Somatostatin receptor 2 agonists and their use

Abstract

The subject matter described herein concerns somatostatin receptor activating compounds, methods for preparing such compounds, pharmaceutical compositions, and their use in the treatment of diseases related to somatostatin receptors.

Description

[Technical Field]

[0001] Cross-references to related applications This patent application claims the interests and priority of PCT application PCT / CN2022 / 128301, filed on 28 October 2022, the entire contents of which are incorporated herein by reference.

[0002] The subject matter described herein concerns somatostatin receptor activating compounds, methods for preparing such compounds, pharmaceutical compositions, and their use in the treatment of diseases related to somatostatin receptors. [Background technology]

[0003] Somatostatin (SST) is a peptide with many biological functions, including regulating the secretion of growth hormone, insulin, glucagon, and gastric acid. Furthermore, SST exhibits potent antiproliferative effects.

[0004] The mechanism of action of somatostatin proceeds via high-affinity membrane-associated somatostatin receptors (SSTRs). There are five heterogeneously distributed, pharmacologically distinct SSTRs (SSTR1-5). SSTR2 is of particular interest because it has been shown to mediate the inhibition of growth hormone release from the anterior pituitary gland and glucagon release from the pancreas. Growth hormone plays a causal role in diabetes-related complications such as diabetic retinopathy. The regulation of glucagon and growth hormone release by somatostatin allows for the use of SSTR2 activators or agonists as treatments for diabetes and diabetes-related conditions, including retinopathy, neuropathy, and nephropathy. Furthermore, somatostatin and SSTR2 are involved in various other biological processes, including nociception, inflammation, and cell proliferation.

[0005] Therefore, the compounds and methods described herein may also be useful in treating a variety of conditions, including diabetes, diarrhea, inflammatory bowel disease, irritable bowel syndrome, cancer, acromegaly, depression, chronic atrophic gastritis, Crohn's disease, ulcerative colitis, retinopathy, arthritis, restenosis, neuroendocrine tumors (NETs), and pain.

[0006] Therefore, what is needed in the art but not effectively addressed is a compound that acts as an agonist of SSTR2, which can be efficiently formulated and administered with the desired activity to enhance SSTR2. This deficiency is addressed by the subject matter described herein.

[0007] Simple explanation In certain embodiments, the subject matter described herein covers compounds of formula I, including formula Ia, Ia-1, Ia-2, Ia-3, Ia-4, Ia-4A, Ia-5, Ia-6, Ia-7, Ib, Ib-1a, Ib-1b, Ib-1c, Ib-1d, Ib-1e, Ib-2, Ib-3, Ic, Id, Ie, If, Ig, and I-2, or pharmaceutically acceptable salts thereof.

[0008] In certain embodiments, the subject matter described herein concerns pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof.

[0009] In certain embodiments, the subject matter described herein relates to a method of treating a disease or disorder by administering a compound of formula I or a pharmaceutical composition thereof.

[0010] In certain embodiments, the subject matter described herein relates to a method for treating a subject suffering from a somatostatin-related disease, the method comprising administering to the subject a compound of formula I or a pharmaceutical composition thereof.

[0011] In certain embodiments, the subject matter described herein relates to a method for activating somatostatin receptors in a subject, which includes administering a compound of formula I or a pharmaceutical composition thereof to the subject.

[0012] Other embodiments are also described. [Overview of the project]

[0013] The subject matter of this disclosure will be described more fully thereafter. However, many modifications and other embodiments of the subject matter of this disclosure described herein will be conjured upon those skilled in the art who are interested in the teachings presented in the preceding description. Therefore, it should be understood that the subject matter of this disclosure is not limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included in the appended claims. In other words, the subject matter described herein encompasses all substitutes, modifications, and equivalents. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. All publications, patent applications, patents, and other references described herein are incorporated in their entirety by reference. If one or more of the incorporated documents, patents, and similar materials differ from or conflict with this application, including but not limited to defined terms, use of terms, and described techniques, this application shall prevail.

[0014] I. Definition Where used herein, the following words, phrases, and symbols are intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0015] A dash ("-") is used between two letters or symbols to indicate the bonding point of a substituent. For example, -C(O)NH2 is bonded via a carbon atom. Dashes at the beginning or end of a chemical group are for convenience only, and the chemical group can be represented with or without one or more dashes without losing its usual meaning. A wavy line or dash drawn through or across the end of a line in a structure indicates a specific bonding point of the group. Unless chemically or structurally required, the order in which chemical groups are described or named does not indicate or imply directionality or stereochemistry.

[0016] Prefix “C” u -C v The notation "&" indicates that the following group has u to v carbon atoms. For example, "C1-C6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0017] References to values ​​or parameters in this specification using the term "about" include (and describe) embodiments that apply to the value or parameter itself. In certain embodiments, the term "about" includes ±50% of the indicated amount. In certain other embodiments, the term "about" includes ±20% of the indicated amount. In certain other embodiments, the term "about" includes ±10% of the indicated amount. In other embodiments, the term "about" includes ±5% of the indicated amount. In certain other embodiments, the term "about" includes ±1% of the indicated amount. In certain other embodiments, the term "about" includes ±0.5% of the indicated amount, and in certain other embodiments, 0.1%. These variations are appropriate for carrying out the disclosed method or adopting the disclosed composition. Also, the term "about x" includes a description of "x". Also, the singular "a" and "the" include multiple references unless the context explicitly indicates otherwise. Thus, for example, a reference to "compound" includes multiple such compounds, and a reference to "assay" includes a reference to one or more assays and their equivalents known to those skilled in the art.

[0018] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to a chain with 1 to 20 carbon atoms (i.e., C1-C1). 20 Alkyl), 1 to 12 carbon atoms (i.e., C1-C 12 Alkyl groups have 1 to 8 carbon atoms (i.e., C1-C8 alkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), 1 to 4 carbon atoms (i.e., C1-C4 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbon atoms is named by a chemical name or identified by a molecular formula, all positional isomers having that number of carbon atoms may be included. For example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0019] The term "alkylene" refers to a divalent radical derived from alkanes such as methylene-CH2- and ethylene-CH2CH2-, either by itself or as part of another substituent. For example, "hydroxymethylene" is HO-CH2- * It refers to, * This is a bond point to the molecule.

[0020] Unless explicitly indicated otherwise, when a combination of groups is referred to herein as one part, for example, arylalkyl or aralkyl, the last group mentioned contains an atom to which the part is bonded to the rest of the molecule.

[0021] "Alkoxy" refers to an "alkyl - O -" group. Examples of alkoxy groups include, for example, methoxy, ethoxy, n - propoxy, isopropoxy, n - butoxy, tert - butoxy, sec - butoxy, n - pentoxy, n - hexoxy, and 1,2 - dimethylbutoxy.

[0022] "Amino" refers to a - NR y R z group, where R y and R z are independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be optionally substituted as defined herein.

[0023] "Aryl" refers to an aromatic carbocyclic group having a monocyclic (e.g., monocyclic) or polycyclic (e.g., bicyclic or tricyclic) ring system including fused rings. As used herein, aryl has 6 - 20 ring carbon atoms (i.e., C6 - C 20 aryl), 6 - 12 carbon ring atoms (i.e., C6 - C 12 aryl), or 6 - 10 carbon ring atoms (i.e., C6 - C 10 aryl). Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not include heteroaryl as defined below and does not overlap with it in any form. When one or more aryl groups are fused to heteroaryl, the resulting ring system is heteroaryl. When one or more aryl groups are fused to heterocyclyl, the resulting ring system is heterocyclyl.

[0024] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a monocyclic or polycyclic ring system including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond) and at least one sp 3It comprises a carbocyclic fused ring system having carbon atoms (i.e., at least one non-aromatic ring). As used herein, cycloalkyl refers to a ring with 3 to 20 carbon atoms (i.e., C3-C3). 20 Cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-C 12 Cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-C 10 The group has 3 to 8 ring carbon atoms (i.e., C3-C8 cycloalkyl), 3 to 7 ring carbon atoms (i.e., C3-C7 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-C6 cycloalkyl). Examples of monocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic groups include bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl, dekalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Furthermore, the term cycloalkyl is intended to encompass any non-aromatic ring that can be fused to the aryl ring, regardless of its bonding to the rest of the molecule. Furthermore, this also includes "spirocycloalkyl" compounds where there are two substitution positions on the same carbon atom, such as spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0025] "Halogen" or "halo" refers to atoms that occupy Group VIIA of the periodic table, such as fluorine, chlorine, bromine, or iodine.

[0026] "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by halogens. For example, if a residue is replaced by two or more halogens, it may be referred to by using a prefix corresponding to the number of halogen moieties bonded. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two ("di") or three ("tri") halo groups, which may or may not be the same halogen. Examples of haloalkyls include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl. "C1-C3 haloalkyl" and "halo-C1-C3 alkyl" are used interchangeably herein and refer to an alkyl chain having 1 to 3 carbon atoms, in which one or more hydrogen atoms in the alkyl chain are replaced by halogens. Furthermore, a C1-C3 fluoroalkyl (or fluoro-C1-C3 alkyl) refers to an alkyl chain having 1 to 3 carbon atoms, in which one or more hydrogen atoms in the alkyl chain are replaced by fluoro atoms. Non-restrictive examples of haloalkyls include -CH2CH2CF3, -CHF2, -CF3, -CH2CHF2, and -CH2CF3.

[0027] "Haloalkoxy" refers to the alkoxy group defined above in which one or more hydrogen atoms (e.g., 1 to 6 or 1 to 3) are replaced by halogens. "C1-C3 haloalkoxy" and "halo-C1-C3 alkoxyl" are used interchangeably herein and refer to alkoxy groups having 1 to 3 carbon atoms in the alkyl unit of the alkoxy group, in which one or more hydrogen atoms in the alkyl chain are replaced by halogens. Non-limiting examples of haloalkoxy groups include -OCH2CHF2, -OCH2CF3, and -OCF3.

[0028] "Hydroxyalkyl" or "hydroxyalkylene" and similar terms refer to alkyl or alkylene groups as defined above, in which one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by hydroxyl groups. For example, the terms "hydroxy-C1-C3 alkyl," "C1-C3 hydroxyalkyl," or "hydroxy-C1-C3 alkylene" refer to a 1 to 3-carbon alkyl chain in which one or more hydrogen atoms on any carbon are replaced by hydroxyl groups, in particular, one hydrogen atom on one carbon in the chain is replaced by a hydroxyl group.

[0029] "Heteroaryl" refers to an aromatic group having a monocyclic, multicyclic, or multi-fused ring having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to a ring group having 1 to 20 ring carbon atoms (i.e., C1-C1). 20 Heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-C 12A heteroaryl ring (or a heteroaryl ring) comprises 3 to 8 carbon atoms (i.e., a C3-C8 heteroaryl ring) and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, oxygen, and sulfur. In certain examples, the heteroaryl rings include 9-10 membered ring systems (9-10 membered heteroaryl rings), 6-10 membered ring systems (6-10 membered heteroaryl rings), 5-10 membered ring systems (5-10 membered heteroaryl rings), 5-7 membered ring systems (5-7 membered heteroaryl rings), or 5-6 membered ring systems (5-6 membered heteroaryl rings), each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl Examples include isoquinolyl, isoxazolyl, naphthilidinyl, oxadiazolyl, oxazolyl, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and triazinyl. Examples of condensed heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, where the heteroaryl can be linked via any of the rings in the condensation system.Any aromatic ring having one or more fused rings containing at least one heteroatom is considered a heteroaryl, regardless of its bonding to the rest of the molecule (i.e., via any one of the fused rings). A heteroaryl does not encompass or overlap with an aryl as defined above.

[0030] A "heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridging heterocyclyl groups, condensed heterocyclyl groups, and spiroheterocyclyl groups. Heterocyclyls may be monocyclic or multicyclic, and the multicyclic rings may be condensed, bridging, or spiro, and have one or more (e.g., 1 to 3) oxo (=O) or N-oxide (-O) atoms. - ) may include a portion. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl regardless of bonding (i.e., it may be bonded via carbon atoms or heteroatoms). Furthermore, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which may be condensed into an aryl ring or a heteroaryl ring regardless of bonding to the rest of the molecule. As used herein, a heterocyclyl is a ring containing 2 to 20 carbon atoms (i.e., C2-C2-C2). 20 Heterocyclines), 2 to 12 ring carbon atoms (i.e., C2-C 12 Heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-C 10 Heterocyclyl), 2-8 ring carbon atoms (i.e., C2-C8 heterocyclyl), 3-12 ring carbon atoms (i.e., C3-C 12A heterocyclyl ring has 3 to 8 ring carbon atoms (i.e., a C3-C8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., a C3-C6 heterocyclyl), and has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, sulfur, or oxygen. When the heterocyclyl ring contains 4 or 6 ring atoms, it is also referred to herein as a 4 or 6-membered heterocyclyl. When the heterocyclyl ring contains 5 to 7 ring atoms, it is also referred to herein as a 5 to 7-membered heterocyclyl. When the heterocyclyl ring contains 5 to 10 ring atoms, it is also referred to herein as a 5 to 10-membered heterocyclyl. Examples of heterocyclyl groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxynyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolidinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolinyl Examples include 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxyranil, oxetanil, phenothiazinyl, phenoxadinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianil, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term "heterocyclyl" also includes "spiroheterocyclyl" when there are two positions for substitution on the same carbon atom.Examples of spiro-heterocyclyl rings include, for example, bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of condensed heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl, where the heterocyclyl can be linked via any of the rings in the condensation system.

[0031] "(C1-C3 alkoxy)-C1-C3 alkyl" refers to an alkyl-alkoxy group, where both the alkoxy unit and the alkyl unit each individually contain an alkyl chain having 1 to 3 carbon atoms.

[0032] "(C1-C3-alkoxy)-C1-C3 alkoxy" refers to an alkoxy-alkoxy group, where both alkoxy units each individually contain an alkyl chain having 1 to 3 carbon atoms.

[0033] The terms “optional” or “at will” mean that the event or situation described below may or may not occur, and that the description includes both cases in which the event or situation occurs and cases in which it does not. Furthermore, the term “optionally substituted” means that any one or more hydrogen atoms (e.g., 1-5, 1-4, or 1-3) on a specified atom or group may or may not be substituted by non-hydrogen parts.

[0034] As used herein, the term "substituted" means that at least one (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are replaced by, for example, alkyl, alkoxy, amino, aryl, aralkyl, carboxyl, carboxyl ester, cyano, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroaryl, heterocyclyl, -NHNH2, hydroxy, oxo, nitro, -S(O)OH, -S(O)2OH, N-oxide, or -Si(R y )3 is substituted by bonding with non-hydrogen atoms, and each R y is independently any of the above groups (i.e., alkyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclyl).

[0035] In certain embodiments, "substituted" means that one or more (e.g., 1-5, 1-4, or 1-3) hydrogen atoms are independently substituted for deuterium, halo, cyano, nitro, oxo, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g S(=O) 1-2 R h -C(=O)R g , -C(=O)OR g , -OC(=O)OR g -OC(=O)R g -C(=O)NR g R h -OC(=O)NR g R h , -OR g , -SR g-S(=O)R g -S(=O)2R g -OS (=O) 1-2 R g -S(=O) 1-2 Ure g , -NR g S(=O) 1-2 NR g R h ,=NSO2R g 、=NOR g -S(=O) 1-2 NR g R h The group comprises any of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups described above, which are substituted with -SF5, -SCF3, or -OCF3. In certain embodiments, "substituted" means that one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are -C(=O)R g , -C(=O)OR g -C(=O)NR g R h ,-CH2SO2R g , or -CH2SO2NR g R h It also means any of the above bases that are substituted by. As mentioned above, R g and R h These are identical or different, and independently are hydrogen, alkyl, alkoxy, aryl, cycloalkyl, haloalkyl, heterocyclyl, and / or heteroaryl. In certain embodiments, “substitution” is also a substitution in which one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are substituted by bonding with amino, cyano, hydroxyl, nitro, oxo, halo, alkyl, alkoxy, alkylamino, aryl, cycloalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heteroaryl, or R g and R h and R iTwo of these groups, together with the atom to which they are bonded, form a heterocyclyl ring that is optionally substituted with an oxo, halo, or alkyl group optionally substituted with an oxo, halo, amino, hydroxyl, or alkoxy group.

