7-naphthiridine-8-yl)(methyl)carbamate tert-butyl (360 mg, 1.06 mmol) in DMA (4 mL), piperazine-1-carboxylate tert-butyl (197 mg, 1.06 mmol), Cs2CO3 (691 mg, 2.12 mmol), and RuPhosPdG3 (89 mg, 0.11 mmol) were added, and the reaction mixture was stirred at 150°C for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound (290 mg, 62%). LCMS (m / z): 444.3 [M+H] + .

[0791] Step 4: Synthesis of N-methyl-3-(piperazin-1-yl)-1,7-naphthyridine-8-amine. To a solution of 4-(8-((tert-butoxycarbonyl)(methyl)amino)-1,7-naphthyridine-3-yl)piperazin-1-carboxylate tert-butyl (290 mg, 0.65 mmol) in DCM (3 mL), TFA (1 mL) was added. The reaction mixture was stirred at 20°C for 1 hour, then quenched with saturated NaHCO3 solution and extracted with MeOH / DCM (1 / 10). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (140 mg, 88%). LCMS (m / z): 244.1 [M+H] + .

[0792] Example S-4: Synthesis of 1-ethyl-3-(4-((4-(8-(methylamino)-1,7-naphthyridine-3-yl)piperazine-1-yl)methyl)pyridine-2-yl)urea (compound 257).

[0793] [ka] Step 1: Synthesis of 1-(4-(chloromethyl)pyridine-2-yl)-3-ethylurea in DMF (25 mL): To a stirred solution of 4-(chloromethyl)pyridine-2-amine hydrochloride (5 g, 27.9 mmol), ethyl isocyanate (4 g, 55.8 mmol) and Et3N (5.6 g, 55.8 mmol) were added. The reaction mixture was stirred at 50°C for 16 hours, then quenched with NH4Cl aqueous solution and extracted with RINKAN. The combined organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound (1.2 g, 20%). LCMS (m / z): 214.1 [M+H] + .

[0794] Step 2: Synthesis of 1-ethyl-3-(4-((4-(8-(methylamino)-1,7-naphthyridine-3-yl)piperazine-1-yl)methyl)pyridine-2-yl)urea: A mixture of N-methyl-3-(piperazine-1-yl)-1,7-naphthyridine-8-amine (50 mg, 0.21 mmol), 1-[4-(chloromethyl)pyridine-2-yl]-3-ethylurea (44 mg, 0.21 mmol), KI (68 mg, 0.41 mmol), and DIPEA (53 mg, 0.41 mmol) in CH3CN (3 mL) was stirred at 20°C for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to obtain the crude product, which was then purified by preparative HPLC and SFC to obtain the title compound (21 mg, 24%). LCMS (m / z): 421.3 [M+H] + ; 1 HNMR(400MHz,CD3OD)δ8.59(d,J=2.6 Hz,1H),8.12(d,J=5.2 Hz,1H),7.67(d,J=6.0 Hz,1H),7.24(d , J=2.5Hz,1H),7.10(s,1H),6.98(d,J=5.1Hz,1H),6.70(d,J=6.1Hz,1H),3.56(s,2H),3.44-3.36(m,4H),3.35 - 3.30(q,J=7.2 Hz,2H),3.04(s,3H),2.69 - 2.61(m,4H),1.18(t,J=7.2 Hz,3H).

[0795] Example S-5: Synthesis of 3-fluoro-N-methyl-4-(piperazin-1-yl)benzamide hydrochloride.

[0796] [ka] Step 1: Synthesis of 4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate tert-butyl. A suspension of methyl 3-fluoro-4-iodobenzoate (1 g, 3.57 mmol), piperazine-1-carboxylate tert-butyl (738 mg, 3.94 mmol), Xphos (341 mg, 0.72 mmol), Pd2(dba)3 (328 mg, 0.36 mmol), and Cs2CO3 (2.3 g, 7.17 mmol) in toluene (80 mL) was stirred at 90°C for 24 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound (870 mg, 72%). LCMS (m / z): 339.0 [M+H] + .

[0797] Step 2: Synthesis of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-fluorobenzoic acid. A solution of tert-butyl 4-(2-fluoro-4-(methoxycarbonyl)phenyl)piperazin-1-carboxylic acid (870 mg, 2.57 mmol) and lithium hydroxide monohydrate (322 mg, 7.69 mmol) in MeOH / H2O (3:2, 100 mL) was stirred at 30°C for 5 hours. This was poured into water and extracted with TBME. The pH of the aqueous phase was adjusted to 2-3 and extracted with ELISA. The organic layer was concentrated to supply the title compound (700 mg, 84%). LC-MS: m / z: 325.1[M+H]+.

[0798] Step 3: Synthesis of tert-butyl 4-(2-fluoro-4-(methylcarbamoyl)phenyl)piperazine-1-carboxylate. A solution of 4-(4-(tert-butoxycarbonyl)piperazine-1-yl)-3-fluorobenzoic acid (650 mg, 2.0 mmol), methylamine hydrochloride (150 mg, 2.2 mmol), DIPEA (1.1 g, 8.8 mmol), and HATU (759 mg, 2.0 mmol) in DMF (10 mL) was stirred at 0°C for 1.5 hours. The resulting solution was poured into water and extracted with ethyl acetate. The combined organic layers were concentrated under vacuum, and the residue was purified by silica gel chromatography to obtain the title compound (560 mg, 83%). LCMS (m / z): 338.1 [M+H] + .

[0799] Step 4: Synthesis of 3-fluoro-N-methyl-4-(piperazin-1-yl)benzamide hydrochloride. A solution of 4-(2-fluoro-4-(methylcarbamoyl)phenyl)piperazin-1-carboxylate tert-butyl (560 mg, 1.7 mmol) in HCl / dioxane (4 M, 30 mL) was stirred at 25°C for 2 hours. The reaction mixture was concentrated to produce the title compound (3.27 g, crude product). LC-MS (m / z): 238.1 [M+H] + .

[0800] Example S-6: Synthesis of 4-(4-((2-(3-ethylureido)pyridine-4-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylbenzamide (compound 31).

[0801] [ka] Step 1: Synthesis of 4-(4-((2-(3-ethylureido)pyridine-4-yl)methyl)piperazine-1-yl)-3-fluoro-N-methylbenzamide: A mixture of 1-(4-(chloromethyl)pyridine-2-yl)-3-ethylurea (60 mg, 0.28 mmol), 3-fluoro-N-methyl-4-(piperazine-1-yl)benzamide dihydrochloride (174 mg, 0.56 mmol), KI (70 mg, 0.42 mmol), and DIPEA (362 mg, 2.80 mmol) in CH3CN (5 mL) was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the crude product, which was then purified by preparative HPLC to obtain the title compound (21 mg, 18%). LCMS (m / z): 415.3 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ9.12(s,1H),8.35 - 8.30(m,1H),8.21 - 8.15(m,1H),8.11(d,J=5.2 Hz,1H),7.63 - 7.54(m,2H),7.34(s,1H),7.08 - 7.03(m,1H),6.91 - 6.88(m,1H),3.50(s,2H),3.22 - 3.14(m,2H),3.14 - 3.08(m,4H),2.75(d,J=4.5 Hz,3H),2.57 - 2.52(m,4H),1.09(t,J=7.2 Hz,3H).

[0802] Example S-7: Synthesis of 1-(6-methyl-5-(piperazin-1-yl)pyridine-2-yl)propan-1-one hydrochloride.

[0803] [ka] Step 1: Synthesis of 1-(5-bromo-6-methylpyridine-2-yl)propan-1-one. To a stirred solution of 5-bromo-6-methylpicolinonitrile (5 g, 25.4 mmol) in THF (50 mL) at -70°C, tert-butyldimethylsilyl chloride (3.83 g, 25.4 mmol), CuBr (0.11 g, 0.7 mmol), and ethylmagnesium bromide (3 M in Et2O, 18.6 mL, 55.8 mmol) were added. The reaction mixture was stirred at 20°C for 2.5 hours, then quenched with NH4Cl and filtered. The resulting solution was poured into cold water and extracted with RINKAN. The combined organic layers were concentrated, and the residue was purified by silica gel column chromatography to obtain the title compound (2.72 g, 47%). LCMS (m / z): 228.1 [M+H] + .

[0804] Step 2: Synthesis of 4-(2-methyl-6-propionylpyridine-3-yl)piperazine-1-carboxylate tert-butyl. A suspension of 1-(5-bromo-6-methylpyridine-2-yl)propan-1-one (2.67 g, 11.7 mmol), piperazine-1-carboxylate tert-butyl (3.26 g, 17.5 mmol), RuPhosPdG3 (0.98 g, 1.2 mmol), and Cs2CO3 (7.61 g, 23.4 mmol) in dioxane (40 mL) was stirred at 80°C for 16 hours under an N2 atmosphere. The resulting solution was poured into cold water and extracted with ethyl acetate. The combined organic layers were concentrated, and the residue was purified by silica gel column chromatography to obtain the title compound (2.57 g, 66%). LCMS (ESI-MS) m / z = 334.1 [M + H] + .

[0805] Step 3: Synthesis of 1-(6-methyl-5-(piperazin-1-yl)pyridine-2-yl)propan-1-one hydrochloride. A solution of 4-(2-methyl-6-propionylpyridine-3-yl)piperazin-1-carboxylate tert-butyl (2.57 g, 7.7 mmol) in 1,4-dioxane / HCl (4 M, 30 mL) was stirred at 25°C for 2 hours. The reaction mixture was concentrated to produce the title compound (3.27 g, crude product). LC-MS (ESI-MS) m / z = 234.3 [M + H] + .

[0806] Example S-8: Synthesis of 1-ethyl-3-(4-((4-(2-methyl-6-propionylpyridine-3-yl)piperazine-1-yl)methyl)pyridine-2-yl)urea (compound 7).

[0807] [ka] Step 1: Synthesis of 1-ethyl-3-(4-((4-(2-methyl-6-propionylpyridine-3-yl)piperazine-1-yl)methyl)pyridine-2-yl)urea: A mixture of 1-(4-(chloromethyl)pyridine-2-yl)-3-ethylurea (90 mg, 0.42 mmol), 1-(6-methyl-5-(piperazine-1-yl)pyridine-2-yl)propan-1-one dihydrochloride (257 mg, 0.84 mmol), KI (205 mg, 0.63 mmol), and DIPEA (543 mg, 4.2 mmol) in CH3CN (4 mL) was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the crude product, which was then purified by preparative HPLC to obtain the title compound (50 mg, 29%). LCMS(m / z):411.3[M+H] + ; 1HNMR(400MHz,DMSO-d6)δ9.10(s,1H),8.16-8.11(m,1H),8.07(d,J=5.2 Hz,1H),7.73(d,J=8.3 Hz,1H),7.43(d,J=8.4 Hz,1H),7.30(s,1H),6.87-6.84(m,1H),3.48(s,2H),3.18-3.10(m,2H),3.10-3. 03(m,2H),2.98-2.92(m,4H),2.57-2.49(m,4H),2.45(s,3H),1.06-0.99(m,6H).

[0808] Example S-9: Synthesis of N,6-dimethyl-5-(piperazin-1-yl)picolinamide dihydrochloride.

[0809] [ka] Step 1: Synthesis of 4-[6-(methoxycarbonyl)-2-methylpyridine-3-yl]piperazine-1carboxylate tert-butyl: To a stirred solution of methyl 5-bromo-6-methylpyridine-2-carboxylate (10 g, 43.47 mmol) in dioxane (200 mL), piperazine-1-carboxylate tert-butyl (12.15 g, 65.23 mmol), RuPhosPdG3 (3.64 g, 4.35 mmol) and Cs2CO3 (28.35 g, 0.087 mmol) were added. The reaction mixture was stirred under N2 at 80°C for 18 hours, then quenched with aqueous NH4Cl solution and extracted with siRNA (200 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel chromatography yielded the title compound (8.7 mg, 60%). LCMS(m / z):336.2[M+H] + .