[0036] In certain embodiments described herein, the description "R" 1 "And Z, together with the rings to which they are bonded, form a fused bicyclic ring" refers to a compound having the following structure: [ka]

[0037] In certain embodiments, the description "R 1 and R C1 "Together with the rings to which they are bonded, each ring forms a fused tricyclic ring" refers to a compound having the following structure: [ka]

[0038] In certain embodiments, the description "R 2 and R B1 "Together with the rings to which they are bonded, each ring forms a fused tricyclic ring" refers to a compound having the following structure: [ka]

[0039] Polymers or similar amorphous structures obtained by defining substituents and adding substituents indefinitely (e.g., substituted aryls having a substituted alkyl that itself is substituted with a substituted aryl group, and a substituted aryl further substituted with a substituted heteroalkyl group) are not intended to be included herein. Unless otherwise stated, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryls. Similarly, the above definitions are not intended to include unacceptable substitution patterns (e.g., a methyl group substituted with five fluorine atoms, or a heteroaryl group having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term “substituted” may describe other chemical groups as defined herein.

[0040] In certain embodiments, as used herein, the phrase "one or more" refers to numbers one through five. In certain embodiments, as used herein, the phrase "one or more" refers to numbers one through four. In certain embodiments, as used herein, the phrase "one or more" refers to numbers one through three.

[0041] Any compound or structure given herein is intended to represent both the unlabeled and isotope-labeled forms (isotopologes) of the compound. These forms of the compound may also be referred to as “isotope-enriched analogues,” and may include them. An isotope-labeled compound has the structure shown herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of this disclosure are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O,18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. The various isotopically labeled compounds of the present disclosure, for example, 3 H, 13 C, and 14 compounds incorporating radioactive isotopes such as C. Such isotopically labeled compounds can be useful in detection or imaging techniques such as metabolic studies, kinetic studies, positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in the radioactive treatment of patients.

[0042] The term "isotope-enriched analog" includes "deuterated analogs" of the compounds described herein in which one or more hydrogens are replaced by deuterium such as hydrogens on a carbon atom. Such compounds show increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, "Deuterium Isotope Effects in Studies of Drug Metabolism," by Foster, Trends Pharmacol. Sci. 5(12):524-527(1984). Such compounds are synthesized by means well known in the art, for example, by employing starting materials in which one or more hydrogens are replaced by deuterium.

[0043] The deuterium-labeled or substituted therapeutic compounds of the present disclosure can have improved DMPK (drug metabolism and pharmacokinetics) properties in relation to distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope such as deuterium can result in certain therapeutic advantages arising from greater metabolic stability, such as an increase in in vivo half-life, a reduction in dosing requirements, and / or an improvement in the therapeutic index. 18 F, 3 H, 1114C-labeled compounds may be useful in PET, SPECT, or other imaging studies. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by performing the procedures disclosed in the schemes or examples and preparations described below, by substituting readily available isotope-labeling reagents for non-isotope-labeling reagents. In this context, deuterium is understood to be a substituent in the compounds described herein.

[0044] The concentrations of these heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. In the compounds of this disclosure, any atom not specifically designated as a particular isotope represents any stable isotope of that atom. Unless otherwise stated, where a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in its naturally occurring isotopic composition. Thus, in the compounds of this disclosure, any atom specifically designated as deuterium (D) represents deuterium. Furthermore, in some embodiments, corresponding deuterated analogs are provided.

[0045] In many cases, the compounds of this disclosure can form acid salts and / or base salts due to the presence of an amino group and / or a carboxyl group or similar groups.

[0046] Also provided herein are pharmaceutically acceptable salts, isotopic enriched analogs, deuterated analogs, isomers (such as stereoisomers), mixtures of isomers (such as mixtures of stereoisomers), prodrugs, and metabolites of the compounds described herein.

[0047] "Pharmacologically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other materials useful for preparing pharmaceutical compositions suitable for veterinary or human use.

[0048] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. Examples of "pharmaceutically acceptable salts" or "physiologically acceptable salts" include salts having an inorganic acid and salts having an organic acid. Furthermore, if the compounds described herein are obtained as acid addition salts, the free base can be obtained by basicizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt, in particular a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize the various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Examples of salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of salts derived from organic acids include acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Examples of salts derived from inorganic bases include sodium salts, potassium salts, lithium salts, aluminum salts, ammonium salts, calcium salts, and magnesium salts.Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), and di(substituted alkenyl)amines (i.e., Examples include salts of HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3), mono-, di-, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines. Specific examples of suitable amines, though only a few examples, include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, and N-ethylpiperidine.

[0049] The term "hydrate" refers to a complex formed by the bonding of a compound described herein with water.

[0050] A “solvate” refers to an association or complex of one or more solvent molecules with a compound of the present disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine.

[0051] Some compounds exist as tautomers. Tautomers exist in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imido acid tautomer. Regardless of which tautomer is shown and the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that a compound contains both an amide acid tautomer and an imido acid tautomer. Therefore, an amide-containing compound is understood to contain its imido acid tautomer. Similarly, an imido acid-containing compound is understood to contain its amide tautomer.

[0052] This compound, or its pharmaceutically acceptable salts, may contain a chiral center and therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- with respect to an amino acid. This subject means all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R) and (S), or (D) and (L) isomers may be prepared by chiral synthesis or using chiral reagents, or by decomposition using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include, for example, chiral synthesis from suitable optically pure precursors using chiral high-pressure liquid chromatography (HPLC), or decomposition of racemates (or racemates of salts or derivatives). If a compound described herein contains an olefin double bond or other geometrically asymmetric center, unless otherwise specified, the compound is intended to include both E and Z geometric isomers.

[0053] A "stereoisomer" refers to a compound that is composed of the same atoms bonded together by the same bonds, but has different, incompatible three-dimensional structures. This topic aims to explore various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers that are mirror images of each other and cannot be superimposed.

[0054] A "diastereomer" is a stereoisomer that has at least two chiral atoms but is not a mirror image of one another.

[0055] The relative centers of the compounds illustrated herein are shown using a "thick bond" style (thick or parallel lines), and absolute stereochemistry is shown using wedge bonds (thick or parallel lines).

[0056] "Prodrug" means any compound that, when administered to a mammalian subject, releases an active parent drug in vivo according to the structure described herein. Prodrugs of the compounds described herein are prepared by modifying functional groups present in the compounds described herein such that the modification can be cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying functional groups present in the compounds such that the modification can be cleaved into the parent compound either in a routine operation or in vivo. Prodrugs include the compounds described herein, wherein the hydroxyl, amino, carboxyl, or sulfhydryl groups in the compounds described herein are bonded to any group that can be cleaved in vivo to regenerate a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters of the hydroxyl functional groups in the compounds described herein (e.g., acetate esters, formate esters, and benzoate ester derivatives), amides, guanidines, and carbamates (e.g., N,N-dimethylaminocarbonyl). The preparation, selection, and use of prodrugs are described in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the ACS Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated herein by reference in its entirety.

[0057] As used herein, the term “metabolite” refers to the resulting products formed when a compound disclosed herein is metabolized. As used herein, the term “metabolism” refers to the sum of processes (including, but not limited to, hydrolysis and enzyme-catalyzed reactions) in which a particular substance, such as a compound disclosed herein, is transformed by a living organism. For example, the aldehyde moiety (-C(O)H) of a compound of the preceding subject may be reduced to the -CH2OH moiety in vivo.

[0058] As used herein, terms such as “somatostatin receptor agonist” refer to compounds that activate, increase, or modulate one or more of the biological activities of somatostatin receptors. The activity may increase, for example, the activity of somatostatin receptors by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95%, or 100% compared to a suitable control. The increase may be statistically significant.

[0059] "Treatment" or "treating" is an approach to obtain beneficial or desirable outcomes, including clinical outcomes. Beneficial or desirable clinical outcomes may include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition, and / or reducing the severity of the disease or condition); b) preventing or delaying the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (e.g., metastasis)); and / or c) alleviating the disease, i.e., causing regression of clinical symptoms (e.g., improving the disease state, achieving partial or complete remission of the disease or condition, enhancing the effects of another drug, slowing the progression of the disease, improving quality of life, and / or extending survival).

[0060] "Prevention" or "prevention" means any treatment of a disease or condition that prevents the development of clinical symptoms of the disease or condition. In some embodiments, the compound may be administered to subjects (including humans) who are at risk of or have a family history of the disease or condition.

[0061] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be used for the purpose of treatment, observation, or experimentation. The methods described herein may be useful for human therapeutic and / or veterinary use. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0062] The terms “therapeutic effective dose” or “effective dose” of any compound or pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog described herein mean an amount sufficient to produce a therapeutic effect when administered to a subject and to provide a therapeutic benefit such as improvement of symptoms or slowing of disease progression. For example, a therapeutic effective dose may be an amount sufficient to reduce the symptoms of pyruvate kinase deficiency (PKD). The therapeutic effective dose may vary depending on the subject, as well as the disease or condition being treated, the subject’s weight and age, the severity of the disease or condition, and the method of administration, which can be readily determined by those skilled in the art.

[0063] If necessary, additional definitions can be provided below.

[0064] II. Compounds As described herein, in certain embodiments, the subject is a compound of formula I, [ka] The formula applies to pharmaceutically acceptable salts thereof, in which, g is either 1 or 0. Z either does not exist, or is -N(H)-C(=O)-, or -C(=O)-NH-. R 1is either hydrogen or a halogen, or R 1 And Z, along with the ring to which each is joined, one or two R 8 It forms a condensed bicyclic ring that can be substituted as desired, or R 1 and R C1 Each of these, along with the rings to which they are bonded, forms a fused tricyclic ring. Ring C is such that each of them is R C1 , R C2 , and R C3 The substitution is made from a group consisting of 4-10 member monocyclic or bicyclic condensed heterocyclines, 6-10 member aryls, and 5-10 member heteroaryls, Here, each of the 4-10 membered monocyclic or bicyclic condensed heterocyclyls or 5-10 membered heteroaryls independently contains 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S, and, R C1 is either hydrogen or R 1 , R 3 , or R 6 It can be combined with, R C2 and R C3 These are, independently, hydrogen, halogen, cyano, C1-C6 alkyl, hydroxy, -C(=O)NH2, -O-C2-C6 alkenyl, -C1-C6 alkoxy, and -NH-(CH2) 1‐5 -NH2, -O-piperidinyl, -O-(CH2) qC -O-(CH2) rC -Selected from the group consisting of CH3, qC and rC are each independent integers from 1 to 4. R 2 is either hydrogen or a halogen, or R 2 and R B1 Each of these, along with the rings to which they are bonded, forms a fused tricyclic ring. R 3 If present, R C1 It is a group covalently bonded to it, Ring B is either phenyl or pyridinyl, and each is RB1 It is either replaced by R B1 and R B2 It is replaced twice, Here, R B1 and R B2 Each of these is independently hydrogen, cyano, C1-C6 alkyl, halogen, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, hydroxy, C1-C6 alkoxy, -O-C2-C6 alkenyl, -NH-(CH2) 1-5 -NH2, -O-(CH2) q2 -O‐(CH2) r2 -Selected from the group consisting of CH3, q2 and r2 are each independently integers from 1 to 4, -C(O)-NR Na R Nb And each R Na and R Nb Each is independently selected from the group consisting of hydrogen and C1-C6 alkyl groups. Furthermore, A is selected from the following group: i.-NR 4 R 5 Here, R 4 These are optionally substituted C1-C6 alkyl, -NH-C1-C6 alkyl-NHR 4a , and -C1-C6 alkyl-NHR 4a And R 4a is hydrogen or methyl, and R 5 This is a C1-C6 alkyl group that is substituted with hydrogen or optionally substituted. The optional substituents are selected from the group consisting of halogens and hydroxyls. or R 5 and R B1 R 5 N and R that bind together B1 Together with ring B to which it is attached, it forms a condensed heterocycline. or R 5 and R C1 R 5 N and R that bind together C1Together with the ring C to which it is attached, it forms a condensed heterocycline. or R 5 and R 8 R 5 N and R that bind together 8 Together with the ring to which it is bonded, it forms a condensed heterocycline. ii.-NH-R 6 Or R S A spiro ring is substituted by, where, R S These are hydrogen or -C(=O)-C1-C6 alkyl, Furthermore, iii. Each of them is -NH-R 6 It is replaced by R F and R G Substituted with -O-(C3-C8 cycloalkyl), 5-11 member heterocyclyl, or 5-6 member heteroaryl, where R F These include hydroxyl, hydroxy-C1-C6 alkyl, nitro, -C(=O)H, -C1-C6 alkoxy, -C(=NH)-NH2, -NH-C(=NH)-NH2, -C(=O)-C1-C6 alkyl, -(C=O)-O-C1-C6 alkyl, and -(C1-C6 alkyl) x -NR F1 R F2 Selected from the group consisting of, x is either 0 or 1, and R F1 and R F2 These are, independently, H, -(C=O)-O-C1-C6 alkyl, and C1-C6 alkyl, R G is either hydrogen or a -C1-C6 alkoxy, or R G R C1 Along with, -O-(CH2) k -O- is formed, where k is an integer from 1 to 5, or R F and R G They together form a carboxyl group, and R 6 RC1 together with the following to form [Chemical formula] wherein [Chemical formula] is the bonding point of R to A, 6 and p is an integer from 1 to 4, R 7a and R 7b in each case are independently selected from the group consisting of hydroxyl, optionally substituted -C1-C6 alkyl, -N3, -NR a R b and are independently H or C1-C6 alkyl, [[ID=,30]] a and R b are each independently H or C1-C6 alkyl, E is absent, -O- or -N(R b )-, and R b is H or optionally substituted C1-C6 alkyl, J is -C(O)- or -C(R 7a R 7b )-, and L is absent, -O- or -N(H)-, the optional substituent is selected from the group consisting of halogen, -NH2, and hydroxy, provided that the compound is not one of the following. [Chemical formula]

[0065] In certain of the above embodiments, useful compounds are those in which Z is absent.

[0066] In certain of the above embodiments, useful compounds are those in which Z is -N(H)-C(=O)- or -C(=O)-NH- and y is 1.

[0067] In the specific embodiments described above, the useful compound is the compound in which g is 0.

[0068] In the specific embodiments described above, the useful compounds are compounds having the structure of formula Ia or Ib, where Z and R 1 Each of them, along with the ring to which they are joined, is condensed: [ka] Forms, and in the formula, X 1 and X 2 These are O, N, and NR, each independent of the others. 8 , S, and CR 8 Selected from the group consisting of, R 8 These are hydrogen, optionally substituted C1-C6 alkyl groups, and -C(=O)OR 8a Selected from the group consisting of R 8a The element is hydrogen or a C1-C6 alkyl group, and optional substituents are selected from the group consisting of halogens, -NH2, and hydroxyl groups.

[0069] In the specific embodiments described above, the useful compound is a compound having the structure of formula Ia-1. [ka]

[0070] In the specific embodiments described above, the useful compound is a compound having the structure of formula Ia-2. [ka]

[0071] In the specific embodiments described above, the useful compound is a compound having the structure of formula Ia-3. [ka]

[0072] In certain of the above embodiments, the useful compound is a compound having the structure of formula Ib-1. [Chemical formula]

[0073] In certain of the above embodiments, the useful compound is a compound having the structures of formulae Ib-1a to Ib-1e. [Chemical formula]

[0074] In certain of the above embodiments, the useful compound is a compound in which the positions of R B1 and R B2 are as follows. [Chemical formula]

[0075] In certain of the above embodiments, the useful compound is a compound in which R B1 and R B2 are each independently selected from the group consisting of C1-C6 alkyl, halogen, and C1-C6 alkoxy.