[0810] Step 2: Synthesis of 4-[2-methyl-6-(methylcarbamoyl)pyridine-3-yl]piperazine-1-carboxylate tert-butyl: To a stirred solution of 4-[6-(methoxycarbonyl)-2-methylpyridine-3-yl]piperazine-1-carboxylate tert-butyl (8.7 g, 25.94 mmol) in MeOH (20 mL), MeNH2 (33% in MeOH, 100 mL) was added, and the reaction mixture was stirred at room temperature for 18 hours. The mixture was then concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (8 g, 92%). LCMS (m / z): 335.3 [M+H] + .

[0811] Step 3: Synthesis of N,6-dimethyl-5-(piperazin-1-yl)picolinamide dihydrochloride: To a stirred solution of 4-[2-methyl-6-(methylcarbamoyl)pyridine-3-yl]piperazin-1-carboxylate tert-butyl (8 g, 23.92 mmol) in DCM (60 mL), 4 M HCl in dioxane (20 mL) was added, and the reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound (6.7 g, 91%). LCMS (m / z): 235.2 [M+H] + .

[0812] Example S-10: Synthesis of 5-(4-((2-(3-isopropylureido)pyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide (compound 259).

[0813] [ka] Step 1: Synthesis of 1-(4-(chloromethyl)pyridine-2-yl)-3-isopropylurea: To a stirred solution of 4-(chloromethyl)pyridine-2-amine hydrochloride (100 mg, 0.56 mmol) in DMF (3 mL), isopropyl isocyanate (57 mg, 0.67 mmol) and Et3N (113 mg, 1.12 mmol) were added, and the reaction mixture was stirred at 50°C for 5 hours. The reaction mixture was quenched with aqueous NH4Cl solution and extracted with  (50 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (50 mg, 39%). LCMS (m / z): 228.2 [M+H] + .

[0814] Step 2: Synthesis of 5-(4-((2-(3-isopropylureido)pyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide: A mixture of 1-(4-(chloromethyl)pyridine-2-yl)-3-isopropylurea (50 mg, 0.22 mmol), N,6-dimethyl-5-(piperazine-1-yl)picolinamide dihydrochloride (101 mg, 0.33 mmol), KI (55 mg, 0.33 mmol), and DIPEA (284 mg, 2.2 mmol) in CH3CN (5 mL) was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the crude product, which was then purified by preparative HPLC to obtain the title compound (33 mg, 35%). LCMS (m / z): 426.3 [M+H] + ; 1HNMR(400MHz,DMSO-d6)δ9.04(s,1H),8.47-8.39(m,1H),8.11(q,J=5.2 Hz,1H),8.01(d,J=5.9 Hz,1H),7.80(d,J=8.3 Hz,1H),7.48(d,J=8.3 Hz,1H),7.38(s,1H),6.90(d,J=4.8 Hz,1H),3.88-3.75(m,1H),3.52(s,2H),3.01-2.89(m,4H),2.80(d,J=4.8 Hz, 3H), 3.01-2.89 (m, 4H), 2.49 (s, 3H), 1.13 (d, J=6.5 Hz, 6H).

[0815] Example S-11: Synthesis of 5-(4-((2-(3-cyclopropylureido)pyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide (compound 46).

[0816] [ka] Step 1: Synthesis of 1-(4-(chloromethyl)pyridine-2-yl)-3-cyclopropylurea: To a stirred solution of 4-(chloromethyl)pyridine-2-amine hydrochloride (100 mg, 0.56 mmol) in DMF (1.5 mL), cyclopropyl isocyanate (55.7 mg, 0.67 mmol) and Et3N (113 mg, 1.12 mmol) were added, and the reaction mixture was stirred at 50°C for 3 hours. The reaction mixture was quenched with aqueous NH4Cl solution and extracted with RINKAN (20 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (130 mg, crude product). LCMS (m / z): 226.1 [M+H] + .

[0817] Step 2: Synthesis of 5-(4-((2-(3-cyclopropylureido)pyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide: A mixture of 1-(4-(chloromethyl)pyridine-2-yl)-3-cyclopropylurea (130 mg, 0.58 mmol), N,6-dimethyl-5-(piperazine-1-yl)picolinamide dihydrochloride (178 mg, 0.58 mmol), KI (143 mg, 0.86 mmol), and DIPEA (744 mg, 5.76 mmol) in CH3CN (5 mL) was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the crude product, which was then purified by preparative HPLC to obtain the title compound (44 mg, 19%). LCMS (m / z): 424.3 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ9.07(s,1H),8.45-8.39(m,1H),8.23-8.15(m,1H),8.11(d,J=5.2 Hz,1H),7.79(d,J=8.3 Hz,1H),7.49(d,J=8.3 Hz,1H),7.41(s,1H)),6.91(d,J=5.2 Hz,1H),3.52(s,2H),2.99‐2.92(m,4H),2.80(d,J=4.9 Hz,3H),2.63-2.53(m,5H),2.49(s,3H),0.68-0.63(m,2H),0.46-0.40(m,2H).

[0818] Example S-12: Synthesis of N,6-dimethyl-5-(4-((2-(3-methylureido)pyridine-4-yl)methyl)piperazine-1-yl)picolinamide trifluoroacetate (compound 42).

[0819] [ka] Step 1: Synthesis of 5-(4-((2-aminopyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide: A mixture of 4-(chloromethyl)pyridine-2-amine hydrochloride (150 mg, 0.84 mmol), N,6-dimethyl-5-(piperazine-1-yl)picolinamide dihydrochloride (258 mg, 0.84 mmol), KI (209 mg, 1.26 mmol), and DIPEA (1.09 g, 8.4 mmol) in CH3CN (15 mL) was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound (130 mg, 45%). LCMS (m / z): 341.3 [M+H] + .

[0820] Step 2: Synthesis of N,6-dimethyl-5-(4-((2-(3-methylureido)pyridine-4-yl)methyl)piperazin-1-yl)picolinamide trifluoroacetate: To a mixture of 5-(4-((2-aminopyridine-4-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (60 mg, 0.176 mmol) in pyridine (2 mL), DMAP (2 mg, 0.0176 mmol) was added, followed by the addition of N-methylcarbamoyl chloride (25 mg, 0.264 mmol). The reaction mixture was stirred at 40°C for 48 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title compound (5 mg, 5%). LCMS (m / z): 398.0 [M+H] + ; 1 HNMR(400MHz,CD3OD)δ8.35(d,J=5.4 Hz,1H),7.93(d,J=8.3 Hz,1H),7.59(d,J=8.3 Hz,1H),7.47(s,1H),7.21(d,J=5.4 Hz,1H),4.42(s,2H),3.57-3.43(m,4H),3.32-3.22(m,4H),2.97(s,3H),2.89(s,3H),2.61(s,3H).

[0821] Example S-13: Synthesis of 5-(4-((2-(3-ethylureido)pyridine-4-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (compound 9).

[0822] [ka] Step 1: Synthesis of Methyl 5-Bromo-6-Fluoropikolinate: To a stirred solution of methyl 5-bromopicolinate (7 g, 32.4 mmol) in CH3CN (50 mL), AgF2 (23.6 g, 162 mmol) was added, and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was then filtered, the filter cake was washed with MeOH (50 mL x 3), and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to obtain the title compound (2.9 g, 38%). LCMS (m / z): 234.0 [M+H] + .

[0823] Step 2: Synthesis of 4-(2-fluoro-6-(methoxycarbonyl)pyridine-3-yl)piperazine-1-carboxylate tert-butyl: To a stirred solution of methyl 5-bromo-6-fluoropicolinate (2.9 g, 12.39 mmol) in dioxane (50 mL), piperazine-1-carboxylate tert-butyl (2.77 g, 14.87 mmol), RuPhosPd G3 (1.04 g, 1.24 mmol), and Cs2CO3 (8.08 g, 24.8 mmol) were added, and the reaction mixture was stirred at 80°C for 18 hours under an N2 atmosphere. The reaction mixture was quenched to pH 7 with aqueous NH4Cl solution (50 mL) and extracted with siRNA (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (2 g, 48%). LCMS(m / z):340.2[M+H] + .

[0824] Step 3: Synthesis of 4-(2-fluoro-6-(methylcarbamoyl)pyridine-3-yl)piperazine-1-carboxylate tert-butyl: To a stirred solution of 4-(2-fluoro-6-(methoxycarbonyl)pyridine-3-yl)piperazine-1-carboxylate tert-butyl (2 g, 5.89 mmol) in MeOH (10 mL), MeOH (10 mL) containing 33% methylamine was added, and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound (1.98 mg, 99%). LCMS (m / z): 235.2 [M+H] + .

[0825] Step 4: Synthesis of 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide hydrochloride: 4-(2-fluoro-6-(methylcarbamoyl)pyridine-3-yl)piperazin-1-carboxylate tert-butyl (1.98 g, 5.85 mmol) was added to a stirred solution in DCM (15 mL). 4 M HCl in dioxane (5 mL) was added, and the reaction mixture was stirred at 25°C for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (1.5 g, 93%). LCMS (m / z): 239.2 [M+H] + .

[0826] Step 5: Synthesis of 5-(4-((2-aminopyridine-4-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide: To a stirred solution of 6-fluoro-N-methyl-5-(piperazine-1-yl)picolinamide dihydrochloride (200 mg, 0.73 mmol) in CH3CN (4 mL), 4-(chloromethyl)pyridine-2-amine hydrochloride (131 mg, 0.73 mmol), DIPEA (282 mg, 2.18 mmol), and KI (121 mg, 0.73 mmol) were added, and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound (170 mg, 68%). LCMS (m / z): 345.2 [M+H] + .

[0827] Step 6: Synthesis of 5-(4-((2-(3-ethylureido)pyridine-4-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide: To a stirred solution of 5-(4-((2-aminopyridine-4-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (160 mg, 0.46 mmol) in DMF (3 mL), ethyl isocyanate (50 mg, 0.70 mmol) and Cs2CO3 (303 mg, 0.93 mmol) were added, and the resulting reaction was stirred at 80°C for 4 hours. The reaction mixture was then filtered, the filter cake was washed with MeOH (3 mL x 2), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the crude product, which was then purified by preparative HPLC to obtain the title compound (54 mg, 28%). LCMS (m / z): 416.1 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ9.13(s,1H),8.40(q,J=4.5 Hz,1H),8.22-8.13(m,1H),8.11(d,J=5.2 Hz,1H),7.85(dd,J=8.0,1.1 Hz,1H),7.57(dd,J=10.6,8.2 Hz,1H),7.34(s,1H),6.89(dd,J=5.2,1.0 Hz,1H),3.50(s,2H),3.32(s,2H),3.21‐3.18(m,4H),2.77(d,J=4.8 Hz, 3H), 2.60-2.53 (m, 4H), 1.09 (t, J=7.2 Hz, 3H).

[0828] Example S-14: Synthesis of 1-(4-((4-(5-cyanopyridine-2-yl)piperazine-1-yl)methyl)pyridine-2-yl)-3-ethylurea (compound 263).

[0829] [ka] Step 1: Synthesis of 1-(4-((4-(5-cyanopyridine-2-yl)piperazin-1-yl)methyl)pyridine-2-yl)-3-ethylurea: To a stirred solution of 1-(4-(chloromethyl)pyridine-2-yl)-3-ethylurea (80 mg, 0.37 mmol) in CH3CN (2 mL), 6-(piperazin-1-yl)nicotinonitrile (70 mg, 0.37 mmol), DIPEA (145 mg, 1.12 mmol), and KI (62 mg, 0.37 mmol) were added, and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was quenched with water and extracted with MeOH:DCM (1:10, 5 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the crude product, which was then purified by preparative HPLC to obtain the title compound (28 mg, 21%). LCMS (m / z): 366.1 [M+H] + ; 1 HNMR(400MHz,CD3OD)δ8.40(d,J=2.1 Hz,1H),8.16(d,J=5.3 Hz,1H),7.73(dd,J=9.1,2.3 Hz,1H),7.14(s,1H),7.01(d,J=5.2 Hz,1H),6.86(d,J=9.1 Hz,1H),3.81-3.70(m,4H),3.58(s,2H),3.38-3.34(m,2H),2.65-2.52(m,4H),1.23(t,J=7.2 Hz,3H).

[0830] Example S-15: Synthesis of N-methyl-5-(piperazin-1-yl)-6-(trifluoromethyl)picolinamide hydrochloride.

[0831] [ka] Step 1: Synthesis of methyl 5-chloro-6-(trifluoromethyl)picolinate. To a solution of 5-chloro-6-(trifluoromethyl)picolinic acid (900 mg, 3.99 mmol) in MeOH (10 mL), SOCl2 (0.6 mL, 7.98 mmol) was added. The reaction mixture was stirred at 65°C for 2 hours, then concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (900 mg, 94%). LCMS (m / z): 239.8 [M+H] + .

[0832] Step 2: Synthesis of 4-(6(methoxycarbonyl)-2-(trifluoromethyl)pyridine-3-yl)piperazine-1-carboxylate tert-butyl. To a solution of methyl 5-chloro-6-(trifluoromethyl)picolinate (900 mg, 3.76 mmol) in dioxane (10 mL), piperazine-1-carboxylate tert-butyl (840 mg, 4.51 mmol), Cs2CO3 (2.44 g, 7.49 mmol), and RuPhosPdG3 (316 mg, 0.38 mmol) were added, and the reaction mixture was stirred at 100°C for 10 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (490 mg, 33%). LCMS (m / z): 390.1 [M+H] + .

[0833] Step 3: Synthesis of 4-(6(methylcarbamoyl)-2-(trifluoromethyl)pyridine-3-yl)piperazine-1-carboxylate tert-butyl. 40 mg, 0.10 mmol of 4-(6-(methoxycarbonyl)-2-(trifluoromethyl)pyridine-3-yl)piperazine-1-carboxylate tert-butyl (1 mL) was dissolved in MeOH (1 mL). Methylamine (33% in methanol, 2 mL) was added, and the reaction mixture was stirred at 25°C for 2 hours. The mixture was then concentrated under reduced pressure to obtain the title compound (39 mg, 98%). LCMS (m / z): 332.9 [M+H] + .

[0834] Step 4: Synthesis of N-methyl-5-(piperazin-1-yl)-6-(trifluoromethyl)picolinamide hydrochloride. A solution of 4-(6-(methylcarbamoyl)-2(trifluoromethyl)pyridine-3-yl)piperazin-1-carboxylate tert-butyl (39 mg, 0.1 mmol) in dioxane (3 mL) in 4 M HCl was stirred at 25°C for 2 hours. The reaction product was concentrated to obtain the title compound (50 mg, crude product). LCMS (m / z): 289.2 [M+H] + .

[0835] Example S-16: Synthesis of 5-(4-((2-(3-ethylureido)pyridine-4-yl)methyl)piperazine-1-yl)-N-methyl-6-(trifluoromethyl)picolinamide trifluoroacetate (compound 21).

[0836] [ka] Step 1: Synthesis of 5-(4-((2-(3-ethylureido)pyridine-4-yl)methyl)piperazine-1-yl)-N-methyl-6-(trifluoromethyl)picolinamide trifluoroacetate: A mixture of 1-(4-(chloromethyl)pyridine-2-yl)-3-ethylurea (64 mg, 0.30 mmol), N-methyl-5-(piperazine-1-yl)-6-(trifluoromethyl)picolinamide (86 mg, 0.30 mmol), KI (100 mg, 0.6 mmol), and DIPEA (76 mg, 0.6 mmol) in CH3CN (3 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the crude product, which was then purified by preparative HPLC to obtain the title compound (21 mg, 12%). LCMS (m / z): 466.3 [M+H] + ; 1HNMR(400MHz,DMSO-d6)δ10.14(br s,1H),9.43(br s,1H),8.50(d,J=4.8 Hz,1H),8.27(dd,J=14.2,6.8 Hz,2H),8.10(d,J=8.5 Hz,1H),7.71(s,1H),7.62(s,1H),7.11(s,1H),4.42(s,2H),3.45(s,2H),3.06-3.37(m,8H),2.83(d,J=4.8 Hz,3H),1.09(t,J=7.2 Hz,3H).

[0837] Example S-17: Synthesis of (R)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide.

[0838] [ka] Step 1: Synthesis of 4-benzyl 1-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate. To a stirred solution of (R)-2-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (4 g, 18.49 mmol) in DCM (100 mL), Et3N (7.7 mL, 55.54 mmol) and CbzCl (5.3 mL, 36.99 mmol) were added. The reaction mixture was stirred at 25°C for 18 hours, then quenched with water (100 mL) and extracted with CH2Cl2 (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (3.8 g, 59%). LCMS (m / z): 373.3 [M+Na] + .

[0839] Step 2: Synthesis of 4-benzyl 1-(tert-butyl)(R)-2-(((3-bromo-6-(methoxycarbonyl)pyridine-2-yl)oxy)methyl)piperazine-1,4-dicarboxylate. To a stirred solution of DEAD (8.5 mL, 53.98 mmol) in THF (50 mL) at 0°C, PPh3 (17 g, 64.81 mmol) was added, and the reaction mixture was stirred at the same temperature for 1 hour. Then, a solution of 4-benzyl 1-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (3.8 g, 10.84 mmol) and methyl 5-bromo-6-hydroxypicolinate (2.51 g, 10.82 mmol) in THF (50 mL) was added at 0°C, and the resulting solution was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound (4.6 mg, 75%). LCMS (m / z): 586.2 [M + Na] + .

[0840] Step 3: Synthesis of benzyl(R)-3-(((3-bromo-6-(methoxycarbonyl)pyridine-2-yl)oxy)methyl)piperazine-1-carboxylate. 4-benzyl 1-(tert-butyl)(R)-2-(((3-bromo-6-(methoxycarbonyl)pyridine-2-yl)oxy)methyl)piperazine-1,4-dicarboxylate (4.6 g, 8.15 mmol) in a stirred solution in dioxane (50 mL) was mixed with 4N HCl in dioxane (50 mL), and the reaction mixture was stirred at 25°C for 18 hours. The mixture was then neutralized to pH=8 with aqueous Na2CO3 solution and extracted with CH2Cl2 (50 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (3.6 mg, 95%). LCMS(m / z):464.2[M+H] + .

[0841] Step 4: Synthesis of 3-benzyl 8-methyl(R)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3,8(4H)-dicarboxylate. PdCl2DPEPhos (0.92 g, 1.29 mmol) and Cs2CO3 (4.2 g, 12.89 mmol) were added to a stirred solution of benzyl(R)-3-(((3-bromo-6-(methoxycarbonyl)pyridine-2-yl)oxy)methyl)piperazine-1-carboxylate (2 g, 4.31 mmol) in DMF (50 mL), and the reaction mixture was stirred under N2 at 80°C for 18 hours. The reaction mixture was quenched with aqueous NH4Cl solution and extracted with ELISA (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel chromatography yielded the title compound (600 mg, 36%). LCMS (m / z): 384.2 [M+H] + .

[0842] Step 5: Synthesis of benzyl(R)-8-(methylcarbamoyl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3,8(4H)-carboxylate. To a stirred solution of 3-benzyl8-methyl(R)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3,8(4H)-dicarboxylate (600 mg, 1.56 mmol) in MeOH (3 mL), MeNH2 (33% in MeOH, 3 mL) was added, and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound (420 mg, 70%). LCMS (m / z): 383.3 [M+H] + .

[0843] Step 6: Synthesis of (R)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide. To a stirred solution of benzyl(R)-8-(methylcarbamoyl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3(4H)-carboxylate (420 mg, 1.1 mmol) in i-PrOH (5 mL), NH4OH (1 mL) and 10% Pd / C (117 mg) were added, and the reaction mixture was stirred under H2 at room temperature for 4 hours. The reaction mixture was filtered, and the filter cake was washed with MeOH (5 mL x 3). The filtrate was concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound (260 g, 95%). LCMS(m / z):249.2[M+H] + .

[0844] Example S-18: Synthesis of (R)-3-((2-(3-ethylureido)pyridine-4-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (compound 264).

[0845] [ka] Step 1: Synthesis of (R)-3-((2-(3-ethylureido)pyridine-4-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide: A mixture of 1-(4-(chloromethyl)pyridine-2-yl)-3-ethylurea (35 mg, 0.16 mmol), (R)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (46 mg, 0.18 mmol), KI (42 mg, 0.25 mmol), and DIPEA (106 mg, 0.82 mmol) in CH3CN (3 mL) was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the crude product. This crude product was then purified by preparative HPLC to obtain the title compound (22 mg, 32%). LCMS (m / z): 426.2 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ9.10(s,1H),8.19-8.10(m,2H),8.08(d,J=5.2 Hz,1H),7.49(d,J=8.1 Hz,1H),7.30-7.23(m,2H),6.87-6.84(m,1H),4.37(dd,J=11.0,2.8 Hz,1H),4.01(dd,J=10.9,9.1 Hz,1H),3.75(d,J=13.0 Hz,1H),3.47(dd,J=33.1,14.3 Hz,2H),3.22-3.10(m,3H),2.93-2.73(m,3H),2.70(d,J=4.8 Hz, 3H), 2.21-2.13 (m, 1H), 1.77 (t, J=10.8 Hz, 1H), 1.04 (t, J=7.2 Hz, 3H).

[0846] Example S-19: Synthesis of 5-(4-((2-((N-ethylsulfamoyl)amino)pyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide (compound 105).

[0847] [ka] Step 1: Synthesis of 5-(4-((2-aminopyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide: To a stirred solution of N,6-dimethyl-5-(piperazine-1-yl)picolinamide dihydrochloride (20 mg, 0.065 mmol) in CH3CN (2 mL), 4-(chloromethyl)pyridine-2-amine hydrochloride (12 mg, 0.067 mmol), DIPEA (25 mg, 0.19 mmol), and KI (11 mg, 0.066 mmol) were added, and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was quenched to pH 8 with aqueous NaHCO3 solution and extracted with DCM (5 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (22 mg, 99%). LCMS(m / z):341.1[M+H] + .

[0848] Step 2: Synthesis of 5-(4-((2-((N-ethylsulfamoyl)amino)pyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide: Ethyl sulfamoyl chloride (10 mg, 0.071 mmol) and Et3N (13 mg, 0.13 mmol) were added to a stirred solution of 5-(4-((2-aminopyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide (22 mg, 0.065 mmol) in DCM (1 mL), and the reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title compound (2 mg, 9%). LCMS (m / z): 448.0 [M+H] + ; 1HNMR(400MHz,DMSO-d6)δ8.43(q,J=4.7 Hz,1H),8.36(s,1H),8.15(d,J=5.1 Hz,1H),7.80(d,J=8.2 Hz,1H),7.49(d,J=8.3 Hz,1H),7.22(s,1H),7.03(s,1H),6.95(d,J=4.8 Hz,1H),3.54(s,2H),3.01-2.93(m,4H),2.90-2.86(m,2H),2.80(d,J=4.9 Hz, 3H), 2.64-2.54 (m, 4H), 2.49 (s, 3H), 0.98 (t, J=7.2 Hz, 3H).

[0849] Example S-20: Synthesis of N-cyano-5-(4-((2-(3-ethylureido)pyridine-4-yl)methyl)piperazine-1-yl)-6-methylpicolinamide dihydrochloride (compound 3).

[0850] [ka] Step 1: Synthesis of methyl 5-(4-((2-(3-ethylureido)pyridine-4-yl)methyl)piperazine-1-yl)-6-methyl picolinate: To a stirred solution of methyl 6-methyl-5-(piperazine-1-yl) picolinate dihydrochloride (300 mg, 0.97 mmol) in CH3CN (5 mL), 1-(4-(chloromethyl)pyridine-2-yl)-3-ethylurea (207 mg, 0.97 mmol), DIPEA (629 mg, 4.87 mmol), and KI (161 mg, 0.97 mmol) were added, and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was quenched with water and extracted with DCM (10 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (400 g, 99.6%). LCMS (m / z): 413.2 [M+H] + .