[0076] In certain of the above embodiments, the useful compound is a compound in which the C1-C6 alkyl is methyl, the halogen is fluoro, and the C1-C6 alkoxy is methoxy.

[0077] In certain of the above embodiments, the useful compound is a compound in which at least one of R B1 and R <{ B2 is fluoro.

[0078] In certain of the above embodiments, the useful compound is a compound in which both R B1 and R B2 are fluoro. ]

[0079] In the specific embodiments described above, the useful compound is R C1 is hydrogen, R C2 and R C3 The compound is such that the position is as follows. [ka]

[0080] In the specific embodiments described above, the useful compounds are R C2 However, hydroxy, C1-C6 alkoxy, -O-piperidinyl, -N-(CH2)3-NH2, -O-C2-C6 alkenyl, -O-(CH2) q1 -O-(CH2) r1 -Selected from the group consisting of CH3, where q1 and r1 are each independently integers from 1 to 4, and R C3 However, it is a compound selected from the group consisting of cyano and halogen compounds.

[0081] In the specific embodiments described above, the useful compounds are R C2 However, selected from the group consisting of hydroxy, methoxy, -O-CH2-CH=CH2, and -O-CH2-O-CH3, R C3 However, it is a compound selected from the group consisting of cyano and bromine.

[0082] In the specific embodiments described above, the useful compound is R C1 is hydrogen, R C2 and R C3 The compound is such that the position is as follows. [ka]

[0083] In the specific embodiments described above, the useful compounds are R C2 and R C3 These are compounds in which each of them is a halogen.

[0084] In certain embodiments described above, the useful compounds are those in which the halogen is fluoro.

[0085] In the specific embodiments described above, the useful compound is R C1 is hydrogen, R C2 and R C3 The compound is such that the position is as follows. [ka]

[0086] In the specific embodiments described above, the useful compounds are R C2 and R C3 However, each of these compounds is independently selected from the group consisting of hydroxyl, C1-C6 alkoxy, halogen, -(C=O)-NH2, -O-C2-C6 alkenyl, and C1-C6 alkyl.

[0087] In the specific embodiments described above, the useful compounds are R C2 and R C3 However, each of these compounds is independently selected from the group consisting of -(C=O)-NH2, methoxy, fluoro, and methyl.

[0088] In the specific embodiments described above, the useful compounds are Ring B is R B1 and R B2 It is a disubstituted phenyl, and also, The compound is one in which ring C is a monocyclic or bicyclic heterocycline with 4 to 10 members.

[0089] In certain embodiments described above, useful compounds are those in which the C ring is a bicyclic lactam or cyclic urea with 9 to 10 members.

[0090] In the specific embodiments described above, a useful compound is one in which ring C is selected from the group consisting of the following: [ka]

[0091] In the specific embodiments described above, the useful compound is a compound having the structure of formula Ic, where Z is absent and R is absent. 1 and R C1 R 1 The ring to which R is bonded C1 Along with the ring to which it is bonded, R 8 It forms a fused ring that is substituted by [the specified element]. [ka]

[0092] In the specific embodiments described above, the useful compound is R 8 It is a compound in which hydrogen is present.

[0093] In the specific embodiments described above, the useful compound is one in which the ring C is R C2 and R C3 It is a compound that is an 8-10 member heteroaryl substituted with a specific compound.

[0094] In the specific embodiments described above, a useful compound is a compound in which the ring C is as follows: [ka]

[0095] In the specific embodiments described above, the useful compound is R C2 and R C3 Each of these is a compound in which fluoropolymer is present.

[0096] In the specific embodiments described above, the useful compound is one in which ring B is R B1 and R B2 It is a compound that is a disubstituted phenyl compound.

[0097] In the specific embodiments described above, the useful compound is R B1 is halogen, R B2 It is a compound in which the halogen or C1-C6 alkyl group is present.

[0098] In the specific embodiments described above, the useful compound is R B1 is fluoro, R B2 It is a compound in which the compound is fluoro or methyl.

[0099] In the specific embodiments described above, the useful compound is R in the phenyl ring. B1 and R B2 The compound is such that the position is as follows: [ka]

[0100] In the specific embodiments described above, the useful compound is a compound having the structure of formula Id, where Z and R 1 Each of these rings forms a fused ring with the ring to which it is bonded. [ka]

[0101] In the specific embodiments described above, the useful compound is R 8 It is a compound in which hydrogen is present.

[0102] In the specific embodiments described above, the useful compound is one in which the ring C is R C1 , R C2 , and R C3 It is a compound in which phenyl is substituted with [a specific compound].

[0103] In the specific embodiments described above, the useful compound is R C1 is hydrogen, R C2 and R C3 The compound is such that the position is as follows. [ka]

[0104] In the specific embodiments described above, the useful compound is R C2 and R C3However, each of these compounds is independently selected from the group consisting of C1-C6 alkyl groups and halogens.

[0105] In certain embodiments described above, useful compounds are those in which the C1-C6 alkyl group is methyl and the halogen group is fluoro.

[0106] In the specific embodiments described above, the useful compound is one in which ring B is R B1 and R B2 It is a compound that is a disubstituted phenyl compound.

[0107] In the specific embodiments described above, the useful compound is R B1 is halogen, R B2 It is a compound in which the halogen or C1-C6 alkyl group is present.

[0108] In the specific embodiments described above, the useful compound is R B1 is fluoro, R B2 It is a compound in which the compound is fluoro or methyl.

[0109] In the specific embodiments described above, the useful compound is R in phenyl. B1 and R B2 The compound is such that the position is as follows: [ka]

[0110] In the specific embodiments described above, the useful compound is a compound having the structure of formula Ie, where R 2 and R B1 R 2 The ring to which R is bonded B1 Together with the ring to which it is bonded, it forms a fused ring. [ka] During the ceremony, Q is either O or CH2, [ka] is a single bond, or Q is N, [ka] It is a double bond, R 1 is hydrogen or halogen, and Ring B is R B2 It is a phenyl compound substituted with [a specific compound].

[0111] In the specific embodiments described above, the useful compound is R 1 It is a compound in which hydrogen is present.

[0112] In the specific embodiments described above, the useful compound is one in which the ring C is R C1 , R C2 , and R C3 It is a compound that is an 8-10 member heteroaryl substituted with a specific compound.

[0113] In the specific embodiments described above, the useful compound is R C1 The compound is one in which hydrogen is present and the ring C is as follows: [ka]

[0114] In the specific embodiments described above, the useful compound is R B2 It is a compound in which halogen is present.

[0115] In the specific embodiments described above, the useful compound is R B2 It is a compound that is fluoro.

[0116] In the specific embodiments described above, the useful compound is one in which Q is N, [ka] It is a compound in which a double bond is present.

[0117] In the specific embodiment described above, the useful compound is one in which Q is O, [ka] It is a compound in which the bond is a single bond.

[0118] In the specific embodiments described above, the useful compounds are A, each being -NH-R 6 It is replaced by or R F and R G These are compounds that are substituted with a 5-11 member heterocyclyl or a 5-6 member heteroaryl.

[0119] In the specific embodiments described above, a useful compound is one in which A has the following structure: [ka] During the ceremony, Ring A1 is a 5-6 member heteroaryl or 5-6 member heterocyclyl.

[0120] In the specific embodiments described above, a useful compound is one in which A has the following structure: i. [ka] During the ceremony, G is N, D is CH2, y is 0 or 1, each [ka] It is a single bond, G is C, D is CH2, and y is 1. [ka] It is a double bond, and the other [ka] Each is a single bond, G is N, D is CH2, and y is 0. [ka] Each of them is a double bond, and the other [ka] Each is a single bond, G is C, D is N or CH, y is 1, each [ka] It is a double bond.

[0121] In the specific embodiments described above, a useful compound is one in which A is selected from the group consisting of the following: [ka]

[0122] In the specific embodiments described above, a useful compound is a compound in which A is a spirocyclic structure having the following structure: [ka] In the formula, t, t1, u, and u1 are each independently either 1 or 2.

[0123] In the specific embodiments described above, a useful compound is one in which A is selected from the group consisting of the following: [ka]

[0124] In the specific embodiments described above, the useful compound is one in which A is -NH-R 6 Replaced by, or R F and R G It is a compound that is a -O-(C3-C8 cycloalkyl) substituted with .

[0125] In the specific embodiments described above, a useful compound is one in which A has the following structure: [ka] During the ceremony, Ring A2 is a C4-C6 cycloalkyl group.

[0126] In the specific embodiments described above, a useful compound is one in which A is selected from the group consisting of the following: [ka]

[0127] In the specific embodiments described above, the useful compounds are R 6 R C1 It is a compound that forms the following together with the following: [ka] During the ceremony, [ka] R 6 This represents the connection point to A, p is an integer between 1 and 4. R 7a and R 7b In each case, hydroxyl, optionally substituted -C1-C6 alkyl, -N3, -NR are used. a R b Independently selected from the group consisting of R a and R b Each of these is independently H or a C1-C6 alkyl group. E does not exist, or it is -O- or -N(R b )- and R b is a C1-C6 alkyl group that is optionally substituted with H, J is -C(O)- or -C(R 7a R 7b )-and, as well as L either does not exist, or is -O- or -N(H)-.

[0128] In the specific embodiments described above, the useful compound is R6 R C1 It is a compound that forms the following with [another compound]. [ka] [ka]

[0129] In the specific embodiments described above, the useful compound is a compound having the structure of formula Ia-4. [ka]

[0130] In the specific embodiments described above, the useful compound is a compound having the structure of formula Ia-4A. [ka]

[0131] In the specific embodiments described above, the useful compound is R C1 The compound has the following structure at the ring C to which it is bonded. [ka]

[0132] In the specific embodiments described above, the useful compound is R C1 The compound has the following structure at the ring C to which it is bonded. [ka]

[0133] In the specific embodiments described above, the useful compound is R C2 It is a compound in which the parent is cyano or -(C=O)-NH2.

[0134] In the specific embodiments described above, the useful compounds are those having the structures of formulas Ia-6, Ia-7, Ib-2, and Ib-3. [ka]

[0135] In the specific embodiments described above, the useful compounds are R in Ia-6, Ia-7, Ib-2, and Ib-3, respectively. B1 and R B2 The compound is such that the position is as follows. [ka]

[0136] In the specific embodiments described above, the useful compound is R B1 and R B2 Each of these compounds is independently selected from the group consisting of C1-C6 alkyl, halogen, and C1-C6 alkoxy compounds.

[0137] In certain embodiments described above, useful compounds are those in which the C1-C6 alkyl group is methyl, the halogen is fluoro, and the C1-C6 alkoxy group is methoxy.

[0138] In the specific embodiments described above, the useful compound is R B1 and R B2 It is a compound in which at least one of the elements is fluoro.

[0139] In the specific embodiments described above, the useful compound is R B1 and R B2 It is a compound in which both are fluoro.

[0140] In the specific embodiments described above, the useful compound is R C2 and R C3 The compound is such that the position is as follows. [ka]

[0141] In the specific embodiments described above, the useful compounds are R C2 However, hydroxy, C1-C6 alkoxy, -O-piperidinyl, -N-(CH2)3-NH2, -O-C2-C6 alkenyl, -O-(CH2) q1 -O-(CH2) r1 -Selected from the group consisting of CH3, where q1 and r1 are each independently integers from 1 to 4, and R C3 However, it is a compound selected from the group consisting of cyano and halogen compounds.

[0142] In the specific embodiments described above, the useful compounds are R C2 However, selected from the group consisting of hydroxy, methoxy, -O-CH2-CH=CH2, and -O-CH2-O-CH3, R C3 However, it is a compound selected from the group consisting of cyano and bromine.

[0143] In the specific embodiments described above, the useful compound is R C1 is hydrogen, R C2 and R C3 The compound is such that the position is as follows. [ka]

[0144] In the specific embodiments described above, the useful compounds are R C2 and R C3 These are compounds in which each of them is a halogen.

[0145] In certain embodiments described above, the useful compounds are those in which the halogen is fluoro.

[0146] In the specific embodiments described above, the useful compound is R C1 is hydrogen, R C2 and R C3 The compound is such that the position is as follows. [ka]

[0147] In the specific embodiments described above, the useful compounds are R C2 and R C3 However, each of these compounds is independently selected from the group consisting of hydroxyl, C1-C6 alkoxy, halogen, -(C=O)-NH2, -O-C2-C6 alkenyl, and C1-C6 alkyl.

[0148] In the specific embodiments described above, the useful compounds are R C2 and R C3 However, each of these compounds is independently selected from the group consisting of -(C=O)-NH2, methoxy, fluoro, and methyl.

[0149] In the specific embodiments described above, the useful compound is A-NR 4 R 5 It is a compound that is [this compound].

[0150] In the specific embodiments described above, the useful compounds are R 4 However, these are C1-C6 alkyl, -C1-C6 alkyl-NH-CH3, C1-C6 alkyl-NH2, -NH-C1-C6 alkyl-NH-CH3, and -NH-C1-C6 alkyl-NH2, which can be substituted as desired. R 5 However, it is a compound that is a C1-C6 alkyl group that is substituted with hydrogen or optionally.

[0151] In the specific embodiments described above, the useful compound is R 4 is -(CH2)3-NH-CH3, and R 5 It is a compound in which hydrogen is present.

[0152] In the specific embodiments described above, the useful compound is a compound having the structure of formula If, where R 5 and R B1 R 5 N and R are bonded together. B1Together with ring B to which it is bonded, it forms a fused ring. [ka] During the ceremony, M stands for carbonyl or CR M1 R M2 And R M1 and R M2 Each of these is independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, and C1-C6 alkyl-NH2, and the optional substituent is selected from the group consisting of halogens and hydroxyls.

[0153] In the specific embodiments described above, the useful compounds are M is CH2, R 1 and R 2 However, each is hydrogen, and R 4 However, C1-C6 alkyl-NHR 4a It is a compound that is [this compound].

[0154] In the specific embodiments described above, the useful compounds are those in which Z is -C(=O)-NH-.

[0155] In the specific embodiments described above, the useful compounds are Ring B is R B1 It is a monosubstituted phenyl, or R B1 and R B2 It is a compound that is a disubstituted phenyl compound.

[0156] In the specific embodiments described above, the useful compound is R B1 and R B2 These are compounds in which each is fluoro.

[0157] In certain embodiments described above, the useful compounds are those in which ring C is a 4-10 membered monocyclic or bicyclic condensed heterocyclyl, or a 5-10 membered heteroaryl, each of which is R C1 , R C2 , and R C3It is a compound that is substituted with [a specific compound].

[0158] In the specific embodiments described above, the useful compound is one in which the ring C is R C1 , R C2 , and R C3 It is a compound that is a 6- to 10-membered aryl substituted with [a specific compound].

[0159] In the specific embodiments described above, the useful compound is a compound having the structure of formula Ig, where Z is absent and R is present. 5 and R C1 R 5 N and R are bonded together. C1 Together with the bonded ring C, it forms a fused ring. [ka] During the ceremony, M stands for carbonyl, or CR. M1 R M2 And R M1 and R M2 Each of these is independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, and C1-C6 alkyl-NH2, where the optional substituent is a halogen or hydroxyl.

[0160] In the specific embodiments described above, the useful compounds are M is a carbonyl group, R 1 and R 2 However, each is hydrogen, and R 4 However, C1-C6 alkyl-NHR 4a It is a compound that is [this compound].

[0161] In the specific embodiments described above, the useful compounds are Ring B is R B1 It is a monosubstituted phenyl, or R B1 and R B2 It is a compound that is a disubstituted phenyl compound.

[0162] In the specific embodiments described above, the useful compound is R B1 and R B2 These are compounds in which each is fluoro.

[0163] In certain embodiments described above, the useful compounds are those in which ring C is a 4-10 membered monocyclic or bicyclic condensed heterocyclyl, or a 5-10 membered heteroaryl, each of which is R C1 , R C2 , and R C3 It is a compound that is substituted with [a specific compound].

[0164] In certain embodiments described above, the useful compounds are those in which g is 1. These compounds will have counterions such as halos.

[0165] In the specific embodiments described above, the useful compound is R C1 However, R 3 Together with the following, [ka] During the ceremony, [ka] R 6 This represents the connection point to A, p is an integer between 1 and 4. R 7a and R 7b In each case, hydroxyl, optionally substituted -C1-C6 alkyl, -N3, -NR are used. a R b Independently selected from the group consisting of R a and R b Each of these is independently H or a C1-C6 alkyl group. E does not exist, or it is -O- or -N(R b )- and R b is a C1-C6 alkyl group that is optionally substituted with H, J is -C(O)- or -C(R 7a R 7b )-and, as well as L is either absent or a compound that is -O- or -N(H)-.

[0166] In the specific embodiments described above, the useful compound is a compound having the structure of formula I-2. [ka]

[0167] In the specific embodiments described above, the useful compound is -LJE-(CR 7a R 7b ) p - is a compound that forms the following: [ka] [ka]

[0168] In the specific embodiments described above, the useful compound is one in which ring B is R B1 and R B2 It is a compound that is a disubstituted phenyl compound.

[0169] In the specific embodiments described above, the useful compound is R B1 is halogen, R B2 It is a compound in which the halogen or C1-C6 alkyl group is present.

[0170] In the specific embodiments described above, the useful compound is R B1 is fluoro, R B2 It is a compound in which the compound is fluoro or methyl.

[0171] In the specific embodiments described above, the useful compound is R in the phenyl ring. B1 and R B2 The compound is such that the position is as follows: [ka]

[0172] In the specific embodiments described above, the useful compound is R C1 The compound has the following structure at the ring C to which it is bonded. [ka]

[0173] In the specific embodiments described above, the useful compound is R C2 It is a compound in which the compound is cyano.

[0174] In the specific embodiments described above, a useful compound is one in which A has the following structure: [ka] During the ceremony, G is N, D is CH2, y is 0 or 1, each [ka] It is a single bond, G is C, D is CH2, and y is 1. [ka] It is a double bond, and the other [ka] Each is a single bond, G is N, D is CH2, and y is 0. [ka] Each of them is a double bond, and the other [ka] Each is a single bond, G is C, D is N or CH, y is 1, each [ka] It is a double bond.

[0175] In the specific embodiments described above, a useful compound is one in which A is selected from the group consisting of the following: [ka]

[0176] In the specific embodiments described above, a useful compound is one in which A has the following structure: [ka] In the formula, ring A2 is a compound that is a C4-C6 cycloalkyl group.

[0177] In the specific embodiments described above, a useful compound is one in which A is selected from the group consisting of the following: [ka]

[0178] In certain embodiments described above, the useful compounds are those listed in Table 1, or pharmaceutically acceptable salts thereof.

[0179] In certain embodiments, the subject matter described herein covers pharmaceutical compositions comprising any of the compounds of the above embodiments, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

[0180] In certain embodiments, the subject matter described herein relates to a method of treating a subject suffering from a somatostatin-related disease, comprising administering any of the compounds or pharmaceutical compositions of the above embodiments to the subject.

[0181] In certain embodiments, the subject matter described herein relates to methods for treating subjects suffering from a disease, the disease being selected from the group consisting of diabetes, diarrhea, inflammatory bowel disease, irritable bowel syndrome, cancer, acromegaly, depression, chronic atrophic gastritis, Crohn's disease, ulcerative colitis, retinopathy, arthritis, restenosis, neuroendocrine tumors (NETs), and pain.

[0182] In certain embodiments, the subject matter described herein relates to a method for activating somatostatin receptors in a subject, comprising administering the subject to any of the compounds or pharmaceutical compositions of the above embodiments.

[0183] In certain embodiments, the subject matter described herein covers the compounds shown in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] * This indicates that stereochemistry is assigned arbitrarily.

[0184] III. Pharmaceutical Compositions and Dosage Modes The compounds provided herein are typically administered in the form of pharmaceutical compositions. Accordingly, pharmaceutical compositions comprising one or more of the compounds described herein, or their pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients are also provided herein. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in ways well known in the pharmaceutical art. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & C.T. Rhodes, Eds.).

[0185] The pharmaceutical composition may be administered as a single dose or in multiple doses. The pharmaceutical composition may be administered by various methods, including, for example, rectally, orally, intranasally, and transdermally. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0186] One mode of administration is, for example, parenteral administration by injection. Forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions or emulsions having sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0187] Oral administration may be another route for administering the compounds described herein. Administration may be, for example, via capsules or enteric-coated tablets. When preparing a pharmaceutical composition comprising at least one of the compounds described herein, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, the active ingredient is usually diluted with an excipient and / or encapsulated in a carrier, which may be in the form of a capsule, pouch, paper, or other container. If the excipient functions as a diluent, it may be in the form of a solid, semi-solid, or liquid material acting as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, lozenges, pouches, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), for example, ointments, soft and hard gelatin capsules, sterile injection solutions, and sterile packaging powders containing up to 10% by weight of the active compound.

[0188] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulation may further contain lubricants, wetting agents, emulsifiers and suspending agents such as talc, magnesium stearate, and mineral oil, as well as preservatives such as methyl and propyl hydroxybenzoates, sweeteners, and flavoring agents.

[0189] Compositions comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, stereoisomer, or mixture of stereoisomers, can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a subject by employing procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems comprising polymer-coated storage units or drug polymer matrix formulations. Examples of controlled-release systems are provided in U.S. Patents 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the manner disclosed herein employs a transdermal delivery device ("patch"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for drug delivery are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445, and 5,001,139. ​​Such patches may be constructed for continuous, pulsatile, or on-demand drug delivery.

[0190] To prepare solid compositions such as tablets, the main active ingredient may be mixed with a pharmaceutically acceptable excipient to form a solid pre-formulation composition containing a homogeneous mixture of the compounds described herein, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof. When these pre-formulation compositions are referred to as homogeneous, the active ingredient may be evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0191] Tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form that offers the benefit of a longer action or to protect from the acidic conditions of the stomach. For example, a tablet or pill may contain an inner dose component and an outer dose component, the latter in the form of an envelope covering the former. The two components may be separated by an enteric coating that functions to resist breakdown in the stomach and allow the inner component to enter the duodenum intact or to delay its release. Various materials may be used for such enteric coatings or coatings, and such materials include numerous polymer acids and mixtures of polymer acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0192] Compositions for inhalation or inhalation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, compositions are administered by oral or nasal respiratory routes for topical or systemic effects. In other embodiments, compositions in pharmaceutically acceptable solvents may be sprayed using an inert gas. The sprayed solution may be inhaled directly from the spraying device, or the spraying device may be attached to a face mask tent or an intermittent positive pressure breathing apparatus. The solution, suspension, or powder composition may be administered preferably orally or nasally from a device for delivering formulations in an appropriate manner.

[0193] The specific dose level of the compounds of this application for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health status, sex, diet, administration time, route of administration, and excretion rate, drug combinations, and the severity of the specific disease in the subject receiving treatment. For example, the dose may be expressed as milligrams (mg / kg) of the compound described herein per kilogram of body weight of the subject. Doses of about 0.1 to 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments, doses of 0.5 to 60 mg / kg may be appropriate. Normalization by body weight of the subject is particularly useful when adjusting doses between subjects of significantly different sizes, such as when using the drug in both children and adults, or when converting an effective dose in a non-human subject, such as a dog, to a dose suitable for a human subject. Doses may be administered once daily (QID), twice daily (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including the absorption, distribution, metabolism, and excretion of the specific compound. Furthermore, toxic factors may affect the dosage and administration regimen. When administered orally, pills, capsules, or tablets may be taken daily or less frequently for a specific period. The regimen may be repeated over several treatment cycles.

[0194] IV. Treatment method The methods described herein may be applied to cell populations in vivo or ex vivo. “In vivo” means within a living organism, such as an animal or a human. In this context, the methods described herein may be used therapeutically in an organism. “Ex vivo” means outside a living organism. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including bodily fluid or tissue samples obtained from an organism. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo to determine the optimal schedule and / or dosage of the compounds disclosed for a given indication, cell type, organism, and other parameters. Information gathered from such use may be used for experimental or clinical purposes to establish protocols for in vivo treatment. Other ex vivo uses of the compounds and compositions described herein may be described below or will be apparent to those skilled in the art. Selected compounds may be further characterized by studies of their safety or tolerance in human or non-human subjects. Such properties may be investigated using methods generally known to those skilled in the art.

[0195] In certain embodiments, the administration and treatment methods described herein further include the co-administration of one or more additional pharmaceutically active compounds.

[0196] In combination therapy, pharmaceutically active compounds may be administered simultaneously, in the same formulation, or at different times. Such combination therapy includes the co-administration of a compound of formula I or a pharmaceutically acceptable salt thereof with at least one additional pharmaceutically active compound. Combination therapy in fixed-dose combination therapy includes the co-administration of a compound of formula I or a pharmaceutically acceptable salt thereof in a fixed-dose formulation with at least one additional pharmaceutically active compound. Combination therapy in free-dose combination therapy includes the co-administration of a compound of formula I or a pharmaceutically acceptable salt thereof with at least one additional pharmaceutically active compound, either by co-administration of the individual compounds or by sequential use of the individual compounds over a period of time, at free doses of each compound.

[0197] V. Method for preparing the compound of formula I and its pharmaceutically acceptable salt. The starting materials and reagents used in the preparation of the compounds described herein are available from suppliers such as Sigma-Aldrich Chemical Co. (Milwaukee, Wis.) and Bachem (Torrance, Calif.), or can be prepared by methods known to those skilled in the art, following the procedures described in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely examples of several methods by which the compounds of this disclosure can be synthesized, and various modifications to these schemes can be made, which will be suggested to those skilled in the art who read this disclosure. The starting materials and intermediates of the reaction, as well as the final product, may be isolated and purified as necessary using conventional techniques, including but not limited to filtration, distillation, crystallization, and chromatography. Such materials may be characterized using conventional means, including physical constants and spectral data.

[0198] Synthetic chemical transformations and protecting group methodologies (protection and deprotection) useful for the synthesis of compounds, necessary reagents, and intermediates are known in the art, for example, R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW Greene and PGMWuts, Protective Groups in Organic Synthesis, 3 rd This includes the information found in John Wiley and Sons (1999) and L. Paquette (ed.), *Encyclopedia of Reagents for Organic Synthesis*, John Wiley and Sons (1995) and subsequent editions.

[0199] The compounds can be prepared individually or as a compound library containing at least two compounds, for example, 5 to 1,000 compounds, or 10 to 100 compounds. A library of compounds of formula I can be prepared by procedures known to those skilled in the art, either by a “split and mix” approach of combinations or by multiple parallel synthesis using either solution-phase or solid-phase chemistry. Accordingly, according to further embodiments, a compound library containing at least two compounds, or pharmaceutically acceptable salts thereof, is provided.

[0200] Unless otherwise specified, the reactions described herein are carried out over a temperature range of about -78°C to about 150°C, for example, about 0°C to about 125°C, and further, for example, at room temperature (or ambient temperature), for example, about 20°C and atmospheric pressure. The routes shown and described herein are illustrative only and are not intended to limit the claims in any way, nor should they be construed as such. Those skilled in the art will recognize modifications of the disclosed synthesis and may devise alternative routes based on the disclosure herein, but all such modifications and alternative routes are within the scope of the claims.

[0201] The following examples are provided for illustrative purposes only and not for limiting purposes. [Examples]

[0202] I. Synthesis Examples Example A Synthesis of common intermediate compounds 1-3 (6-bromo-4-chloro-3-iodoquinoline) [ka] Step 1: Synthesis of 6-bromo-3-iodoquinoline-4-ol (compound 1-1-1-2) [ka] A mixture of compound 1-1-1-1 (8 g, 35.71 mmol) and 2-iodocyclopentan-1,3-dione (NIS, 8.00 g, 35.71 mmol) in acetic acid (100 mL) at 25°C was stirred at 60°C for 5 hours. The reaction was monitored by LC-MS, which indicated that the reaction was complete. The reaction mixture was filtered, the precipitated solid was washed with PE (50 mL x 3), and dried under vacuum to obtain the title compound 6-bromo-3-iodo-quinoline-4-ol (compound 1-1-1-2, 11.20 g, 32.00 mmol, yield 89.63%) as a white solid. MS (m / z) 349.9 (M+H) + .

[0203] Step 2: Synthesis of 6-bromo-4-chloro-3-iodoquinoline (compound 1-1-1) [ka] A solution of compound 1-1-1-2 (10 g, 28.58 mmol) in phosphorus oxychloride (20 mL) was stirred at 100°C for 2 hours. The reaction mixture was concentrated to dryness. Dichloromethane (100 mL) was added to the residue, and many solids were observed before filtration. The filtered cake was washed with 20 mL of dichloromethane and dried under vacuum to obtain compound 1-1-1 (6.00 g, 15.39 mmol, yield 53.87%, purity 94.52%) as a yellow solid. MS (m / z) 367.90 (M+H) + .

[0204] Example 1 [ka] Scheme 1 Step 1: ((1S,3S)-3-((6-bromo-3-iodoquinoline-4-yl)oxy)cyclopentyl)carbamate tert-butyl (compound 1-1-2) [ka] To a solution of 6-bromo-4-chloro-3-iodoquinoline (compound 1-1-1, 150 mg, 407.17 μmol) in N,N-dimethylformamide (5 mL), tert-butyl N-[(1S,3S)-3-hydroxycyclopentyl]carbamate (98.34 mg, 488.60 μmol) was added at 25°C, and the resulting mixture was stirred at 25°C for 1 minute. Potassium tert-butoxide (137.07 mg, 1.22 mmol) was added at 25°C, and the resulting mixture was stirred at 25°C for 30 minutes. The reaction mixture was diluted with water and ethyl acetate. The mixture was then separated, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). All organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was then purified by silica gel column chromatography (100-200 mesh) with PE:siRNA = 4:1 elution, yielding ((1S,3S)-3-((6-bromo-3-iodoquinoline-4-yl)oxy)cyclopentyl)carbamate tert-butyl (compound 1-1-2, 150.00 mg) as a white solid. Note that although the product is not perfectly pure after purification, it is used in the next step without further purification. MS (m / z) 349.9 (M+H) + .

[0205] Step 2: ((1S,3S)-3-((6-bromo-3-(3-fluoro-5-methylphenyl)quinoline-4-yl)oxy)cyclopentyl)carbamate tert-butyl (compound 1-1-3) [ka] To a solution of compound 1-1-2 (150 mg, 281.95 μmol) and (3-fluoro-5-methylphenyl)boronic acid (118.89 mg, 699.55 μmol) in a mixed solvent of 1,4-dioxane (10 mL) and H2O (1 mL), PdCl2 (dppf) (102.66 mg, 139.91 μmol) and K2CO3 (290.05 mg, 2.10 mmol) were added at 25°C, and the resulting mixture was stirred in N2 at 120°C for 3 hours. The progress of the reaction was monitored by LC-MS, indicating that the reaction was successful. The reaction mixture was diluted with water and ethyl acetate. This was then separated, and the aqueous phase was extracted with water (50 mL x 2). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a residue. This residue was purified by chromatography with PE:siRNA=3 / 2 to obtain the title compound 1-1-3 (70 mg) as a yellow oil. MS(m / z) 352.3(M+H) + .

[0206] Step 3: ((1S,3S)-3-((6-(3-carbamoyl-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)quinoline-4-yl)oxy)cyclopentyl)carbamate tert-butyl (compound 1-1-4) [ka] To a solution of compound 1-1-3 (70.00 mg, 135.81 μmol) and (3-carbamoyl-5-fluorophenyl)boronic acid (24.85 mg, 135.81 μmol) in dioxane (5 mL) and H2O (0.5 mL), PdCl2 (dppf) (19.93 mg, 27.16 μmol) and K2CO3 (56.31 mg, 407.44 μmol) were added. The resulting mixture was then degassed with N2 and stirred at 120°C for 2 hours under N2 conditions. The progress of the reaction was monitored by LC-MS, which indicated that the reaction was successful. The reaction mixture was diluted with water and ethyl acetate. This was then separated, and the aqueous phase was extracted with water (50 mL × 2). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a residue. This residue was purified by chromatography with 5 / 1 to 1 / 1 PE / siRNA to obtain compound 1-1-4 (40.00 mg) as a yellow oil. MS (m / z) 391.1 (M+H) + .