[0851] Step 2: Synthesis of 5-(4-((2-(3-ethylureido)pyridine-4-yl)methyl)piperazin-1-yl)-6-methylpicolinate: To a stirred solution of methyl 5-(4-((2-(3-ethylureido)pyridine-4-yl)methyl)piperazin-1-yl)-6-methylpicolinate (380 mg, 0.92 mmol) in MeOH (4 mL), H2O (1 mL) and NaOH (114 mg, 2.85 mmol) were added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched to pH 6 with 1 M HCl. The reaction mixture was filtered, and the filter cake was washed with MeOH (5 mL x 3). The filtrate was concentrated under reduced pressure, and the residue was purified by C18 chromatography with water / CH3CN to obtain the title compound (290 g, 79%). LCMS (m / z): 399.1 [M + H] + .

[0852] Step 3: Synthesis of N-cyano-5-(4-((2-(3-ethylureido)pyridine-4-yl)methyl)piperazin-1-yl)-6-methylpicolinamide dihydrochloride: To a stirred solution of 5-(4-((2-(3-ethylureido)pyridine-4-yl)methyl)piperazin-1-yl)-6-methylpicolinic acid (270 mg, 0.68 mmol) in DMF (10 mL), DMAP (182 mg, 1.49 mmol), EDCI (312 mg, 1.63 mmol), and NH2CN (31 mg, 0.75 mmol) were added, and the resulting reaction was stirred at room temperature for 72 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title compound (11 mg, 3%). LCMS (m / z): 423.3 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ9.15(s,1H),8.21(s,1H),8.11(d,J=5.2 Hz,1H),7.80(d,J=8.2 Hz,1H),7.40(d,J=7.9 Hz,1H),7.33(s,1H),7.28-6.95(m,2H),6.90(d,J=5.1 Hz,1H),3.52(s,2H),3.25-3.14(m,2H),2.99-2.87(m,4H),2.64-2.54(m,4H),2.45(s,3H),1.09(t,J=7.2 Hz,3H).

[0853] Example S-21: Synthesis of 5-(4-((2-(3-ethylureido)-3-fluoropyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide (compound 82).

[0854] [ka] Step 1: Synthesis of 2-((diphenylmethylene)amino)-3-fluoroisonicotinate methyl: To a stirred solution of 2-chloro-3-fluoroisonicotinate methyl (4 g, 21.1 mmol) in dioxane (40 mL), diphenylmethaneimine (5.7 g, 31.7 mmol), Pd(OAc)2 (951 mg, 4.2 mmol), BINAP (5.2 g, 8.4 mmol), and Cs2CO3 (13.8 g, 42.4 mmol) were added, and the reaction mixture was stirred at 80°C for 18 hours under an N2 atmosphere. The reaction mixture was quenched with aqueous NH4Cl solution and extracted with RINKAN (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (2 g, 28%). LCMS (m / z): 335.0 [M+H] + .

[0855] Step 2: Synthesis of methyl 2-amino-3-fluoroisonicotinate: To a stirred solution of methyl 2-((diphenylmethylene)amino)-3-fluoroisonicotinate (2 g, 5.98 mmol) in THF (16 mL), concentrated HCl (4 mL) was added, and the reaction mixture was stirred at 0°C for 3 hours. The reaction mixture was quenched to pH 8 with aqueous NaHCO3 solution and extracted with MeOH:DCM (1:10, 50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (600 mg, 59%). LCMS (m / z): 171.2 [M+H] + .

[0856] Step 3: Synthesis of (2-amino-3-fluoropyridine-4-yl)methanol: To a stirred solution of methyl 2-amino-3-fluoroisonicotinate (600 mg, 3.53 mmol) in THF (10 mL), LiAlH4 (3.6 mL, 1 M in THF) was added at 0°C, and the reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with Na2SO4·10H2O (1 g). The reaction mixture was filtered, and the filter cake was washed with MeOH:DCM (1:10, 10 mL x 3). The filtrate was concentrated under reduced pressure, and the crude residue was purified by silica gel chromatography to obtain the title compound (210 mg, 42%). LCMS (m / z): 143.1[M+H]+.

[0857] Step 4: Synthesis of 4-(chloromethyl)-3-fluoropyridine-2-amine: To a stirred solution of (2-amino-3-fluoropyridine-4-yl)methanol (310 mg, 2.18 mmol) in DCM (5 mL), DMF (32 mg, 0.44 mmol) and SOCl2 (259 mg, 2.18 mmol) were added at 0°C, and the resulting reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with aqueous NaHCO3 solution at pH 8 and extracted with MeOH:DCM (1:10, 10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (180 mg, 51%). LCMS (m / z): 161.1 [M+H] + .

[0858] Step 5: Synthesis of 5-(4-((2-amino-3-fluoropyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide: To a stirred solution of 4-(chloromethyl)-3-fluoropyridine-2-amine (180 mg, 1.12 mmol) in CH3CN (5 mL), N,6-dimethyl-5-(piperazine-1-yl)picolinamide dihydrochloride (344 mg, 1.12 mmol), DIPEA (725 mg, 5.61 mmol), and KI (186 mg, 1.12 mmol) were added, and the mixture was stirred at 25°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel chromatography to obtain the title compound (100 mg, 25%). LCMS (m / z): 359.3 [M+H] + .

[0859] Step 6: Synthesis of 5-(4-((2-(3-ethylureido)-3-fluoropyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide: To a stirred solution of 5-(4-((2-amino-3-fluoropyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide (80 mg, 0.22 mmol) in DMF (1 mL), ethyl isocyanate (18 mg, 0.25 mmol) and Cs2CO3 (147 mg, 0.45 mmol) were added, and the resulting reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was quenched to pH 7 with aqueous NH4Cl solution and extracted with MeOH:DCM (1:10, 5 mL x 4). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound (5 mg, 6%). LCMS(m / z):430.1[M+H] + ; 1HNMR(400MHz,DMSO-d6)δ9.07(s,1H),9.02-8.90(m,1H),8.43(q,J=4.6 Hz,1H),8.02(d,J=5.1 Hz,1H),7.79(d,J=8.3 Hz,1H),7.48(d,J=8.3 Hz,1H),7.08(t,J=4.9 Hz,1H),3.65(s,2H),3.28-3.20(m,2H),3.08-2.86(m,4H),2.80(d,J=4.9 Hz, 3H), 2.69-2.53 (m, 4H), 2.48 (s, 3H), 1.11 (t, J=7.2 Hz, 3H).

[0860] Example S-22: Synthesis of 5-(4-((2-(3-ethylureido)-3-methylpyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide hemiformate (compound 260).

[0861] [ka] Step 1: Synthesis of methyl 2-((diphenylmethylene)amino)-3-fluoroisonicotinate: To a stirred solution of methyl 2-chloro-3-fluoroisonicotinate (300 g, 1.62 mmol) in dioxane (5 mL), toluene (5 mL), diphenylmethaneimine (323 g, 1.78 mmol), Pd(dba)2 (91 mg, 0.16 mmol), xanthophos (185 g, 0.32 mmol), and Cs2CO3 (1.06 g, 3.24 mmol) were added, and the reaction mixture was stirred at 100 °C for 18 hours under an N2 atmosphere. The reaction mixture was quenched with water and extracted with RINKAN (20 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography on silica gel to obtain the title compound (280 mg, 52%). LCMS(m / z):331.2[M+H] + .

[0862] Step 2: Synthesis of methyl 2-amino-3-methylisonicotinate: To a stirred solution of methyl 2-((diphenylmethylene)amino)-3-methylisonicotinate (280 mg, 0.85 mmol) in MeOH (4 mL), concentrated HCl (1 mL) was added, and the reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was quenched to pH 8 with aqueous NaHCO3 solution and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (140 g, 99%). LCMS (m / z): 167.2 [M+H] + .

[0863] Step 3: Synthesis of (2-amino-3-methylpyridine-4-yl)methanol: To a stirred solution of methyl 2-amino-3-methylisonicotinate (140 mg, 0.84 mmol) in THF (4 mL), a 1.0 M LiAlH4 solution in THF (0.84 mL) was added at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with Na2SO4·10H2O (300 mg), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (100 mg, 86%). LCMS (m / z): 139.2 [M+H] + .

[0864] Step 4: Synthesis of 4-(chloromethyl)-3-methylpyridine-2-amine: To a stirred solution of (2-amino-3-methylpyridine-4-yl)methanol (80 mg, 0.58 mmol) in DCM (2 mL) at 0°C, DMF (4 mg, 0.058 mmol) and SOCl2 (69 mg, 0.58 mmol) were added, and the reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched with aqueous NaHCO3 solution and extracted with DCM (5 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to obtain the title compound (60 mg, 66%). LCMS (m / z): 157.1 [M+H] + .

[0865] Step 5: Synthesis of 5-(4-((2-amino-3-methylpyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide: To a stirred solution of 4-(chloromethyl)-3-methylpyridine-2-amine (60 mg, 0.38 mmol) in CH3CN (1 mL), N,6-dimethyl-5-(piperazine-1-yl)picolinamide dihydrochloride (117 mg, 0.38 mmol), DIPEA (248 mg, 1.92 mmol), and KI (63 mg, 0.38 mmol) were added, and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound (60 mg, 45%). LCMS (m / z): 355.1 [M+H] + .

[0866] Step 6: Synthesis of 5-(4-((2-(3-ethylureido)-3-methylpyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide hemiformate: To a stirred solution of 5-(4-((2-amino-3-methylpyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide (60 mg, 0.17 mmol) in DMF (1 mL), ethyl isocyanate (12 mg, 0.17 mmol) and Cs2CO3 (111 mg, 0.34 mmol) were added, and the reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was quenched with water and extracted with MeOH:DCM (1:10, 5 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the title compound (8 mg, 11%). LCMS(m / z):426.3[M+H] + ; 1HNMR(400MHz,DMSO-d6)δ9.25(t,J=4.9 Hz,1H),8.39(q,J=4.6 Hz,1H),8.05(s,1H),8.01(d,J=5.1 Hz,1H),7.75(d,J=8.2 Hz,1H),7.44(d,J=8.3 Hz,1H),6.96(d,J=5.2 Hz,1H),3.50(s,2H),3.22-3.17(m,2H),2.93-2.86(m,4H),2.76(d,J=4.9 Hz,3H),2.57-2.51(m,4H),2.45(s,3H),2.17(s,3H),1.07(t,J=7.2 Hz,3H).

[0867] Example S-23: Synthesis of 5-(4-((2-(3-ethylureido)-5-methylpyridine-4-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide formate (compound 70).

[0868] [ka] Step 1: Synthesis of methyl 2-amino-5-methylisonicotinate: To a stirred solution of methyl 2-amino-5-bromoisonicotinate (400 mg, 1.73 mmol) in DMSO (8 mL), trimethylboroxine (436 mg, 3.47 mmol), Pd(OAc)2 (77 mg, 0.34 mmol), S-phos (283 mg, 0.69 mmol), and K3PO4 (1.1 g, 5.19 mmol) were added, and the reaction mixture was stirred at 80°C for 18 hours under an N2 atmosphere. The reaction mixture was quenched with water and extracted with RINKAN (15 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (110 g, 38%). LCMS (m / z): 167.2 [M+H] + .

[0869] Step 2: Synthesis of (2-amino-5-methylpyridine-4-yl)methanol: To a stirred solution of methyl 2-amino-5-methylpyridine-4-carboxylate (110 mg, 0.66 mmol) in THF (2 mL) at 0°C, 1.0 M LiAlH4 in THF (0.7 mL) was added, and the reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was quenched with Na2SO4·10H2O (500 mg), filtered, and the filtrate cake was washed with MeOH:DCM (1:10, 5 mL x 3). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound (80 g, 88%). LCMS (m / z): 139.2 [M+H] + .

[0870] Step 3: Synthesis of 4-(chloromethyl)-5-methylpyridine-2-amine: To a stirred solution of (2-amino-5-methylpyridine-4-yl)methanol (70 mg, 0.51 mmol) in DCM (2 mL) at 0°C, DMF (4 mg, 0.051 mmol) and SOCl2 (60 mg, 0.51 mmol) were added, and the reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound (50 mg, 63%). LCMS (m / z): 157.2 [M+H] + .