[0207] Step 4: 3-(4-(((1S,3S)-3-aminocyclopentyl)oxy)-3-(3-fluoro-5-methylphenyl)quinoline-6-yl)-5-fluorobenzamide (compound 1) [ka] To a solution of compound 1-1-4 (40 mg, 69.73 μmol) in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added at 25°C, and the resulting mixture was stirred at 25°C for 0.5 hours. The reaction solution was diluted with 20 mL of dichloromethane, and the organic phase was concentrated to remove the solvent. The above procedure was repeated three times to confirm the elimination of excess TFA. The crude product was purified by preparative HPLC (preparative C18, 5 μM OBD, 19 × 250 mm, column, Waters, gradient elution from 40% MeCN in water to 55% MeCN in water over 11 minutes, both solvents containing 10 mmol / L NH4HCO3) to obtain compound 1 (4.10 mg, yield 12.15%) as a white solid.

[0208] Compounds 1-11 were synthesized according to the four-step procedure described in Example 1. The analytical data for compounds 1-11 are provided below. [Table 2-1] [Table 2-2] [Table 2-3]

[0209] Example 2 [ka] Scheme 2 Step 1: Synthesis of 6-bromo-4-chloro-3-(3,5-difluorophenyl)quinoline (compound 2-1-2) [ka] To a solution of compound 1-1-1 (2 g, 5.43 mmol) and (3,5-difluorophenyl)boronic acid (1.97 g, 12.49 mmol) in 1,4-dioxane (15 mL), PdCl2 (dppf) (39.83 mg, 54.29 μmol) and K2CO3 (2.25 g, 16.29 mmol) were added at 25 °C. The resulting mixture was then degassed and stirred at 120 °C for 16 hours under N2 conditions. The reaction was monitored by LC-MS and TLC, which indicated that the reaction was complete. The reaction mixture was diluted with water (30 mL) and then extracted with EA (50 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (100-200 mesh) elution with petroleum ether:ethyl acetate (100:0-95:5) to obtain compound 2-1-2 (1.40 g, 2.70 mmol, yield 49.68%, purity 68.31%) as a white solid. MS (m / z) 356.10 (M+H) + .

[0210] Step 2: Synthesis of ((1R,3S)-3-((6-bromo-3-(3,5-difluorophenyl)quinoline-4-yl)oxy)cyclopentyl)carbamate tert-butyl (compound 2-1-3) [ka] To a solution of compound 2-1-2 (176.18 mg, 496.86 μmol) and tert-butyl N-[(1R,3S)-3-hydroxycyclopentyl]carbamate (100 mg, 496.86 μmol) in N,N-dimethylformamide (5 mL), potassium tert-butoxide (167.26 mg, 1.49 mmol) was added at 25°C, and the resulting mixture was stirred at 25°C for 3 hours. Water (50 mL) was added to the reaction mixture, and then it was extracted with EA (50 mL x 3). The combined organic layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel column (100-200 mesh) chromatography using petroleum ether:ethyl acetate (100:0-80:20) to obtain compound 2-1-3 (42.00 mg, 63.37 μmol, yield 12.75%, purity 78.37%) as a white oil. MS (m / z) 519.1 (M+H) + .

[0211] Synthesis of tert-butyl ((2-hydroxycyclohexyl)methyl)carbamate (compound 2-9-ammonia): [ka] To a solution of compound SM (130 mg, 1.06 mmol) in methanol (4 mL), Raney Ni (185.87 mg) and Boc2O (230.38 mg, 1.06 mmol) were added, and the resulting mixture was completely degassed with hydrogen. After degassing, the reaction mixture was stirred at 50°C for 2 hours under H2 conditions. The reaction solution was filtered to collect the reaction liquid, which was concentrated to obtain the crude substance (compound 2-9-ammonia, 150 mg, crude product), which was used in the next step without purification.

[0212] Step 3: Synthesis of ((1R,3S)-3-((3,6-bis(3,5-difluorophenyl)quinoline-4-yl)oxy)cyclopentyl)carbamate tert-butyl (compound 2-1-4) [ka] To a solution of compound 2-1-3 (42 mg, 80.87 μmol) and (3,5-difluorophenyl)boronic acid (12.77 mg, 80.87 μmol) in 1,4-dioxane (3 mL) and water (300 μL), cyclopenta-1,3-dien-1-yl(diphenyl)phosphan; iron; palladium(2+); dichloride (29.67 mg, 40.43 μmol) and potassium carbonate (33.53 mg, 242.60 μmol) were added at 25°C, and the resulting mixture was stirred in N2 at 120°C for 2 hours. The reaction mixture was diluted with water (30 mL) and extracted with HCl (30 mL x 3). The combined organic layer was dried over Na2SO4 and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (100-200 mesh) elution with petroleum ether:ethyl acetate (100:0-70:30) to obtain compound 2-1-4 (20 mg, 11.60 μmol, yield 14.34%) as a yellow solid. MS (m / z) 553.3 (M+H) + .

[0213] Step 4: Synthesis of (1R,3S)-3-((3,6-bis(3,5-difluorophenyl)quinoline-4-yl)oxy)cyclopentanamine (compound 12). [ka] To a solution of compound 2-1-4 (20 mg, 0.036 mmol) in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added at 25°C, and the resulting mixture was stirred at 25°C for 0.5 hours. LC-MS indicated that the reaction was complete. The mixture was distilled under reduced pressure to remove the solvent, and this was purified by preparative HPLC to obtain compound 12 (9.3 mg, yield 55%) as a white solid.

[0214] Compounds 12-22 were synthesized according to the four-step procedure described in Example 2. The analytical data for compounds 12-22 are provided below. [Table 3-1] [Table 3-2] [Table 3-3]

[0215] Example 3 [ka] Scheme 3 Step 1: Synthesis of tert-butyl (5-bromo-4-chloro-3-nitropyridine-2-yl)carbamate (compound 3-1-2) [ka] To a solution of compound 3-1-1 (3000 mg, 12.0 mmol) in THF (30.0 mL), 60% NaH (576 mg, 14.4 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. Boc2O (3140 mg, 2.4 mmol) was added to the reaction mixture. The reaction mixture was stirred for 1 hour and detected by LC-MS, with 80% of the product being detected by LC-MS. The reaction mixture was poured into water, extracted with EA (200 mL x 2), and the combined organic layers were dried, concentrated, and purified by flash (PE:EA = 3:1) to obtain compound 3-1-2 (3680 mg) as a yellow solid. MS (m / z) 295.9 (M + H - 55) + .

[0216] Step 2: Synthesis of (5-bromo-4-chloro-3-nitropyridine-2-yl)(methyl)carbamate tert-butyl (compound 3-1-3) [ka] To a solution of compound 3-1-2 (216 mg, 8.0 mmol) in DMF (20.0 mL), 60% NaH (480 mg, 12.0 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. MeI (1704 mg, 3.0 mmol) was added to the reaction mixture. The reaction mixture was stirred for 1 hour and detected by LC-MS, with 80% of the product being detected by LC-MS. The reaction mixture was poured into water, extracted with EA (100 mL x 2), and the combined organic layer was dried, concentrated, and purified by flash (PE:EA = 3:1) to obtain compound 3-1-3 (2400 mg) as a yellow solid. MS (m / z) 309.9 (M + H - 55) + . 1H NMR (400MHz, DMSO-d6): 9.05 (s, 1H), 3.21 (s, 3H), 1.35 (s, 9H).

[0217] Step 3: Synthesis of (4-chloro-5-(3-fluoro-5-methylphenyl)-3-nitropyridine-2-yl)(methyl)carbamate tert-butyl (compound 3-1-4) [ka] Compound 3-1-3 was added to a 100 mL flask and dissolved in 1,4-dioxane (20 mL). Then (3,5-difluorophenyl)boronic acid (488.47 mg, 3.09 mmol) and dipotassium carbonate (1.07 g, 7.73 mmol) were added to the solution, and the solid was completely dissolved by sonication. Then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (188.62 mg, 257.78 μmol) and H2O (2 mL) were added at 25 °C. The reaction solution was stirred in an oil bath with N2 balls at 110 °C for 5 hours. The resulting liquid solution was dried by centrifugation and then extracted three times with EA (60 mL) and H2O (20 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography (100-200) eluting with PE:Â=93:7, which produces two peaks, to obtain product compound 3-1-4 (425.00 mg, 1.01 mmol, yield 39.18%). MS(m / z)344.0(M+H) + .

[0218] Step 4: Synthesis of 4-chloro-5-(3-fluoro-5-methylphenyl)-N-methyl-3-nitropyridine-2-amine (compound 3-1-5) [ka] To a solution of compound 3-1-4 (2400 mg, 5.5 mmol) in dichloromethane (15 mL), 2,2,2-trifluoroacetic acid (4.25 g, 37.30 mmol, 2.86 mL) was added at 25°C, and the resulting mixture was stirred in N2 at 25°C for 2 hours. The reaction solution was diluted with 20 mL of dichloromethane, the organic phase was concentrated, and the above procedure was repeated three times. The crude product was used in the next step without further purification. Compound 3-1-5 (2.00 g, crude product) was obtained as a yellow oil. MS (m / z) 300.0 (M+H) + .

[0219] Step 5: Synthesis of ((3R,4R)-1-(5-(3,5-difluorophenyl)-2-(methylamino)-3-nitropyridine-4-yl)-3-methoxypiperidine-4-yl)carbamate tert-butyl (compound 3-1-6) [ka] To a solution of compound 3-1-5 (2000 mg, 4.7 mmol) and N-[(3R,4R)-3-methoxy-4-piperidyl]carbamate tert-butyl (1285.4 mg, 5.6 mmol) in 1,4-dioxane (16 mL), DIPEA (1800 mg, 14 mmol) was added at 25 °C, and the resulting mixture was stirred in N2 at 100 °C for 5 hours. Water (50 mL) was added to the reaction mixture. This was then extracted with ethyl acetate (50 mL x 2). All organic phases were combined and dried over anhydrous Na2SO4. The organic phases were concentrated to obtain the crude product. The crude product was purified by silica gel chromatography with PE:siRNA = 5:1 elution to obtain compound 3-1-6 (1500.00 mg, 2.5 mmol, yield 74.10%, purity 82.76%) as a yellow solid. MS (m / z) 494.3 (M+H) + .

[0220] Step 6: Synthesis of ((3R,4R)-1-(3-amino-5-(3,5-difluorophenyl)-2-(methylamino)pyridine-4-yl)-3-methoxypiperidine-4-yl)carbamate tert-butyl (compound 3-1-7) [ka] To a solution of compound 3-1-6(N-[(3R,4R)-1-[5-(3-fluoro-5-methoxyphenyl)-2-(methylamino)-3-nitro-4-pyridyl]-3-methoxy-4-piperidyl]tert-butyl carbamate) (740 mg, 1.32 mmol) in methanol (15 mL), Pd / C (320.00 mg, 131.74 μmol, 312.19 μL, purity 5%) was added under N2. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred under an H2 balloon at 25°C for 1 hour. The suspension was filtered through Celite, and the filter cake was washed with MeOH (10 mL x 2). The combined filtrate was concentrated to dryness to obtain the product compound 3-1-7(N-[(3R,4R)-1-[3-amino-5-(3-fluoro-5-methoxyphenyl)-2-(methylamino)-4-pyridyl]-3-methoxy-4-piperidyl]carbamate tert-butyl) (510.00 mg, 1.07 mmol, yield 81.40%) as a purple solid. MS(m / z)464.3(M+H) + .

[0221] Step 7: Synthesis of 3-(7-((3R,4R)-4-amino-3-methoxypiperidine-1-yl)-6-(3,5-difluorophenyl)-3-methyl-3H-imidazo[4,5-b]pyridine-2-yl)-2-hydroxybenzonitrile (Compound 23) To a solution of compound 3-1-7(N-[(3R,4R)-1-[3-amino-5-(3-fluoro-5-methoxyphenyl)-2-(methylamino)-4-pyridyl]-3-methoxy-4-piperidyl]tert-butyl carbamate) (100 mg, 199.77 μmol) and 3-formyl-2-hydroxybenzonitrile (35.27 mg, 239.72 μmol) in tetrahydrofuran (4 mL), ferric trichloride (97.21 mg, 599.30 μmol) and acetic acid (3.60 mg, 59.93 μmol) were added at 25 °C, and the resulting mixture was stirred at 60 °C for 2 hours. Completion of the reaction was detected by TLC and LC-MS. TLC and LC-MS indicated that the reaction was complete. The mixture was then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain product compound 23 (38.10 mg).

[0222] Compounds 23-34 were synthesized according to the seven-step procedure described in Example 3. The analytical data for compounds 23-34 are provided below. [Table 4-1] [Table 4-2] [Table 4-3]

[0223] Example 4 [ka] Step 1: Synthesis of tert-butyl (5-bromo-4-chloro-3-nitropyridine-2-yl)carbamate (compound 4-1-2) To a solution of compound 4-1-1 (3 g, 11.88 mmol) in THF (40 mL), 60% NaH (950 mg, 14.26 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. (Boc)2O (3.11 g, 14.26 mmol) was added to the reaction mixture. The reaction mixture was stirred for 1 hour and detected by LC-MS. The reaction mixture was poured into water, extracted with EA (200 mL x 3), and the combined organic layers were dried, concentrated, and purified by flash (PE:EA = 3:1) to obtain compound 4-1-2 (3.2 g) as a yellow solid. MS (m / z) 295.9 (M + H - 55) + . Step 2: Synthesis of (5-bromo-4-chloro-3-nitropyridine-2-yl)(methyl)carbamate tert-butyl (compound 4-1-3)

[0224] To a solution of compound 4-1-2 (3.2 g, 9.07 mmol) in DMF (30.0 mL), 60% NaH (544 mg, 3.0 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. MeI (1.9 g, 3.0 mmol) was added to the reaction mixture. The reaction mixture was stirred for 1 hour and detected by LC-MS. The reaction mixture was poured into water, extracted with EA (100 mL x 3), and the combined organic layers were dried, concentrated, and purified by flash (PE:EA = 3:1) to obtain compound 4-1-3 (1.5 g) as a yellow solid. MS (m / z) 309.9 (M + H - 55) + .

[0225] Step 3: Synthesis of 5-bromo-4-chloro-N-methyl-3-nitropyridine-2-amine (compound 4-1-4) To a solution of compound 4-1-3 (1.5 g, 4.09 mmol) in DCM (15 mL), TFA (5 mL) was added at 25°C. The reaction mixture was then stirred at 25°C for 1 hour and detected by LC-MS. The reaction mixture was concentrated to obtain the crude product compound 4-1-4 for the next step. MS (m / z) 266.0 (M+H) + .

[0226] Step 4: Synthesis of tert-butyl (1-(5-bromo-2-(methylamino)-3-nitropyridine-4-yl)piperidine-4-yl)carbamate (compound 4-1-5) To a solution of compound 4-1-4 (1 g, 3.75 mmol), tert-butyl piperidine-4-ylcarbamate (0.9 g, 4.5 mmol) and DIPEA (1.45 g, 11.25 mmol) in 1,4-dioxane (10.0 mL) were added at 25°C. The reaction mixture was 80 o The mixture was heated to C and stirred for 2 hours. The reactants were detected by LC-MS, indicating a successful reaction. LC-MS indicates that the reaction is complete. The solution was then 0 o The mixture was cooled to 1°C, and many solids were observed. After filtration, compound 4-1-5 (1.5 g, 93% yield) was obtained as a yellow solid. MS (m / z) 430.0 (M+H) + .