[0871] Step 4: Synthesis of 5-(4-((2-amino-5-methylpyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide: To a stirred solution of 4-(chloromethyl)-5-methylpyridine-2-amine (50 mg, 0.32 mmol) in CH3CN (2 mL), N,6-dimethyl-5-(piperazine-1-yl)picolinamide dihydrochloride (98 mg, 0.32 mmol), DIPEA (124 mg, 0.96 mmol), and KI (53 mg, 0.32 mmol) were added, and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound (60 mg, 53%). LCMS (m / z): 355.3 [M+H] + .

[0872] Step 5: Synthesis of 5-(4-((2-(3-ethylureido)-5-methylpyridine-4-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide formate: To a stirred solution of 5-(4-((2-amino-5-methylpyridine-4-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (60 mg, 0.17 mmol) in DMF (2 mL), ethyl isocyanate (12 mg, 0.17 mmol) and Cs2CO3 (111 mg, 0.34 mmol) were added, and the reaction mixture was stirred at 80°C for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the crude product, which was then purified by preparative HPLC to obtain the title compound (11 mg, 14%). LCMS (m / z): 426.1 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ9.03(s,1H),8.44(q,J=4.5 Hz,1H),8.17(s,2H),7.94(s,1H),7.80(d,J=8.2 Hz,1H),7.48(d,J=8.3 Hz,1H),7.35(s,1H),3.47(s,2H),3.21-3.14(m,2H),2.99-2.90(m,4H),2.80(d,J=4.9 Hz, 3H), 2.64-2.53 (m, 4H), 2.49 (s, 3H), 2.20 (s, 3H), 1.08 (t, J=7.2 Hz, 3H).

[0873] Example S-24: Synthesis of 5-(4-((6-(3-ethylureido)pyrimidine-4-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide formate (compound 230).

[0874] [ka] Step 1: Synthesis of (6-aminopyrimidine-4-yl)methanol: To a stirred solution of methyl 6-aminopyrimidine-4-carboxylate (500 mg, 3.26 mmol) in MeOH (10 mL), LiBH4 (213 mg, 9.80 mmol) was added, and the reaction mixture was stirred at 70°C for 18 hours. The reaction mixture was quenched to pH 7 with aqueous NH4Cl solution and extracted with MeOH:DCM (1:10, 20 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (370 mg, 91%). LCMS (m / z): 126.2 [M+H] + .

[0875] Step 2: Synthesis of 6-(chloromethyl)pyrimidine-4-amine: To a stirred solution of (6-aminopyrimidine-4-yl)methanol (370 mg, 2.96 mmol) in DCM (10 mL) at 0°C, DMF (22 mg, 0.30 mmol) and SOCl2 (352 mg, 2.96 mmol) were added, and the reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched to pH 8 with aqueous NaHCO3 solution and extracted with MeOH:DCM (1:10, 10 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (300 g, 71%). LCMS (m / z): 144.2 [M+H] + .

[0876] Step 3: Synthesis of 1-(6-(chloromethyl)pyrimidine-4-yl)-3-ethylurea: Ethyl isocyanate (74 mg, 1.04 mmol) and Cs2CO3 (681 mg, 2.09 mmol) were added to a stirred solution of 6-(chloromethyl)pyrimidine-4-amine (150 mg, 1.04 mmol) in DMF (2 mL), and the reaction mixture was stirred at 60°C for 4 hours. The reaction mixture was quenched to pH 7 with aqueous NH4Cl solution and extracted with MeOH:DCM (1:10, 5 mL x 4). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (80 mg, 36%). LCMS (m / z): 215.1 [M+H] + .

[0877] Step 4: Synthesis of 5-(4-((6-(3-ethylureido)pyrimidine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide formate: To a stirred solution of 1-(6-(chloromethyl)pyrimidine-4-yl)-3-ethylurea (70 mg, 0.33 mmol) in CH3CN (2 mL), N,6-dimethyl-5-(piperazine-1-yl)picolinamide dihydrochloride (101 mg, 0.33 mmol), DIPEA (127 mg, 0.98 mmol), and KI (55 mg, 0.33 mmol) were added, and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the crude product, which was then purified by preparative HPLC to obtain the title compound (4 mg, 3%). LCMS (m / z): 413.1 [M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ9.50(s,1H),8.59(d,J=0.9 Hz,1H),8.39(q,J=4.7 Hz,1H),8.20(s,1H),7.76(d,J=8.2 Hz,1H),7.64(s,2H),7.46(d,J=8.3 Hz,1H),3.54(s,2H),3.16-3.10(m,2H),2.96-2.89(m,4H),2.76(d,J=4.9 Hz,3H),2.65-2.54(m,4H),2.45(s,3H),1.04(t,J=7.2 Hz,3H).

[0878] Example S-25: Synthesis of 5-(4-((2-(3-(2-fluoroethyl)ureido)pyridine-4-yl)methyl)piperazin-1-yl)-N,6-dimethylpicolinamide (compound 261).

[0879] [ka] Step 1: Synthesis of 1-(4-(chloromethyl)pyridine-2-yl)-3-(2-fluoroethyl)urea: To a stirred solution of 4-(chloromethyl)pyridine-2-amine hydrochloride (200 mg, 1.12 mmol) in DCM (4 mL), 2-fluoroethane-1-amine hydrochloride (133 mg, 1.34 mmol) and CDI (217 mg, 1.34 mmol) were added, and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound (80 mg, 31%). LCMS (m / z): 232.2 [M+H] + .

[0880] Step 2: Synthesis of 5-(4-((2-(3-(2-fluoroethyl)ureido)pyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide: To a stirred solution of 1-(4-(chloromethyl)pyridine-2-yl)-3-(2-fluoroethyl)urea (70 mg, 0.30 mmol) in CH3CN (2 mL), N,6-dimethyl-5-(piperazine-1-yl)picolinamide dihydrochloride (114 mg, 0.37 mmol), DIPEA (118 mg, 0.91 mmol), and KI (50 mg, 0.30 mmol) were added, and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the crude product, which was then purified by preparative HPLC to obtain the title compound (45 mg, 35%). LCMS (m / z): 430.3 [M+H] + ; 1HNMR(400MHz,CD3OD)δ8.37(d,J=5.6 Hz,1H),7.94(d,J=8.3 Hz,1H),7.61(d,J=8.3 Hz,1H),7.55(s,1H),7.27(dd,J=5.6,1.3 Hz,1H),4.60(t,J=5.0 Hz,1H),4.51-4.40(m,3H),3.65(t,J=4.9 Hz,1H),3.59(t,J=4.9 Hz,1H),3.57-3.39(m,4H),3.32-3.21(m,4H),2.97(s,3H),2.62(s,3H).

[0881] Example S-26: Synthesis of 5-(4-((2-(3-(2,2-difluoroethyl)ureido)pyridine-4-yl)methyl)piperazin-1-yl l)-N,6-dimethylpicolinamide (compound 262).

[0882] [ka] Step 1: Synthesis of 4-nitrophenyl (2,2-difluoroethyl)carbamate: To a stirred solution of 2,2-difluoroethane-1-amine (1 g, 12.34 mmol) in DMF (10 mL), pyridine (1.16 g, 14.7 mmol) was added, and the reaction mixture was stirred at 0°C for 15 minutes. Then, a solution of 4-nitrophenyl chloroformate (2.98 g, 14.78 mmol) in THF (2 mL) was added at 5°C, and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was quenched with water (50 mL) and extracted with RINKAN (50 mL x 2). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (1.5 g, crude product). LCMS (m / z): 247.1 [M + H] + .

[0883] Step 2: Synthesis of 1-(4-(chloromethyl)pyridine-2-yl)-3-(2,2-difluoroethyl)urea: To a stirred solution of 4-nitrophenyl(2,2-difluoroethyl)carbamate (1.3 g, crude product) in CH3CN (20 mL), 4-(chloromethyl)pyridine-2-amine hydrochloride (0.38 g, 2.12 mmol), DIPEA (2.05 g, 15.86 mmol), and KI (0.88 g, 5.31 mmol) were added, and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound (500 mg, crude product). LCMS (m / z): 250.1 [M+H] + .

[0884] Step 3: Synthesis of 5-(4-((2-(3-(2,2-difluoroethyl)ureido)pyridine-4-yl)methyl)piperazine-1-yl)-N,6-dimethylpicolinamide: To a stirred solution of 1-(4-(chloromethyl)pyridine-2-yl)-3-(2,2-difluoroethyl)urea (500 mg, crude product) in CH3CN (10 mL), N,6-dimethyl-5-(piperazine-1-yl)picolinamide dihydrochloride (184 mg, 0.60 mmol), DIPEA (233 mg, 1.80 mmol), and KI (100 mg, 0.60 mmol) were added, and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the crude product, which was then purified by preparative HPLC to obtain the title compound (12.4 mg, 0.3%). LCMS(m / z):448.3[M+H] + ; 1 HNMR(400MHz,CD3OD)δ8.27(d,J=5.2 Hz,1H),7.90(d,J=8.3 Hz,1H),7.54(d,J=8.3 Hz,1H),7.35(s,1H),7.12(d,J=5.2 Hz,1H),5.99(tt,J=56.1,3.8 Hz,1H),4.00(s,2H),3.71(td,J=15.3,3.8 Hz,2H),3.23-3.12(m,4H),3.13-3.02(m,4H),2.96(s,3H),2.59(s,3H).

[0885] Example S-27: Synthesis of N,6-dimethyl-5-(4-((2-(3-(2,2,2-trifluoroethyl)ureido)pyridine-4-yl)methyl)piperazine-1-yl)picolinamide trifluoroacetate (compound 50).

[0886] [ka] Step 1: Synthesis of 4-nitrophenyl (2,2,2-trifluoroethyl)carbamate: To a stirred solution of 4-nitrophenyl chloroformate (2.42 g, 12 mmol) in DMF (10 mL) at 0°C, pyridine (0.95 g, 12 mmol) was added, and the reaction mixture was stirred at 0°C for 1 hour. Next, a solution of 2,2,2-trifluoroethane-1-amine (991 mg, 10 mmol) in THF (5 mL) was added, and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was quenched with water (50 mL) and extracted with RINKAN (50 mL x 2). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (1.3 g, crude product). LCMS (m / z): 265.1 [M+H] + .

[0887] Step 2: Synthesis of 1-(4-(chloromethyl)pyridine-2-yl)-3-(2,2,2-trifluoroethyl)urea: To a stirred solution of 4-nitrophenyl (2,2,2-trifluoroethyl)carbamate (1.2 g, crude product) in DMF (10 mL), 4-(chloromethyl)pyridine-2-amine hydrochloride (0.48 g, 2.68 mmol) and DIPEA (1.05 g, 8.12 mmol) were added, and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was quenched with water and extracted with RINKAN (50 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (0.6 g, crude product). LCMS (m / z): 268.1 [M+H] + .

[0888] Step 3: Synthesis of N,6-dimethyl-5-(4-((2-(3-(2,2,2-trifluoroethyl)ureido)pyridine-4-yl)methyl)piperazine-1-yl)picolinamide trifluoroacetate: To a stirred solution of 1-(4-(chloromethyl)pyridine-2-yl)-3-(2,2,2-trifluoroethyl)urea (600 mg, crude product) in CH3CN (10 mL), N,6-dimethyl-5-(piperazine-1-yl)picolinamide dihydrochloride (412 mg, 1.34 mmol), DIPEA (520 mg, 4.02 mmol), and KI (222 mg, 1.34 mmol) were added, and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was quenched with water and extracted with ELISA (20 mL x 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the crude product, which was then purified by preparative HPLC to obtain the title compound (15 mg, 2%). LCMS (m / z): 466.3 [M+H] + ; 1 HNMR(400MHz,CD3OD)δ8.39(d,J=5.4 Hz,1H),7.94(d,J=8.3 Hz,1H),7.65-7.58(m,2H),7.28(dd,J=5.5,1.4 Hz,1H),4.49(s,2H),4.04(q,J=9.3 Hz,2H),3.62-3.48(m,4H),3.33-3.29(m,4H),2.97(s,3H),2.62(s,3H).

[0889] Example S-28: Synthesis of 5-(4-((6-(3-ethylureido)pyrimidine-4-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide formate (compound 229).

[0890] [ka] Step 1: Synthesis of 5-(4-((6-aminopyridine-4-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide: To a stirred solution of 6-(chloromethyl)pyrimidine-4-amine (160 mg, 1.11 mmol) in CH3CN (5 mL), 6-fluoro-N-methyl-5-(piperazine-1-yl)picolinamide dihydrochloride (349 mg, 1.12 mmol), DIPEA (717 mg, 5.55 mmol), and KI (184 mg, 1.11 mmol) were added, and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was quenched with water and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (70 mg, 18%). LCMS(m / z):346.0[M+H] + .

[0891] Step 2: Synthesis of 5-(4-((6-(3-ethylureido)pyrimidine-4-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide formate: To a stirred solution of 5-(4-((6-aminopyridine-4-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (65 mg, 0.19 mmol) in DMF (1 mL), ethyl isocyanate (20 mg, 0.28 mmol) and Cs2CO3 (124 mg, 0.38 mmol) were added, and the reaction mixture was stirred at 80°C for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by C18 chromatography using water / CH3CN to obtain the crude product, which was then purified by preparative HPLC to obtain the title compound (4 mg, 5%). LCMS (m / z): 417.3 [M+H] + ; 1 HNMR(400MHz,CD3OD)δ8.58(s,1H),8.07(s,1H),7.80(dd,J=8.0,0.8 Hz,1H),7.43(dd,J=10.2,8.2 Hz,1H),7.35(s,1H),3.60(s,2H),3.28-3.21(m,6H),2.81(s,3H),2.68(s,4H),1.11(t,J=7.2 Hz,3H).

[0892] Example S-29: Synthesis of 5-(4-((2-(3-ethylureido)-3-fluoropyridine-4-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide (compound 81).

[0893] [ka] Step 1: Synthesis of 5-(4-((2-amino-3-fluoropyridine-4-yl)methyl)piperazine-1-yl)-6-fluoro-N-methylpicolinamide: To a stirred solution of 4-(chloromethyl)-3-fluoropyridine-2-amine (180 mg, 1.12 mmol) in CH3CN (5 mL), 6-fluoro-N-methyl-5-(piperazine-1-yl)picolinamide dihydrochloride (349 mg, 1.12 mmol), DIPEA (724 mg, 5.6 mmol), and KI (186 mg, 1.12 mmol) were added, and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to obtain the title compound (120 mg, 30%). LCMS (m / z): 363.3 [M+H] + .

[0894] Step 2: Synthesis of 5-(4-((2-(3-ethylureido)-3-fluoropyridine-4-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide: To a stirred solution of 5-(4-((2-amino-3-fluoropyridine-4-yl)methyl)piperazin-1-yl)-6-fluoro-N-methylpicolinamide (100 mg, 0.28 mmol) in DMF (2 mL), ethyl isocyanate (24 mg, 0.34 mmol) and Cs2CO3 (179 mg, 0.55 mmol) were added, and the reaction mixture was stirred at 80°C for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title compound (19 mg, 16%). LCMS (m / z): 434.3 [M+H] + ; 1H NMR(400MHz,CD3OD)δ8.04(d,J=5.2 Hz,1H),7.91(dd,J=8.1,1.2 Hz,1H),7.53(dd,J=10.2,8.1 Hz,1H),7.16(t,J=5.0 Hz,1H),3.73(s,2H),3.39(q,J=7.2 Hz,2H),3.30-3.25(m,4H),2.93(s,3H),2.76-2.69(m,4H),1.24(t,J=7.2 Hz,3H).

[0895] Example S-30: Synthesis of 1-(6-(1H-imidazole-2-yl)-2-methylpyridine-3-yl)piperazine trifluoroacetate.

[0896] [ka] Step 1: Synthesis of 4-(6-(methoxycarbonyl)-2-methylpyridine-3-yl)piperazine-1-carboxylate tert-butyl: A mixture of methyl 5-bromo-6-methyl picolinate (5 g, 21.7 mmol), piperazine-1-carboxylate tert-butyl (4.84 g, 26.0 mmol), Cs2CO3 (14.1 g, 43.4 mmol), and RuPhosPdG3 (1.8 g, 2.2 mmol) in 1,4-dioxane (50 mL) was stirred at 90 °C for 16 hours under an N2 atmosphere. The reaction mixture was quenched with water (200 mL) and extracted with ELISA (200 mL x 3). The combined organic layer was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to obtain the title compound (5 g, 69%). LCMS(m / z):336.3[M+H] + .

[0897] Step 2: Synthesis of 4-(6-(hydroxymethyl)-2-methylpyridine-3-yl)piperazine-1-carboxylate tert-butyl: To a solution of 4-(6-methoxycarbonyl)-2-methylpyridine-3-yl)piperazine-1-carboxylate tert-butyl (2 g, 5.96 mmol) in MeOH:THF (4:1, 10 mL), NaBH4 (1.35 g, 35.67 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (100 mL) and extracted with RINKAN (100 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (1.6 g, 87%). LCMS (m / z): 308.1 [M+H] + .

[0898] Step 3: Synthesis of 4-(6-formyl-2-methylpyridine-3-yl)piperazine-1-carboxylate tert-butyl: 1.5 g, 4.88 mmol of 4-(6-(hydroxymethyl)-2-methylpyridine-3-yl)piperazine-1-carboxylate tert-butyl was dissolved in 20 mL of dioxane, to which MnO2 (2.11 g, 24.32 mmol) was added. The resulting reaction mixture was stirred at 40°C for 24 hours. The solid was removed, and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to obtain the title compound (1.35 g, 91%). LCMS (m / z): 306.2 [M+H] + .

[0899] Step 4: Synthesis of 4-(6-(1H-imidazole-2-yl)-2-methylpyridine-3-yl)piperazine-1-carboxylate tert-butyl: To a solution of 4-(6-formyl-2-methylpyridine-3-yl)piperazine-1-carboxylate tert-butyl (100 mg, 0.33 mmol) in ethanol (4 mL), 40% glyoxal aqueous solution (59 mg, 0.41 mmol) was added, followed by the dropwise addition of NH4OH (1 mL) at -5°C. The solution was stirred at -5°C for 1 hour. The reaction mixture was warmed to room temperature and stirred at the same temperature for 16 hours. The solvent was removed under vacuum. The crude product was purified by silica gel chromatography to obtain the title compound (90 mg, 80%). LCMS (m / z): 235.1 [M+H] + .

[0900] Step 5: Synthesis of 1-(6-(1H-imidazole-2-yl)-2-methylpyridine-3-yl)piperazine trifluoroacetate: 1 mL of TFA was added to a 3 mL solution of 4-(6-(1H-imidazole-2-yl)-2-methylpyridine-3-yl)piperazine-1-carboxylate tert-butyl (70 mg, 0.20 mmol) in DCM. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum to obtain the title compound (70 mg, 97%). LCMS (m / z): 244.0 [M+H] + .

[0901] Example S-31: Synthesis of N-(6-methyl-5-(piperazin-1-yl)pyridine-2-yl)acetamide trifluoroacetate.

[0902] [ka] Step 1: Synthesis of 4-(2-methyl-6-nitropyridine-3-yl)piperazine-1-carboxylate tert-butyl: A mixture of 3-bromo-2-methyl-6-nitropyridine (500 mg, 2.30 mmol), piperazine-1-carboxylate tert-butyl (514 mg, 2.76 mmol), Cs2CO3 (1.5 g, 4.61 mmol), and RuPhosPdG3 (193 mg, 0.23 mmol) in 1,4-dioxane (5 mL) was stirred at 80°C for 16 hours under an N2 atmosphere. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to obtain the title compound (350 mg, 47%). LCMS(m / z):322.9[M+H] + .

[0903] Step 2: Synthesis of 4-(6-amino-2-methylpyridine-3-yl)piperazine-1-carboxylate tert-butyl: A mixture of 4-(2-methyl-6-nitropyridine-3-yl)piperazine-1-carboxylate tert-butyl (250 mg, 0.78 mmol), Zn (252 mg, 3.87 mmol), and NH4Cl (414 mg, 7.73 mmol) in EtOH:H2O (5:1, 6 mL) was stirred at room temperature for 16 hours. The solid was filtered, and the filtrate was concentrated under reduced pressure. The residue was quenched with water (50 mL) and extracted with siRNA (50 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (200 mg, 88%). LCMS (m / z): 293.0 [M+H] + .

[0904] Step 3: Synthesis of 4-(6-acetamido-2-methylpyridine-3-yl)piperazine-1-carboxylate tert-butyl: To a solution of 4-(6-amino-2-methylpyridine-3-yl)piperazine-1-carboxylate tert-butyl (180 mg, 0.62 mmol) in anhydrous DCM (3 mL), acetyl chloride (53 mg, 0.67 mmol) and Et3N (124 mg, 1.23 mmol) were added, and the resulting solution was stirred at room temperature for 1 hour. The solution was then removed under vacuum, and the crude product was purified by silica gel chromatography to obtain the title compound (150 mg, 73%). LCMS (m / z): 335.3 [M+H] + .

[0905] Step 4: Synthesis of N-(6-methyl-5-(piperazin-1-yl)pyridine-2-yl)acetamide trifluoroacetate: To a solution of 4-(6-acetamido-2-methylpyridine-3-yl)piperazin-1-carboxylate tert-butyl (140 mg, 0.42 mmol) in DCM (3 mL), TFA (1 mL) was added, and the resulting solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum to obtain the title compound (80 mg, 55%). LCMS (m / z): 235.1 [M+H] + .

[0906] Example S-32: Synthesis of 1-[2-methyl-6-(pyrazole-1-yl)pyridine-3-yl]piperazine.

[0907] [ka] Step 1: Synthesis of 3-bromo-2-methyl-6-(pyrazole-1-yl)pyridine: To a solution of 3-bromo-6-fluoro-2-methylpyridine (500 mg, 2.63 mmol) in DMSO (5 mL), t-BuOK (590 mg, 5.26 mmol) and 1H-pyrazole (215 mg, 3.16 mmol) were added. The resulting solution was stirred at 100°C for 16 hours, then quenched with water (30 mL), and extracted with ₹ (30 mL × 3). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography to obtain the desired title compound (100 mg, 16%). LCMS (m / z): 238.0 [M + H] + .

[0908] Step 2: Synthesis of 4-(2-methyl-6-(1H-pyrazole-1-yl)pyridine-3-yl)piperazine-1-carboxylate tert-butyl: A mixture of 3-bromo-2-methyl-6-(pyrazole-1-yl)pyridine (100 mg, 0.42 mmol), piperazine-1-carboxylate tert-butyl (94 mg, 0.50 mmol), Cs2CO3 (274 mg, 0.84 mmol), and RuPhosPdG3 (33.5 mg, 0.04 mmol) in 1,4-dioxane (4 mL) was stirred at 80°C for 16 hours under a nitrogen atmosphere. The reaction mixture was quenched with water (10 mL) and extracted with RINKAN (10 mL x 3). The combined organic layer was washed with water and brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography to obtain the desired title compound (50 mg, 35%). LCMS(m / z):344.0[M+H] + .

[0909] Step 3: Synthesis of 1-[2-methyl-6-(pyrazole-1-yl)pyridine-3-yl]piperazine: To a solution of 4-(2-methyl-6-(1H-pyrazole-1-yl)pyridine-3-yl)piperazine-1-carboxylate tert-butyl (50 mg, 0.15 mmol) in DCM (1.5 mL), TFA (0.5 mL) was added, and the resulting solution was stirred at room temperature for 1 hour. The solvent was removed under vacuum. The residue was dissolved in water, neutralized with saturated NaHCO3 aqueous solution, and extracted by DCM. The combined organic layers were concentrated and purified by silica gel chromatography to obtain the title compound (30 mg, 83%). LCMS (m / z): 244.1 [M+H] + .