[0227] Step 5: Synthesis of (1-(5-(3-fluoro-5-methylphenyl)-2-(methylamino)-3-nitropyridine-4-yl)piperidine-4-yl)carbamate tert-butyl (compound 4-1-6) To a solution of compound 4-1-5 (700 mg, 1.63 mmol, 1 equivalent), (3-fluoro-5-methylphenyl)boronic acid (377 mg, 2.45 mmol, 1.5 equivalents), and K2CO3 (676 mg, 4.89 mmol, 3 equivalents) in a mixture of dioxane (15 mL) and H2O (1 mL), PdCl2 (dppf) (117 mg, 0.16 mmol) was added under N2. The suspension was degassed under vacuum and purged several times with N2. The reaction mixture was then 110 o The mixture was stirred in 1C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (40 mL x 3). The combined organic extract was washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. This was purified by chromatography through a pre-packed silica gel column (12 g) with Redi-Sep elution under a gradient of 0% to 10% MeOH in DCM to obtain compound 4-1-6 (545 mg, yield 72.9%) as a white solid. MS (m / z) 460.2 (M+H) + .

[0228] Step 6: Synthesis of (1-(3-amino-5-(3-fluoro-5-methylphenyl)-2-(methylamino)pyridine-4-yl)piperidine-4-yl)carbamate tert-butyl (compound 4-1-7) To a solution of compound 4-1-6 (545 mg, 1.19 mmol, 1 equivalent) in THF (20 mL), Pd / C (126.3 mg, 1.19 mmol) was added. The suspension was degassed under vacuum and purged several times with H2. The reaction mixture was then stirred at rt for 2 hours. TLC and LCMS indicated that the reaction was complete. The reaction mixture was filtered and concentrated to obtain compound 4-1-7 (420 mg, yield 82.4%) as oil. MS (m / z) 430.2 (M+H) + .

[0229] Step 7: Synthesis of 3-(7-(4-aminopiperidine-1-yl)-6-(3-fluoro-5-methylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine-2-yl)-5-fluorobenzamide (compound 35) AcOH (0.05 mL) was added to a solution of compound 4-1-7 (100 mg, 0.233 mmol, 1 equivalent) and 3-fluoro-5-formylbenzamide (47 mg, 0.280 mmol, 1.2 equivalents) in THF (10 mL). Reaction mixture 60 o The mixture was stirred in C for 2 hours. After 1 hour, FeCl3 (37.3 mg, 0.233 mmol, 1 equivalent) was added. Reaction mixture 60 o The mixture was stirred in 1C for 2 hours. TLC and LCMS indicated that the reaction was complete. The reaction mixture was diluted with water (30 mL) and extracted with EA (50 mL x 4). The combined organic extracts were concentrated to obtain the crude product, which was purified by silica gel chromatography eluted with DCM:MeOH (100:1~1:1) to obtain the crude product. The crude product was then purified by preparative HPLC to obtain compound 35 (19.8 mg) as a white solid.

[0230] Synthesis of Compound 42 and Compound 43 [ka] Compound 40 (61 mg, 0.10 mmol, 1.0 equivalent), Zn(CN)2 (26 mg, 0.22 mmol, 2.2 equivalents), and Pd(PPh3)4 (14 mg, 0.02 mmol, 20 mol%) were suspended in DMF (2.0 mL) under the protection of N2, and the reaction mixture was stirred at 120°C for 5 hours. The reaction mixture was purified by HPLC to obtain compound 42 (27 mg) as a white solid.

[0231] To a solution of compound 42 (22 mg, 0.06 mmol) in DCM (2.0 mL), TFA (0.5 mL) was added at 25°C, and then the reaction mixture 25 oThe mixture was stirred in 1C for 2 hours, and 100% of the product was detected by LCM using LCMS. The reaction mixture was concentrated and freeze-dried to obtain compound 43 (16.5 mg) as a white solid of two TFA salts.

[0232] Synthesis of 3-fluoro-5-formylbenzamide (compound 4-1-aldehyde) [ka] To a solution of 3-fluoro-5-formylbenzoic acid (compound 4-1-SM, 100 mg, 0.60 mmol, 1.0 equivalent) and NH4Cl (65 mg, 1.19 mmol, 1.2 equivalents) in DMF (2 mL), DIPEA (230 mg, 1.79 mmol, 3.0 equivalents) and HATU (270 mg, 0.71 mmol, 1.2 equivalents) were added. The mixture was divided into 25 o The mixture was stirred in 1C for 2 hours. The mixture was extracted with water and ethyl acetate, the aqueous phase was extracted with ethyl acetate, the combined organic layer was washed with brine, dried over Na2SO4, and the organic layer was concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography with DCM:MeOH 0%-11% to obtain the product 3-fluoro-5-formylbenzamide (compound 4-1-aldehyde, 35 mg) as a white solid. MS (m / z) 168.1 (M+H) + .

[0233] Compounds 35-43 were synthesized according to the seven-step procedure described in Example 4. The analytical data for compounds 35-43 are provided below. [Table 5-1] [Table 5-2] [Table 5-3]

[0234] Example 5 [ka] Scheme 5 Step 1: Synthesis of Compound 5-1-2 To a solution of compound 5-1-1 (750 mg, 3.0 mmol) in THF (15.0 mL), 60% NaH (144 mg, 3.6 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. Cbz-Cl (614 mg, 0.6 mmol) was added to the reaction mixture. The reaction mixture was stirred for 1 hour and detected by LC-MS, with 80% of the product being detected by LC-MS. The reaction mixture was poured into water, extracted with EA (50 mL x 2), and the combined organic layers were dried, concentrated, and purified by flash (PE:EA = 3:1) to obtain compound 5-1-2 (510 mg) as a yellow solid. MS (m / z) 386.1 (M + H) + .

[0235] Step 2: Synthesis of Compound 5-1-3 Compounds 5-1-2 (425 mg, 1.1 mmol), SM-2 (250 mg, 1.2 mmol), and DIPEA (429 mg, 3.3 mmol) were dissolved in 1,4-dioxane (10.0 mL) at rt. The reaction mixture was then prepared at 80°C. o The mixture was heated to 13C and stirred for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated and purified by flash (PE:EA=1:1) to obtain compound 5-1-3 (280 mg) as a yellow solid. MS (m / z) 550.2 (M+H) + .

[0236] Step 3: Synthesis of Compound 5-1-4 Compound 5-1-3 (200 mg, 0.36 mmol, 1.0 equivalent), SM-3 (68 mg, 0.44 mmol, 1.2 equivalents), Na2CO3 (134 mg, 1.08 mmol, 3.0 equivalents), and PdCl2 [dppf] (52 mg, 0.07 mmol, 20 mol%) were suspended in 1,4-dioxane (6.0 mL) and water (2.0 mL) under the protection of N2, and reaction mixture 110 was prepared. oThe mixture was stirred in 1C for 5 hours. The reaction products were detected by LC-MS, and 70% of the product was detected. The reaction mixture was purified by flash (PE:EA = 3:1 to 1:1) to obtain compound 5-1-4 (140 mg) as a yellow solid. MS (m / z) 584.2 (M+H) + .

[0237] Step 4: Synthesis of Compound 5-1-5 Mixture of compound 5-1-4 (58 mg, 0.10 mmol) and Zn (50 mg) in EtOH (3.0 mL) and NH4Cl aqueous solution (1.0 mL) at 25°C. Reaction mixture 50 o The mixture was stirred in 1C for 3 hours. The mixture was detected by LC-MS, indicating 95% completion of the reaction. The reactants were poured into water and extracted with EA (20 mL x 2). The combined organic phase was dried and concentrated to obtain compound 5-1-5 (74 mg) as a gray solid. MS (m / z) 554.2 (M+H) + .

[0238] Step 5: Synthesis of Compound 5-1-6 To a solution of compound 5-1-5 (74 mg, 0.13 mmol) in DMF (3.0 mL), NaH 60% (5.2 mg, 0.13 mmol) was added at 0°C, and then the reaction mixture was 0°C. o The mixture was stirred in 1°C for 1 hour. MeI (19 mg, 0.13 mmol) was added to the reaction mixture. The reaction mixture was stirred for 1 hour and detected by LC-MS, with 80% of the product being detected by LC-MS. The reaction mixture was poured into water and extracted with EA (50 mL x 2). The combined organic layers were dried, concentrated, and purified by flash (PE:EA = 3:1) to obtain compound 5-1-6 (52 mg) as a yellow solid. MS (m / z) 568.2 (M + H) + .

[0239] Step 6: Synthesis of Compound 5-1-7 To a mixture of compound 5-1-6 (52 mg) in MeOH (5 mL) at 25°C, Pd / C (100 mg) was added to the reaction mixture. The reaction mixture was then subjected to H2 protection at 25°C. oThe mixture was stirred in 1C for 3 hours. The mixture was detected by LC-MS, indicating 95% completion of the reaction. The reaction product was filtered, concentrated, and purified by flash to obtain compound 5-1-7 (42 mg) as a gray solid. MS (m / z) 434.2 (M+H) + .

[0240] Step 7: Synthesis of Compound 44 Compound 5-1-7 (42 mg, 0.10 mmol), SM-4 (24 mg, 0.12 mmol), and AcOH (15 mg, catalyst) were dissolved in THF (5.0 mL) at 25°C. The reaction mixture was then mixed with 60 ml of water. o The mixture was heated to 14°C and stirred for 16 hours. The reaction products were detected by LC-MS, indicating a successful reaction. The reaction mixture was concentrated and purified by HPLC (0.5% FA) to obtain compound 44 (21 mg) as a white solid. A total of 7.3 mg was obtained.

[0241] Step 8: Synthesis of Compound 45 Compound 44 (20 mg), 25 o It was dissolved in DCM (2.0 mL) with C. TFA (0.5 mL) was added to the reaction mixture, and then the reaction mixture was 25 o The mixture was stirred in 1C for 2 hours. The reaction mixture was concentrated and freeze-dried to obtain compound 45 (18.3 mg) as a white solid of one TFA salt.

[0242] Compounds 44 and 45 were synthesized according to the 7 or 8-step procedure described in Example 5. Analytical data for compounds 44 and 45 are provided below. [Table 6]

[0243] Example 6 [ka] Scheme 6 Step 1: Synthesis of tert-butyl (5-bromo-4-chloro-3-nitropyridine-2-yl)carbamate (compound 6-1-2) Compound 6-1-1 (3 g, 11.88 mmol) was dissolved in THF (40 mL) at 25°C. The reaction mixture was cooled to 0°C. 60% NaH (950 mg, 14.26 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 0°C for 1 hour. (Boc)2O (3.11 g, 14.26 mmol) was added to the reaction mixture. The reaction mixture was stirred for 1 hour. The reaction mixture was poured into water and extracted with EA (200 mL x 3). The combined organic phase was dried, concentrated, and purified by flash (PE:EA = 3:1) to obtain compound 6-1-2 (3.2 g) as a yellow solid. MS (m / z) 295.9 (M + H - 55) + .

[0244] Step 2: Synthesis of tert-butyl (4-chloro-5-(3,5-difluorophenyl)-3-nitropyridine-2-yl)carbamate (compound 6-1-3) Compound 6-1-2 (1500 mg, 4.27 mmol, 1 equivalent), (3,5-difluorophenyl)boronic acid (740 mg, 4.70 mmol, 1.1 equivalents), and K2CO3 (1770 mg, 12.82 mmol, 3 equivalents) were dissolved in a mixture of 1,4-dioxane (20 mL) and water (2 mL). PdCl2 (dppf) (310 mg, 0.43 mmol, 0.1 equivalents) was added to this solution. The suspension was degassed under vacuum and purged several times with nitrogen. The mixture was stirred at 80°C for 2 hours under nitrogen. The reaction was monitored by LC-MS and TLC, which indicated that the reaction was complete. The reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL x 3), and the combined organic layer was dried over Na2SO4. The organic phase was dried on silica gel using a rotary evaporator and purified by flash chromatography with 0-10% petroleum ether:ethyl acetate to obtain a liquid product, which was then dried using a rotary evaporator to obtain crude (4-chloro-5-(3,5-difluorophenyl)-3-nitropyridine-2-yl)carbamate tert-butyl (compound 6-1-3, 1216 mg). MS (m / z) 408.1 (M+Na) + , 330.0 (M+H-55) + .

[0245] Step 3: Synthesis of 4-chloro-5-(3,5-difluorophenyl)-3-nitropyridine-2-amine (compound 6-1-4) To a solution of compound 6-1-3 (600 mg, 1.56 mmol, 1 equivalent) in dichloromethane (2.00 mL), trifluoroacetic acid (4 mL) was added. The mixture was stirred at 25°C for 2 hours. The reaction was monitored by LC-MS and TLC, which indicated that the reaction was complete. The reaction liquid was dried using a rotary evaporator to obtain the product as a yellow oil in the form of trifluoroacetate, which was then dried with dichloromethane using a rotary evaporator to obtain crude 4-chloro-5-(3,5-difluorophenyl)-3-nitropyridine-2-amine (compound 6-1-4). MS (m / z) 286.0 (M+H) + .

[0246] Step 4: Synthesis of ((3R,4R)-1-(2-amino-5-(3,5-difluorophenyl)-3-nitropyridine-4-yl)-3-methoxypiperidine-4-yl)carbamate tert-butyl (compound 6-1-5) To a solution of compound 6-1-4 (350 mg, 1.23 mmol, 1 equivalent) in 1,4-dioxane (3.00 mL), tert-butyl ((3R,4R)-3-methoxypiperidine-4-yl)carbamate (283 mg, 1.23 mmol, 1 equivalent) and DIPEA (476 mg, 3.68 mmol, 3 equivalents) were added. The mixture was stirred at 80°C for 16 hours. The reaction was monitored by LC-MS and TLC, which indicated that the reaction was complete. The reaction mixture was extracted with water (10 mL) and ethyl acetate (10 mL x 3), and the organic layer was dried over Na2SO4. The organic phase was dried on silica gel using a rotary evaporator and purified by flash chromatography with 0-20% petroleum ether:ethyl acetate to obtain a liquid product, which was then dried using a rotary evaporator to obtain crude ((3R,4R)-1-(2-amino-5-(3,5-difluorophenyl)-3-nitropyridine-4-yl)-3-methoxypiperidine-4-yl)carbamate tert-butyl (compound 6-1-5, 336 mg). MS (m / z) 480.2 (M+H) + , 502.2(M+Na) + .

[0247] Step 5: Synthesis of ((3R,4R)-1-(2,3-diamino-5-(3,5-difluorophenyl)pyridine-4-yl)-3-methoxypiperidine-4-yl)carbamate tert-butyl (compound 6-1-6) To a solution of compound 6-1-5 (336 mg, 0.70 mmol, 1 equivalent) in methanol (5.00 mL), Pd / C (15 mg, 0.14 mmol, 0.2 equivalents) was added. The mixture was stirred under hydrogen at 25°C for 2 hours. The reaction was monitored by LC-MS and TLC, which indicated that the reaction was complete. The reaction liquid was filtered to obtain a filtrate, which was dried using a rotary evaporator to obtain crude ((3R,4R)-1-(2,3-diamino-5-(3,5-difluorophenyl)pyridine-4-yl)-3-methoxypiperidine-4-yl)carbamate tert-butyl (compound 6-1-6, 122 mg). MS (m / z) 450.2 (M+H) + .