[0910] Example S-33: Synthesis of 1-(4-((4-(6-(1H-imidazole-2-yl)-2-methylpyridine-3-yl)piperazine-1-yl)methyl)pyridine-2-yl)-3-ethylurea formate (compound 272).

[0911] [ka] Step 1: Synthesis of 1-(4-((4-(6-(1H-imidazole-2-yl)-2-methylpyridine-3-yl)piperazine-1-yl)methyl)pyridine-2-yl)-3-ethylurea formate: A mixture of 1-(4-(chloromethyl)pyridine-2-yl)-3-ethylurea (30 mg, 0.14 mmol), 1-(6-(1H-imidazole-2-yl)-2-methylpyridine-3-yl)piperazine trifluoroacetate (60 mg, crude product), KI (35 mg, 0.21 mmol), and DIPEA (181 mg, 1.40 mmol) in CH3CN (3 mL) was stirred at room temperature for 16 hours. The reaction mixture was quenched with water and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC to obtain the compound indicated in the title (8 mg, 12%). LCMS (m / z): 421.1 [M+H] + ; 1H NMR(400MHz,CD3OD)δ8.20-8.16(m,2H),7.85(d,J=8.4Hz,1H),7.56(d,J=8.4 Hz,1H),7.34-7.29(m,2H),7.18(s,1H),7.03(d,J=5.3Hz,1H),3.67(s,2H),3.3 8-3.34(m,2H),3.12-3.06(m,4H),2.80-2.72(m,4H),2.61(s,3H),1.23(t,J=7.2 Hz,3H).

[0912] Example S-34: Synthesis of N-(5-(4-((2-(3-ethylureido)pyridine-4-yl)methyl)piperazine-1-yl)-6-methylpyridine-2-yl)acetamide (compound 269).

[0913] [ka] Step 1: Synthesis of N-(5-(4-((2-(3-ethylureido)pyridine-4-yl)methyl)piperazine-1-yl)-6-methylpyridine-2-yl)acetamide: A mixture of 1-(4-(chloromethyl)pyridine-2-yl)-3-ethylurea (50 mg, 0.23 mmol), N-(6-methyl-5-(piperazine-1-yl)pyridine-2-yl)acetamide trifluoroacetate (98 mg, 0.28 mmol), KI (58 mg, 0.35 mmol), and DIPEA (302 mg, 2.34 mmol) in CH3CN (3 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title compound (17 mg, 18%). LCMS (m / z): 412.2 [M+H] + ; 1 H NMR(400MHz,CD3OD)δ8.17(d,J=5.3 Hz,1H),7.84(d,J=8.6 Hz,1H),7.49(d,J=8.7 Hz,1H),7.14(s,1H),7.02(d,J=5.2 Hz,1H),3.63(s,2H),3.40-3.34(m,2H),3.01-2.93(m,4H),2.75-2.65(m,4H),2.44(s,3H),2.15(s,3H),1.23(t,J=7.2 Hz,3H).

[0914] Example S-35: Synthesis of 1-ethyl-3-(4-((4-(2-methyl-6-(1H-pyrazole-1-yl)pyridine-3-yl)piperazine-1-yl)methyl)pyridine-2-yl)urea (compound 24).

[0915] [ka] Step 1: Synthesis of 1-ethyl-3-(4-((4-(2-methyl-6-(1H-pyrazole-1-yl)pyridine-3-yl)piperazine-1-yl)methyl)pyridine-2-yl)urea: A mixture of 1-(4-(chloromethyl)pyridine-2-yl)-3-ethylurea (50 mg, 0.23 mmol), 1-(2-methyl-6-(1H-pyrazole-1-yl)pyridine-3-yl)piperazine 2,2,2-trifluoroacetate (100 mg, 0.28 mmol), KI (58 mg, 0.35 mmol), and DIPEA (302 mg, 2.34 mmol) in CH3CN (3 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title compound (15 mg, 16%). LCMS(m / z):421.3[M+H] + ; 1 H NMR(400MHz,CD3OD)δ8.48(d,J=2.5 Hz,1H),8.12(d,J=5.3 Hz,1H),7.70-7.63(m,2H),7.58(d,J=8.6 Hz,1H),7.09(s,1H),6.98(d,J=5.2 Hz,1H),6.47(d,J=1.8 Hz,1H),3.57(s,2H),3.34-3.29(m,2H),3.01-2.93(m,4H),2.73-2.58(m,4H),2.52-2.50(m,3H),1.18(t,J=7.2 Hz,3H).

[0916] Example S-36: Synthesis of 5-(4-(3-(3-ethylureido)benzyl)piperazin-1-yl)-N,6-dimethylpicolinamide formate (compound 202).

[0917] [ka] Step 1: Synthesis of 3-((tert-butoxycarbonyl)amino)benzyl 4-methylbenzene sulfonate: To a solution of tert-butyl (3-(hydroxymethyl)phenyl)carbamate (200 mg, 0.9 mmol) in DCM (5 mL), TsCl (172 mg, 0.9 mmol), Et3N (273 mg, 2.7 mmol), and DMAP (110 mg, 0.9 mmol) were added, and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was quenched with water and extracted with DCM (5 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (160 mg, 47%). LCMS (m / z): 400.2 [M + Na] + .

[0918] Step 2: Synthesis of tert-butyl (3-((4-(2-methyl-6-(methylcarbamoyl)pyridine-3-yl)piperazine-1-yl)methyl)phenyl)carbamate: To a stirred solution of methylbenzenesulfonate (160 mg, 0.42 mmol) in 3-((tert-butoxycarbonyl)amino)benzyl 4- in CH3CN (4 mL), methyl 6-methyl-5-(piperazine-1-yl)picolinate dihydrochloride (132 mg, 0.43 mmol) and Et3N (128 mg, 1.27 mmol) were added, and the reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was quenched with saturated NH4Cl and extracted with DCM (4 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the title compound (180 mg, 97%). LCMS(m / z):440.3[M+H] + .

[0919] Step 3: Synthesis of 5-(4-(3-aminobenzyl)piperazine-1-yl)-N,6-dimethylpicolinamide: To a stirred solution of (3-((4-(2-methyl-6-(methylcarbamoyl)pyridine-3-yl)piperazine-1-yl)methyl)phenyl)carbamate tert-butyl (180 mg, 0.41 mmol) in DCM (4 mL), 4 M HCl in dioxane (1 mL) was added, and the reaction mixture was stirred at 25°C for 6 hours. The reaction mixture was quenched to pH 8 with saturated NaHCO3 and extracted with DCM:MeOH (10:1, 4 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain the tit...

Claims

1. Compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, 【Chemistry 2】 These are 5-10 member heteroarylenes, C ３－１０ Cycloalkylene, C ６－１０ Arirene, or a 3- to 10-membered heterocycloalkylene, m is 0, 1, 2, 3, 4, or 5. Each R ａ is independently halogen, -CN, -OH, -NH ２ , -O-(C １－６ alkyl), -NH(C １－６ alkyl), -N(C １－６ alkyl) ２ , C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, C ６－１０ aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl, or two Rs ａ combine to form an oxo, wherein the -O-(C １－６ alkyl), -NH(C １－６ alkyl), -N(C １－６ alkyl) ２ , or -C １－６ alkyl is optionally substituted with one or more oxos, deuteriums, halogens, -CN, -OH, -NH ２ , C １－６ haloalkyl, -O-C<{ １－６ alkyl, -NH-C １－６ alkyl, -N(C １－６ alkyl) ２ , C ３－１０ cycloalkyl, or a 3- to 10-membered heterocycloalkyl, C ６－１０ aryl, or a 5- to 10-membered heteroaryl, and the C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, C ６－１０ aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl is optionally substituted with one or more oxos, deuteriums, halogens, -CN, -OH, -NH ２ , C １－６ alkyl, C １－６ haloalkyl, -O-C １－６ alkyl, -NH-C １－６ alkyl, -N(C １－６ alkyl) ２ , C ３－１０ cycloalkyl, or a 3- to 10-membered heterocycloalkyl, C ６－１０ Optionally substituted with an aryl or 5- to 10-membered heteroaryl, or two R's ａ C ３－１０ Cycloalkyl, C ６－１０ Forms an aryl, a 3-10 member heterocycloalkyl, or a 5-10 member heteroaryl, in the formula, the C ３－１０ Cycloalkyl, C ６－１０ An aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl is associated with one or more oxo, deuterium, halogen, -CN, -OH, or -NH ２ It is arbitrarily replaced with, X is -C (=O)-, -S (=O) ２ - and Y is a bond, -O-, -S-, -NH-, or C １－６ It is an alkylene, in the formula, C １－６ Alkylenes are one or more oxo, halogen, -CN, -OH, -NH ２ , C １－６ Alkyl atoms, or the atom(s) to which they are bonded, together with C ３－１０ Two C atoms that form a cycloalkyl group １－６ Optionally substituted with alkyl, R １ is, -C １－６ Alkyl, H, halogen, -CN, -OH, -NH ２ , -O-(C １－６ Alkyl), -NH(C １－６ Alkyl), -N(C １－６ (Alkyl) (C ２－６ Alkyl) C ３－１０ Cycloalkyl, C ６－１０ The aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein the -C １－６ Alkyl, -O-(C １－６ Alkyl), -NH(C １－６ Alkyl), or -N(C １－６ Alkyl) ２ is one or more oxo, deuterium, halogen, -CN, -OH, -NH ２ , C １－６ Haloalkyl, -O-C １－６ Alkyl, -NH-C １－６ Alkyl, -N(C) １－６ Alkyl) ２ , C ３－１０ Optionally substituted with a cycloalkyl group, a 3-10 member heterocycloalkyl group, or a 5-10 member heteroaryl group, the C ３－１０ Cycloalkyl, C ６－１０ Aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl may contain one or more oxo, halogen, -CN, -OH, or -NH ２ , C １－６ Alkyl, C １－６ Haloalkyl, -O-C １－６ Alkyl, -NH-C １－６ Alkyl, -N(C) １－６ Alkyl) ２ , C ３－１０ Cycloalkyl, or 3-10 member heterocycloalkyl, C ６－１０ Optionally substituted with an aryl or 5- to 10-membered heteroaryl, L is C １－６ alkylene, bond, -O-, -S-, -S(=O)-, -S(=O) ２ -, -NH-, -N(C １ - ６ alkyl)-, -N(C ３ - ６ cycloalkyl)-, -N(C ３ - ６ heterocycloalkyl)-, C ２－６ alkenylene, C ２－６ alkynylene, C ３ - ６ cycloalkylene, or C ３ - ６ heterocycloalkylene, wherein the N(C １ - ６ alkyl)-, -N(C ３ - ６ cycloalkyl)-, -N(C ３ - ６ heterocycloalkyl)-, C １－６ alkylene, C ２－６ alkenylene, C ２－６ alkynylene, C ３ - ６ cycloalkylene is optionally substituted, or C ３ - ６ heterocycloalkylene is optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, or -NH ２ and R ２ These are 3-10 member heterocycloalkylenes, C ３ -10 Cycloalkylene, C ６－１０ Arylene, or 5-10 member heteroarylene, wherein the C ３－１０ Cycloalkylene, C ６－１０ Arylene, 3-10 member heterocycloalkylene, or 5-10 member heteroarylene, one or more R ｂ It is arbitrarily replaced with, Each R ｂ These are independently halogen, -CN, -OH, and -NH ２ , -O-(C １－６ Alkyl), -NH(C １－６ Alkyl), -N(C １－６ Alkyl) ２ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, C ６－１０ It is an aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl, or two R ｂ These are combined to form an oxo, in the formula, the -O-(C １－６ Alkyl), -NH(C １－６ Alkyl), -N(C １－６ Alkyl) ２ , C １－６ Alkyl is one or more oxo, deuterium, halogen, -CN, -OH, -NH ２ , C １－６ Haloalkyl, -O-C １－６ Alkyl, -NH-C １－６ Alkyl, -N(C) １－６ Alkyl) ２ , C ３－１０ Cycloalkyl, or 3-10 member heterocycloalkyl, C ６－１０ Optionally substituted with aryl or 5- to 10-membered heteroaryl, and the C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, C ６－１０ An aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl is one or more oxo, deuterium, halogen, -CN, -OH, -NH ２ , C １－６ Alkyl, C １－６ Haloalkyl, -O-C １－６ Alkyl, -NH-C １－６ Alkyl, -N(C) １－６ Alkyl) ２ , C ３－１０ Cycloalkyl, or 3-10 member heterocycloalkyl, C ６－１０ Optionally substituted with an aryl or 5- to 10-membered heteroaryl, or two R's ｂ C ３－１０ Cycloalkyl, C ６－１０ Forms an aryl, a 3-10 member heterocycloalkyl, or a 5-10 member heteroaryl, in the formula, the C ３－１０ Cycloalkyl, C ６－１０ An aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl is associated with one or more oxo, deuterium, halogen, -CN, -OH, or -NH ２ It is arbitrarily replaced with, L １ These combine to form -O-, -S-, -S(=O)-, -S(=O) ２ -, -NH-, -N(C １ - ６ Alkyl)-,-N(C ３ - ６ Cycloalkyl)-,-N(C ３ - ６ (heterocycloalkyl)-, C １－６ Alkylene, C ２－６ Alkenylene, C ２－６ Alkinylene, C ３ - ６ Cycloalkylene, or C ３ - ６ It is a heterocycloalkylene, in which -N(C) １ - ６ Alkyl)-,-N(C ３ - ６ Cycloalkyl)-,-N(C ３ - ６ (heterocycloalkyl)-, C １－６ Alkylene, C ２－６ Alkenylene, C ２－６ Alkinylene, C ３ - ６ Cycloalkylene, or C ３ - ６ Heterocycloalkylenes are one or more oxo, deuterium, halogen, -CN, -OH, or -NH ２ It is arbitrarily replaced with, R ３ These are 5-10 member heteroaryls, C ３－１０ Cycloalkyl, C ６－１０ The C is an aryl or 3- to 10-membered heterocycloalkyl group. ３－１０ Cycloalkyl, C ６－１０ R contains one or more aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl groups. ｃ It is arbitrarily replaced with, Each R ｃ These are independently halogen, -CN, -OH, and -NH ２ , -C(=O)-H, -C(=O)-NH ２ , -NH-C(=O)-H, -NH-(C=O)-NH ２ , -C(=O)-CN, -NH-C(=O)-CN, -C(=O)-NH-CN, -O-(C １－６ Alkyl), -NH(C １－６ Alkyl), -N(C １－６ Alkyl) ２ , -C(=O)-(C １－６ Alkyl), -C(=O)-NH-(C １－６ Alkyl), -NH-C(=O)-(C １－６ Alkyl),-NH-(C=O)-NH-(C １－６ Alkyl), -NH-(C=O)-O-(C １－６ Alkyl), -C(=O)-NH-(C ３－１０ Cycloalkyl), -C(=O)-NH-(3-10 member heterocycloalkyl), C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, C ６－１０ It is an aryl, a 3- to 10-membered heterocycloalkyl, or a 5- to 10-membered heteroaryl, or two R ｃ These are combined to form an oxo, in the formula, the -O-(C １－６ Alkyl), -NH(C １－６ Alkyl), -N(C １－６ Alkyl) ２ , -C(=O)-(C １－６ Alkyl), -C(=O)-NH-(C １－６ Alkyl), -NH-C(=O)-(C １－６ Alkyl),-NH-(C=O)-NH-(C １－６ Alkyl), or -NH-(C=O)-O-(C １－６ Alkyl) is one or more oxo, deuterium, halogen, -CN, -OH, -NH ２ , C １－６ Haloalkyl, -O-C １－６ Alkyl, -NH-C １－６ Alkyl, -N(C) １－６ Alkyl) ２ , C ３－１０ Cycloalkyl, or 3-10 member heterocycloalkyl, C ６－１０ It can be optionally substituted with an aryl or a 5- to 10-membered heteroaryl, and -C(=O)-NH-(C ３－１０ Cycloalkyl), -C(=O)-NH-(3-10 member heterocycloalkyl), C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, C ６－１０ aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, one or more oxo, deuterium, halogen, -CN, -OH, -NH ２ , C １－６ Alkyl, C １－６ Haloalkyl, -O-C １－６ Alkyl, -NH-C １－６ Alkyl, -N(C) １－６ Alkyl) ２ , C ３－１０ Cycloalkyl, or 3-10 member heterocycloalkyl, C ６－１０ Optionally substituted with an aryl or 5- to 10-membered heteroaryl, or two R's ｃ C ３－１０ Cycloalkyl, C ６－１０ Forms an aryl, a 3-10 member heterocycloalkyl, or a 5-10 member heteroaryl, in the formula, the C ３－１０ Cycloalkyl, C ６－１０ An aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl is associated with one or more oxo, deuterium, halogen, -CN, -OH, or -NH ２ It is arbitrarily replaced with, or one R ｂ and one R ｃ C ３－１０ Cycloalkyl, C ６－１０ Forms an aryl, a 3-10 member heterocycloalkyl, or a 5-10 member heteroaryl, in the formula, the C ３－１０ Cycloalkyl, C ６－１０ One or more aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl compounds are included in R. ｂｃ It is arbitrarily replaced with, Each R ｂｃ These are independently oxo, deuterium, halogen, -CN, -OH, and -NH ２ , -O-(C １－６ Alkyl), -NH(C １－６ Alkyl), -N(C １－６ Alkyl) ２ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, C ６－１０ The aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl, wherein the -O-(C １－６ Alkyl), -NH(C １－６ Alkyl), -N(C １－６ Alkyl) ２ , C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, C ６－１０ An aryl, 3-10 membered heterocycloalkyl, or 5-10 membered heteroaryl is associated with one or more oxo, deuterium, halogen, -CN, -OH, or -NH ２ The compound, which is optionally substituted with the above.

2. The aforementioned compound is the compound of formula II: 【Transformation 3】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The aforementioned compound is the compound of formula V': 【Chemistry 4】 or a pharmaceutically acceptable salt thereof, The compound according to any one of the prior claims, wherein m-v is 0 to 4 in the formula.

4. The aforementioned compound is the compound of formula XXXI': 【Transformation 5】 or a pharmaceutically acceptable salt thereof, The compound according to any one of the prior claims, wherein m-xxxi is 0 to 8 in the formula.

5. The aforementioned compound is the compound of formula VII': 【Transformation 6】 or a pharmaceutically acceptable salt thereof, In the formula, m-vii is between 0 and 8. The compound according to any one of the prior claims, wherein n-vii is 0 to 4.

6. The aforementioned compound is a compound of formula XLIV: 【Transformation 7】 or a pharmaceutically acceptable salt thereof, in the formula, m-xliv is between 0 and 8. A compound according to any one of the prior claims, wherein n-xliv is 0 to 4.

7. R １ However, halogen or C ３－１０ C optionally substituted with cycloalkyl １－６ A compound according to any one of the prior claims, wherein it is alkyl.

8. R １ However, methyl, ethyl, isopropyl, or 【Transformation 8】 The compound according to any one of the prior claims.

9. R １ The compound according to any one of the prior claims, wherein the compound is cyclopropyl or cyclobutyl.

10. A compound according to any one of the prior claims, wherein Y is -NH-.

11. Y is one or more halogens, C １－６ Alkyl, or the atom(s) to which they are bonded, is combined with C １－６ Two C atoms that form an alkyl group １－６ C arbitrarily substituted with alkyl １－６ A compound according to any one of the prior claims, which is an alkylene.

12. A compound according to any one of the prior claims, wherein X is C(=O)-.

13. Ring A has one or more R ａ The compound according to any one of the prior claims, which is a five-membered or six-membered heteroaryl optionally substituted with .

14. Ring A has one or more R ａ The compound according to any one of the prior claims, which is a pyridinyl, pyrimidinyl, or pyridazinyl optionally substituted with.

15. Ring A is 【Chemistry 9】 And in the formula, 【Chemistry 10】 However, it shows binding to -X-NH-, 【Chemistry 11】 The compound according to any one of the prior claims, which exhibits bonding to L.

16. Ring A has one or more R ａ The compound according to any one of the prior claims, which is an imidazolyl, oxazollyl, thiazolyl, thiophenyl, triazollyl, thiadiazolyl, or furanil optionally substituted with the above.

17. Each R ａ C is independent １－６ Alkyl, C １－６ Haloalkyl, -O-C １－６ Alkyl, halogen, or two R ａ A compound according to any one of the prior claims, wherein the elements are combined to form an oxo.

18. L is C which is arbitrarily substituted with an oxo. １ or C ２ A compound according to any one of the prior claims, which is an alkylene.

19. L, 【Chemistry 12】 The compound according to any one of the prior claims.

20. R ２ However, one or more R ｂ The compound according to any one of the prior claims, which is a 3- to 10-membered heterocycloalkylene optionally substituted with .

21. R ２ but, 【Chemistry 13】 (Each of these is one or more R ｂ It can be arbitrarily substituted with, in the formula, * and 【Chemistry 14】 However, you L and L １ A compound according to any one of the prior claims, representing a bonding point to a compound.

22. Each R ｂ C is independent １－６ It is alkyl, or has two R's ｂ They combine to form an oxo, or two R ｂ However, when combined with the atom(s) to which they are bonded, C ３－１０ A compound according to any one of the prior claims, which forms a cycloalkyl group.

23. R ２ However, one or more R ｂ The compound according to any one of the prior claims, wherein piperazinyl is optionally substituted with [the specified compound].

24. R ２ but, 【Chemistry 15】 The compound according to any one of the prior claims.

25. L １ The compound according to any one of the prior claims, wherein the compound is bonded.

26. R ３ However, it is a 5- to 10-membered heteroaryl compound containing at least one N atom, and the heteroaryl compound contains one or more halogens, CN, and -C(=O)-NH ２ , -C(=O)-NH-CN, -C(=O)-NH-(C １－６ Alkyl), or C １－６ Optionally substituted with alkyl, the C １－６ The alkyl compound according to any one of the prior claims, wherein the alkyl is optionally substituted with one or more halogens or deuterium.

27. R ３ However, one or more halogens, CN, -C(=O)-NH ２ , -C(=O)-NH-CN, -C(=O)-NH-(C １－６ Alkyl), or C １－６ A pyridinyl optionally substituted with alkyl, and the C １－６ The alkyl compound according to any one of the prior claims, wherein the alkyl is optionally substituted with one or more halogens or deuterium.

28. R ３ R ３ but, 【Chemistry 16-1】 【Chemistry 16-2】 【Chemistry 16-3】 And in the formula, * is L １ A compound according to any one of the prior claims, representing a bonding site to a compound.

29. R ３ but, 【Chemistry 17】 And in the formula, * is L １ A compound according to any one of the prior claims, representing a bonding site to a compound.

30. R ｃ However, halogen, -C(=O)-NH ２ , -C(=O)-NH-CN, -C(=O)-NH-(C １－６ Alkyl), or C １－６ It is alkyl, and in the formula, the C １－６ The compound according to any one of the prior claims, wherein the alkyl group is optionally substituted with one or more halogens or deuterium.

31. A compound selected from the compounds listed in Table 1, or a pharmaceutically acceptable salt thereof.

32. A pharmaceutical composition comprising the compound described in any one of claims 1 to 31.

33. A method for treating a disease in a subject requiring treatment for the disease, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 31 or a pharmaceutical composition according to claim 32.

34. A compound according to any one of claims 1 to 31, or a pharmaceutical composition according to claim 32, for use in subjects requiring treatment of a disease.

35. A compound according to any one of claims 1 to 31, or a pharmaceutical composition according to claim 32, for the manufacture of a drug for use in subjects requiring treatment of a disease.

36. The method, compound, or use according to any one of claims 33 to 35, wherein the disease is cancer.

37. The method, compound, or use according to claim 36, wherein the cancer is an HR-deficient cancer, a BRCA1- or BRCA2-mutated cancer, or a cancer having a BRCAness phenotype.

38. The method, compound, or use according to claim 37, wherein the cancer having the BRCAness phenotype is selected from breast cancer, ovarian cancer, prostate cancer, or pancreatic cancer.

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