[0248] Step 6: Synthesis of 5-(7-((3R,4R)-4-amino-3-methoxypiperidine-1-yl)-6-(3,5-difluorophenyl)-3H-imidazo[4,5-b]pyridine-2-yl)-1,3-dihydro-2H-benzo[d]imidazole-2-one (compound 46) To a solution of compound 6-1-6 (60 mg, 0.13 mmol, 1 equivalent) and 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (26 mg, 0.16 mmol, 1.2 equivalents) in THF (2.00 mL), AcOH (0.80 mL) was added and the mixture was stirred at 60°C for 2 hours. Then, FeCl3 (32 mg, 0.20 mmol, 1.5 equivalents) was added to the mixture and the mixture was stirred at 60°C for 2 hours. The reaction was monitored by LC-MS and TLC, which indicated that the reaction was complete. The reaction mixture was dried on silica gel using a rotary evaporator and purified by flash chromatography with DCM:methanol at 0-20% to obtain a liquid product, which was then dried using a rotary evaporator to obtain the crude product. The crude product was purified by preparative HPLC to obtain 5-(7-((3R,4R)-4-amino-3-methoxypiperidine-1-yl)-6-(3,5-difluorophenyl)-3H-imidazo[4,5-b]pyridine-2-yl)-1,3-dihydro-2H-benzo[d]imidazole-2-one (compound 46, 22.9 mg, yield 35%) as a white solid.

[0249] Compounds 46-66 were synthesized according to the six-step procedure described in Example 6. The analytical data for compounds 46-66 are provided below. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5]

[0250] Example 7 [ka] Scheme 7 Step 1: Synthesis of 6-bromo-3-iodoquinoline-4-ol (compound 7-1-2) To a solution of compound 7-1-1 (3000 mg, 13.389 mmol, 1 equivalent) in AcOH (50 mL), NIS (3012 mg, 13.389 mmol, 1 equivalent) was added. The mixture was stirred at 60°C for 3 hours. The reaction was monitored by LC-MS, which indicated that the reaction was successful. The solution was cooled to zero degrees, and a large amount of solid was observed. After filtration, 6-bromo-3-iodoquinoline-4-ol (compound 7-1-2, 4.4 g, yield 94%) was obtained as a white solid. MS (m / z) 349.9 (M+H) + .

[0251] Step 2: Synthesis of 6-bromo-4-chloro-3-iodoquinoline (compound 7-1-3) A solution of compound 7-1-2 (2500 mg, 7.144 mmol, 1 equivalent) in POCl3 (15 mL), and a reaction product of 100 o The mixture was stirred at 13°C for 3 hours. Completion of the reaction was detected by TLC and LC-MS. LC-MS indicated completion of the reaction. NaHCO3 (aqueous solution) was added to the solution to adjust the pH to 7, and the reaction mixture was then diluted with water (50 mL) and extracted with EA (80 mL x 4). The combined organic extracts were concentrated to obtain the crude product, which was then purified by silica gel chromatography eluted with PE:siRNA (100:1~5:1) to obtain product compound 7-1-3 (1.5 g) as a pale yellow solid. MS (m / z) 367.8 (M+H) + .

[0252] Step 3: Synthesis of (1-(6-bromo-3-iodoquinoline-4-yl)piperidine-4-yl)carbamate tert-butyl (compound 7-1-4) To a solution of compound 7-1-3 (1000 mg, 2.714 mmol, 1 equivalent) and tert-butyl piperidine-4-ylcarbamate (1082 mg, 5.429 mmol, 2 equivalents) in DMAc (15 mL), K2CO3 (1125 mg, 8.143 mmol, 3.0 equivalents) was added, and the reaction mixture was prepared at 120°C. o The mixture was stirred in 1C for 4 hours. Completion of the reaction was detected by TLC and LC-MS. LC-MS indicated completion of the reaction. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL x 4). The combined organic extracts were concentrated to obtain the crude product, which was then purified by flash (PE:EA = 3:1) to obtain compound 7-1-4 (570 mg, yield 40%) as a white solid. MS (m / z) 531.9 (M+H) + .

[0253] Step 4: Synthesis of (1-(6-bromo-3-(3,5-difluorophenyl)quinoline-4-yl)piperidine-4-yl)carbamate tert-butyl (compound 7-1-5) Compound 7-1-4 (570 mg, 1.07 mmol, 1 equivalent), (3,5-difluorophenyl)boronic acid (169 mg, 1.07 mmol, 1 equivalent), and K2CO3 (443 mg, 3.213 mmol, 3 equivalents) were dissolved in a mixture of dioxane (10 mL) and H2O (1 mL). PdCl2 (dppf) (78 mg, 0.107 mmol, 0.1 equivalent) was added under N2. The suspension was degassed under vacuum and purged several times with N2. The reaction mixture was then 90°C. o The mixture was stirred in 1C for 4 hours. Completion of the reaction was detected by TLC and LC-MS. LC-MS indicated completion of the reaction. The reaction mixture was diluted with water (30 mL) and extracted with EA (50 mL x 4). The combined organic extracts were concentrated to obtain the crude product, which was then purified by flash (PE:EA = 1:1) to obtain compound 7-1-5 (500 mg, yield 90%) as a yellow solid. MS (m / z) 518.1 (M+H) + .

[0254] Step 5: Synthesis of (1-(6-(3-cyano-2-(methoxymethoxy)phenyl)-3-(3,5-difluorophenyl)quinoline-4-yl)piperidine-4-yl)carbamate tert-butyl (compound 7-1-6) Compound 7-1-5 (500 mg, 0.965 mmol, 1 equivalent), 2-(methoxymethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (307 mg, 1.061 mmol, 1.1 equivalents), and K2CO3 (399 mg, 2.894 mmol, 3 equivalents) were added under N2 conditions to a solution of these compounds in a mixture of dioxane (10 mL) and H2O (1 mL). PdCl2 (dppf) (71 mg, 0.096 mmol, 0.1 equivalents) was added under N2 conditions. The suspension was degassed under vacuum and purged several times with N2. The reaction mixture was then 100°C. o The mixture was stirred in 1C for 4 hours. Completion of the reaction was detected by TLC and LC-MS. LC-MS indicated completion of the reaction. The reaction mixture was diluted with water (30 mL) and extracted with EA (50 mL x 4). The combined organic extracts were concentrated to obtain the crude product, which was then purified by flash (PE:EA = 1:1) to obtain compound 7-1-6 (370 mg, yield 63.9%) as a yellow oil. MS (m / z) 601.3 (M+H) + .

[0255] Step 6: Synthesis of 3-(4-(4-aminopiperidine-1-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)-2-hydroxybenzonitrile (compound 7-1-7) To a solution of compound 7-1-6 (370 mg, 0.616 mmol, 1 equivalent) in DCM (5 mL), TFA (1 mL) was added. Then, the reaction mixture was 25 o The mixture was stirred in 1°C for 1 hour. Completion of the reaction was detected by TLC and LC-MS. TLC and LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to obtain the crude compound 7-1-7 as the TFA salt (300 mg). MS (m / z) 457.2 (M+H) + .

[0256] Step 7: Synthesis of (1-(6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinoline-4-yl)piperidine-4-yl)carbamate tert-butyl (compound 7-1-8) (Boc)2O (48 mg, 0.219 mmol, 1 equivalent) was added to a solution of compound 7-1-7 (100 mg, 0.219 mmol, 1 equivalent) and DIPEA (85 mg, 0.657 mmol, 3 equivalents) in DCM (6 mL). Then, reaction mixture 25 o The mixture was stirred in 1°C for 1 hour. Completion of the reaction was detected by TLC and LC-MS. TLC and LC-MS indicated that the reaction was complete. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL x 3). The combined organic extract was concentrated to obtain the crude product, which was purified by silica gel chromatography eluted with PE:Â (100:1~1:1) to obtain product compound 7-1-8 (70 mg, yield 57.4%) as a yellow oil. MS (m / z) 557.3 (M+H) + .

[0257] LCMS: m / z: 557.3 (M+H) at 1.68 min + ).

[0258] Step 8: Synthesis of (1-(6-(2-(3-bromopropoxy)-3-cyanophenyl)-3-(3,5-difluorophenyl)quinoline-4-yl)piperidine-4-yl)carbamate tert-butyl (compound 7-1-9) To a solution of compound 7-1-8 (70 mg, 0.126 mmol, 1 equivalent) and 1,3-dibromopropane (38 mg, 0.189 mmol, 1.5 equivalents) in MeCN (5 mL), K2CO3 (52 mg, 0.377 mmol, 3 equivalents) was added. The reaction mixture was then 90 oThe mixture was stirred in 1°C for 1 hour. Completion of the reaction was detected by TLC and LC-MS. TLC and LC-MS indicated that the reaction was complete. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL x 3). The combined organic extract was concentrated to obtain the crude product, which was purified by silica gel chromatography eluted with PE:Â (100:1~1:1) to obtain product compound 7-1-9 (40 mg, yield 47%) as a yellow oil. MS (m / z) 677.3 (M+H) + .

[0259] Step 9: Synthesis of 3-(4-(4-aminopiperidine-1-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)-2-(3-bromopropoxy)benzonitrile (compound 7-1-10) To a solution of compound 7-1-9 (40 mg, 0.059 mmol, 1 equivalent) in DCM (3 mL), TFA (1 mL) was added under N2 conditions. Then, the reaction mixture was 25 o The mixture was stirred in 1°C for 1 hour. Completion of the reaction was detected by TLC and LC-MS. TLC and LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to obtain compound 7-1-10 (50 mg crude product) as a yellow oil. MS (m / z) 577.1 (M+H) + .

[0260] The intermediate steps for compounds 68 and 69 were similar to those for compound 67, but the acid used was HCl / EA.

[0261] Step 10: Synthesis of 3-(4-(4-aminopiperidine-1-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)-2-(3-bromopropoxy)benzonitrile (compound 67) NaH (6 mg, 0.156 mmol, 3 equivalents) was added to a solution of compound 7-1-10 (30 mg, 0.052 mmol, 1 equivalent) in DMAc (2 mL). Reaction mixture 100 oThe mixture was stirred in 1°C for 1 hour. Completion of the reaction was detected by LC-MS. LC-MS indicated that the reaction was complete. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL x 3). The combined organic extract was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by preparative HPLC to obtain compound 67 (5.7 mg) as a yellow solid.

[0262] The synthesis of the other compounds was similar to that of compound 67, but the base was K2CO3, the additive was KI, and the solvent was DMF.

[0263] Compounds 67-77 were synthesized according to the 10-step procedure described in Example 7. The analytical data for compounds 67-77 are provided below. [Table 8-1] [Table 8-2] [Table 8-3]

[0264] Example 8 [ka] Scheme 8 Step 1: Synthesis of 1-(6-bromo-3-(3,5-difluorophenyl)quinoline-4-yl)piperidine-4-amine (compound 8-1-2) [ka] (1-(6-bromo-3-(3,5-difluorophenyl)quinoline-4-yl)piperidine-4-yl) tert-butyl carbamate (compound 8-1-1) (500 mg, 0.97 mmol, 1.0 equivalent) was dissolved in HCl / 1,4-dioxane (4 M, 10 mL). The reaction mixture was stirred at room temperature for 2 hours. The desired product was detected by LC-MS. The reaction mixture was concentrated under vacuum to obtain the crude product 1-(6-bromo-3-(3,5-difluorophenyl)quinoline-4-yl)piperidine-4-amine (compound 8-1-2, 404 mg, 0.97 mmol, 100%) for the next step. MS (m / z) 418.1 (M+H) + .

[0265] Step 2: Synthesis of (2-((1-(6-bromo-3-(3,5-difluorophenyl)quinoline-4-yl)piperidine-4-yl)amino)ethyl)carbamate tert-butyl (compound 8-1-3) [ka] 1-(6-bromo-3-(3,5-difluorophenyl)quinoline-4-yl)piperidine-4-amine (4.7 g, 9.7 mmol, 1.0 equivalent), methyl 6-bromopicolinate (compound 8-1-2, 404 mg, 0.97 mmol, 1.0 equivalent), K2CO3 (400 mg, 2.9 mmol, 3.0 equivalents), and KI (249 mg, 1.5 mmol, 1.5 equivalents) were dissolved in DMF (10 mL), and then (2-bromoethyl)carbamate tert-butyl (434 mg, 1.94 mmol, 2.0 equivalents) was added to the solution. The reaction mixture was stirred and heated to 90°C for 3 hours. The desired product was detected by LC-MS. The reaction mixture was extracted with ethyl acetate (50 mL x 3), washed with brine, and dried over anhydrous Na2SO4. The filtrate was concentrated under vacuum, and the residue was purified by FCC (PE:EA=3:1) to obtain (2-((1-(6-bromo-3-(3,5-difluorophenyl)quinoline-4-yl)piperidine-4-yl)amino)ethyl)-carbamate tert-butyl (compound 8-1-3, 170 mg, 0.30 mmol, 31%) as a yellow oil. MS(m / z) 561.2(M+H) + .

[0266] Step 3: Synthesis of (4-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)piperidine-1-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)boronic acid (compound 8-1-4) [ka] (4-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)piperidine-1-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)boronic acid (compound 8-1-3, 170 mg, 0.3 mmol, 1.0 equivalent), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (120 mg, 0.47 mmol, 1.5 equivalents), and CH3COOK (61 mg, 0.62 mmol, 2.0 equivalents) were dissolved in 1,4-dioxane (6 mL), and then Pd(dppf)Cl2 (46 mg, 0.062 mmol, 0.2 equivalents) was added to the solution under a nitrogen atmosphere. The reaction mixture was stirred for 3 hours. The desired product was heated to 90°C for 2 hours under a nitrogen atmosphere. The desired product was detected by TLC. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum to obtain the crude product (4-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)piperidine-1-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)boronic acid (compound 8-1-4, 157 mg, 0.3 mmol, 100%) for the next step.

[0267] Step 4: Synthesis of 6-((2E,4E)-4-(4-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)piperidine-1-yl)-5-(3,5-difluorophenyl)pyridine-2(3H)-ylide-ene)buta-2-en-2-yl)methyl picolinate (compound 8-1-5) [ka] 6-((2E,4E)-4-(4-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)piperidine-1-yl)-5-(3,5-difluorophenyl)pyridine-2(3H)-ylidene)buta-2-en-2-yl)methyl picolinate (compound 8-1-4, 157 mg, 0.3 mmol, 1.0 equivalent), 6-bromopicolinate (102 mg, 0.47 mmol, 1.5 equivalents), and K2CO3 (86 mg, 0.62 mmol, 2.0 equivalents) were dissolved in 1,4-dioxane (4 mL):H2O (1 mL) = 4:1, and then Pd(dppf)Cl2 (46 mg, 0.06 mmol, 0.2 equivalents) was added to the solution under a nitrogen atmosphere. The reaction mixture was stirred and heated to 90°C for 2 hours under a nitrogen atmosphere. The desired product was detected by LC-MS. The reaction mixture was extracted with ethyl acetate (20 mL x 3), washed with brine, and dried over anhydrous Na₂SO₄. The filtrate was concentrated under vacuum, and the residue was purified by preparative TLC (PE:EA=1:1) to obtain 6-((2E,4E)-4-(4-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)piperidine-1-yl)-5-(3,5-difluorophenyl)pyridine-2(3H)-ylidene)buta-2-en-2-yl)methyl picolinate (compound 8-1-5, 100 mg, 0.16 mmol, 53%) as a gray solid. MS (m / z) 618.5 (M+H) + .

[0268] Step 5: Synthesis of 6-(4-(4-((2-aminoethyl)amino)piperidine-1-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)methyl picolinate (compound 8-1-6) [ka] 6-(4-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)piperidine-1-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)methyl picolinate (compound 8-1-5, 100 mg, 0.16 mmol, 1.0 equivalent) was dissolved in a solution of HCl / 1,4-dioxane (4 M, 4 mL). The reaction mixture was stirred at room temperature for 1 hour. The desired product was detected by TLC. The reaction mixture was concentrated under vacuum to obtain the crude product 6-(4-(4-((2-aminoethyl)amino)piperidine-1-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)methyl picolinate (compound 8-1-6, 83 mg, 0.16 mmol, 100%) as a gray solid, which was used in the next step.

[0269] Step 6: Synthesis of Compound 78 [ka] 6-(4-(4-((2-aminoethyl)amino)piperidine-1-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)methyl picolinate (compound 8-1-6, 83 mg, 0.16 mmol, 1.0 equivalent) was dissolved in NMP (4 mL), and then DBU (48 mg, 0.32 mmol, 2.0 equivalents) was added to the solution. The reaction mixture was stirred and heated to 120°C for 3 hours. The desired product was detected by LC-MS. The reaction mixture was extracted with ethyl acetate (20 mL x 3), washed with brine, and dried over anhydrous Na2SO4. The filtrate was concentrated under vacuum, and the residue was purified by preparative TLC (EA:PE=1:0, Rf=0.16) to obtain the crude product. The crude product was purified by preparative HPLC (0.1% TFA in water) to obtain the crude product. 3 -(3,5-difluorophenyl)-4,7-diaza-2(6,4)-quinolina-1(2,6)-pyridina-3(1,4)-piperidina-cyclooctafan-8-one (compound 78, 18.3 mg, 0.038 mmol, 24%) was obtained as a yellow solid.

[0270] Synthesis of compound 79: The synthesis method for compound 8-2-5 was the same as that for compound 8-1-5. [ka] Step 1': Synthesis of 3-(4-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)piperidine-1-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)picolinic acid (compound 8-2-6)

[0271] To a solution of 3-(4-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)piperidine-1-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)methyl picolinate (compound 8-2-5, 210 mg, 0.34 mmol, 1 equivalent) in THF (4 ml), MeOH (1.5 ml), and H2O (1.5 ml), sodium hydroxide (136 mg, 3.4 mmol, 10 equivalents) was added, and the solution was stirred at 25°C for 12 hours. The reaction was monitored by TLC, and after completion, HCl (2 M) was added to the reaction mixture and it was filtered. The solid was concentrated under reduced pressure to obtain 3-(4-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)piperidine-1-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)picolinic acid (compound 8-2-6, 140 mg, 0.23 mmol, 68.21%) as a white solid. MS(m / z)604(M+H) + .

[0272] Step 6: Synthesis of 3-(4-(4-((2-aminoethyl)amino)piperidine-1-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)picolinic acid (compound 8-2-7) To a solution of 3-(4-{4-[(2-{[(tert-butoxy)carbonyl]amino}ethyl)amino]piperidine-1-yl}-3-(3,5-difluorophenyl)quinoline-6-yl)pyridine-2-carboxylic acid (compound 8-2-6, 210 mg, 0.35 mmol, 1 equivalent) in EA (2 ml), HCl / 1,4-dioxane (2 ml) was added, and the solution was stirred at 25°C for 12 hours. The reaction was monitored by TLC under reduced pressure, and after completion, the reaction was concentrated under reduced pressure to obtain crude compound 8-2-7 as a yellow oil. MS(m / z)504(M+H) + .

[0273] Step 7:2 3 Synthesis of -(3,5-difluorophenyl)-4,7-diaza-2(6,4)-quinolina-1(3,2)-pyridina-3(1,4)-piperidinacyclooctafan-8-one (compound 79) A solution of 3-(4-{4-[(2-aminoethyl)amino]piperidine-1-yl}-3-(3,5-difluorophenyl)quinoline-6-yl)pyridine-2-carboxylic acid (compound 8-2-7, 135 mg, 0.27 mmol, 1 equivalent) and ethylbis(propan-2-yl)amine (70 mg, 0.54 mmol, 2 equivalents) in DMF (2.5 ml, 100.0%) is prepared by adding [bis(dimethylamino)methylidene]({3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl})oxidant-ium hexafluoro-λ 5 -Phosphanoid (154 mg, 0.405 mmol, 1.5 equivalents) was added, and the solution was stirred at 25°C for 2 hours. The reaction product was monitored by LC-MS and TLC, and after completion, the reaction mixture was diluted with water (100 mL) and extracted with EA (200 mL x 3). The combined organic extracts were concentrated to obtain the crude product, and the above mixture was purified by preparative HPLC. 3 -(3,5-difluorophenyl)-4,7-diaza-2(6,4)-quinolina-1(3,2)-pyridina-3(1,4)-piperidinacyclooctafan-8-one (compound 79, 2 mg, 1.54%) was obtained as a yellow solid.

[0274] The synthesis method for compound 80 was the same as that for compound 79.

[0275] Compounds 78-80 were synthesized according to the 6 or 7-step procedure described in Example 8. The analytical data for compounds 78-80 are provided below. [Table 9]

[0276] Example 9 [ka] Scheme 9 Step 1: Synthesis of (1-(3-(3,5-difluorophenyl)-6-(3-((4-hydroxybutyl)(methyl)carbamoyl)phenyl)quinoline-4-yl)piperidine-4-yl)carbamate tert-butyl (compound 9-1-2) A solution of compound 9-1-1 (201.46 mg, 0.36 mmol, 1 equivalent) in DMF (5 mL, 100.0%) is prepared by adding [[bis(dimethylamino)methylidene]({3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl})oxidanium hexafluoro-λ 5 -Phosphanoid (509.6 mg, 1.34 mmol, 3 equivalents) and DIPEA (139.58 mg, 1.08 mmol, 3 equivalents) were added, and the solution was stirred at 20°C for 10 minutes. 4-(methylamino)butan-1-ol (92.84 mg, 0.9 mmol, 2 equivalents) was added to the mixture. The solution was stirred at 20°C for 3 hours. The reaction product was diluted with EA and water. The solution was extracted with EA (3 × 25 mL). The organic layer was separated, washed with saturated NaCl solution, and concentrated under vacuum. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether to obtain compound 9-1-2 (270 mg, 0.42 mmol, 93.33%). MS(m / z)645(M+H) + .

[0277] Step 2: Synthesis of (1-(3-(3,5-difluorophenyl)-6-(3-(methyl(4-oxobutyl)carbamoyl)phenyl)quinoline-4-yl)piperidine-4-yl)carbamate tert-butyl (compound 9-1-3) To a solution of compound 9-1-2 (150 mg, 0.23 mmol, 1 equivalent) in DCM (5 mL), pyridinium chlorochromate (100.3 mg, 0.47 mmol, 2 equivalents) was added, and the solution was stirred at 20°C for 3 hours. TLC (DCM:MeOH = 10:1) showed that the material was consumed and major dots were detected. The reaction product was diluted with DCM and water. The solution was extracted with EA (3 × 25 mL). The organic layer was separated, washed with saturated NaCl solution, and concentrated under vacuum. The residue was purified using silica gel column chromatography eluting with ethyl acetate in petroleum ether to obtain compound 9-1-3 (72 mg, 0.11 mmol, 48.15%).

[0278] Step 3: Synthesis of 3-(4-(4-aminopiperidine-1-yl)-3-(3,5-difluorophenyl)quinoline-6-yl)-N-methyl-N-(4-oxobutyl)benzamide (compound 9-1-4) To a solution of compound 9-1-3 (32.2375 mg, 0.05 mmol, 1 equivalent) in [1,4-dioxane (3 mL)], (hydrochloride salt 4 mol / L.) was added, and the solution was stirred at 20°C for 3 hours. TLC (DCM:MeOH = 10:1) showed that the material was consumed and major points were detected. After completion, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 9-1-4 (10 mg, 0.02 mmol, 31.12%).

[0279] Step 4: Synthesis of 23-(3,5-difluorophenyl)-5-methyl-5,10-diaza-2(4,6)-quinolina-1(1,4)-piperidina-3(1,3)-benzenacyclodecafan-4-one (compound 81) Sodio-λ is added to a solution of compound 5 (10 mg, 0.02 mmol, 1 equivalent) in DCM (5 mL). 4-Trimethyl boranetricarboxylate (8.44 mg, 0.04 mmol, 2 equivalents) was added, and the solution was stirred at temperature (30°C) for 16 hours. The reaction product was diluted with DCM and water. The solution was extracted with DCM (2 × 5 mL). The organic layer was separated, washed with saturated NaCl solution, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain compound 81 (2 mg, 18.99%).

[0280] The analytical data for compound 81 is provided below. [Table 10]

[0281] Example 10 [ka] Scheme 10 Step 1: Synthesis of 6-bromo-3-chloro-1,4-dihydroquinoline-4-one (compound 10-1-2) To a stirred solution of 6-bromo-1,4-dihydroquinoline-4-one (compound 10-1-1, 30 g, 133.9 mmol) in AcOH (500 mL), 1-chloropyrrolidine-2,5-dione (17.88 g, 133.9 mmol) was added at 0°C. The reaction mixture was stirred at 60°C for 2 hours. TLC (PE:siRNA = 1:1) indicated that the reaction was complete. The reaction mixture was filtered, concentrated, and evaporated to obtain 6-bromo-3-chloro-1,4-dihydroquinoline-4-one (compound 10-1-2, 25 g, 96.71 mmol, 72.23%) as a white solid. MS (m / z) 257.9 / 259.9 (M+H) + .

[0282] Step 2: Synthesis of 6-bromo-3,4-dichloroquinoline (compound 10-1-3) To a stirred solution of 6-bromo-3-chloro-1,4-dihydroquinoline-4-one (compound 10-1-2, 24.83 g, 96.05 mmol, 1 equivalent) in phosphoroyl trichloride (250 ml, 1629.97 mmol, 16.97 equivalents), N,N-dimethylformamide (702.03 mg, 9.61 mmol, 0.1 equivalent) was added at 20°C. The reaction mixture was stirred at 97°C for 2 hours. TLC (PE:siRNA = 5:1) indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was diluted with toluene (500 mL), washed with saturated NaHCO3 (500 mL), dried over Na2SO4, and evaporated to obtain 6-bromo-3,4-dichloroquinoline (compound 10-1-3, 26 g, 93.88 mmol, 97.74%) as a white solid. MS(m / z)275.9 / 277.9(M+H) + .

[0283] Step 3: Synthesis of 8-(6-bromo-3-chloroquinoline-4-yl)-1,4-dioxa-8-azaspiro[4.5]decane (compound 10-1-4) To a stirred solution of 6-bromo-3,4-dichloroquinoline (compound 10-1-3, 15.00 g, 54.16 mmol, 1 equivalent) in DMF (150 ml), 1,4-dioxa-8-azaspiro[4.5]decane (11.6322 g, 81.24 mmol, 1.5 equivalents) and dipotassium carbonate (14.97 g, 108.32 mmol, 2 equivalents) were added at 20°C. The reaction mixture was stirred at 100°C for 16 hours. TLC (PE:SiO=5:1) indicated that the reaction was complete. The reaction mixture was poured into H2O (1 L), filtered, and concentrated to obtain 8-(6-bromo-3-chloroquinoline-4-yl)-1,4-dioxa-8-azaspiro[4.5]decane (compound 10-1-4, 20 g, 52.13 mmol, 96.25%). MS(m / z)383.1 / 385.1(M+H) + .

[0284] Step 4: Synthesis of 1-(6-bromo-3-chloroquinoline-4-yl)piperidine-4-one (compound 10-1-5) To a stirred solution of 8-(6-bromo-3-chloroquinoline-4-yl)-1,4-dioxa-8-azaspiro[4.5]decane (compound 10-1-4, 20.0006 g, 52.13 mmol, 1 equivalent) in H2O (100 ml), trifluoroacetic acid (100 ml, 877 mmol, 16.82 equivalents) and 1,2-dichloroethane (100 ml, 1011 mmol, 19.39 equivalents) were added at 20°C. The reaction mixture was stirred at 87°C for 16 hours. TLC (PE:siRNA = 5:1) indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (500 mL), washed with saturated NaHCO3 (500 mL), dried over Na2SO4, and evaporated to obtain 1-(6-bromo-3-chloroquinoline-4-yl)piperidine-4-one (compound 10-1-5, 15 g, 44.17 mmol, 84.73%) as a white solid. MS(m / z)339 / 341(M+H) + .

[0285] Step 5: Synthesis of 1-[3-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-4-yl]piperidine-4-one (compound 10-1-6) A stirred solution of 1-[3-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-4-yl]piperidine-4-one (compound 10-1-5, 2g, 5.17 mmol, 87.83%) in 1,4-dioxane (70 ml) was prepared by adding 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboro) to a stirred solution of 1,4-dioxane (70 ml). Lan-2-yl)-1,3,2-dioxaborolane (2243.22 mg, 8.83 mmol, 1.5 equivalents), potassium acetate (1155.91 mg, 11.78 mmol, 2 equivalents), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (449.23 mg, 0.59 mmol, 0.1 equivalents) were added at 20°C. The reaction mixture was stirred at 100°C for 1 hour. TLC (PE:siRNA = 5:1) indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was diluted with siRNA (100 mL), washed with saturated NaHCO3 (500 mL), dried over Na2SO4, and evaporated to obtain 1-[3-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-4-yl]piperidine-4-one (compound 10-1-6, 2 g, 5.17 mmol, 87.83%) as a white solid. MS(m / z)387.2(M+H) + .

[0286] Step 6: Synthesis of 6-[3-chloro-4-(4-oxopiperidine-1-yl)quinoline-6-yl]pyridine-2-carboxylate methyl (compound 10-1-7) To a stirred solution of 1-[3-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-4-yl]piperidine-4-one (compound 10-1-6, 2g, 5.17 mmol, 1 equivalent) in 1,4-dioxane (60 ml), water (15 ml), methyl 6-bromopyridine-2-carboxylate (1116.88 mg, 5.17 mmol, 1 equivalent), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (394.37 mg, 0.52 mmol, 0.1 equivalent), and dipotassium carbonate (1429.09 mg, 10.34 mmol, 2 equivalents) were added at 20°C. The reaction mixture was stirred at 90°C for 1 hour. TLC (PE:HCl = 5:1) indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was diluted with HCl (100 mL), washed with saturated NaHCO3 (50 mL), dried over Na2SO4, and evaporated to obtain the residue. The residue was purified by column chromatography on silica gel eluted with PE / HCl (9:1~1:1) to obtain 6-[3-chloro-4-(4-oxopiperidine-1-yl)quinoline-6-yl]pyridine-2-carboxylate methyl (compound 10-1-7, 1.9 g, 4.8 mmol, 92.84%) as a white solid. MS (m / z) 396.1 (M+H) + .

[0287] Step 7: Synthesis of 6-[3-(3,5-difluorophenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl]pyridine-2-carboxylate methyl (compound 10-1-8) To a stirred solution of 6-[3-chloro-4-(4-oxopiperidine-1-yl)quinoline-6-yl]pyridine-2-carboxylate methyl (compound 10-1-7, 1.9 g, 4.8 mmol, 1 equivalent) in 1,4-dioxane (60 mL), water (15 mL), (3,5-difluorophenyl)boronic acid (757.97 mg, 4.8 mmol, 1 equivalent), dipotassium carbonate (1326.82 mg, 9.6 mmol, 2 equivalents), and dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (339.87 mg, 0.48 mmol, 0.1 equivalent) were added at 20°C. The reaction mixture was stirred at 100°C for 1 hour. TLC (PE:SiO=1:1) indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was diluted with toluene (100 mL), washed with saturated NaHCO3 (50 mL), dried over Na2SO4, and evaporated to obtain the residue. The residue was purified by column chromatography on silica gel eluted with PE / toluene (9:1~1:1) to obtain 6-[3-(3,5-difluorophenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl]pyridine-2-carboxylate methyl (compound 10-1-8, 1.6 g, 3.38 mmol, 70.42%) as a white solid. MS (m / z) 474.2 (M+H) + LCMS: m / z: 474.2 (M+H).

[0288] Step 8: Synthesis of 6-[3-(3,5-difluorophenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl]pyridine-2-carboxylic acid (compound 10-1-9) To a stirred solution of methyl 6-[3-(3,5-difluorophenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl]pyridine-2-carboxylate (compound 10-1-8, 1.4 g, 3.05 mmol, 90.17%) in THF (20 ml), sodium hydroxide (675.95 mg, 16.9 mmol, 5 equivalents) and water (5 ml) were added at 0°C. The reaction mixture was stirred at 40°C for 2 hours. TLC (PE:HCl = 1:1) indicated that the reaction was complete. The pH of the reaction mixture was adjusted to 3-4. The reaction mixture was filtered, concentrated, and evaporated to obtain 6-[3-(3,5-difluorophenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl]pyridine-2-carboxylic acid (compound 10-1-9, 1.4 g, 3.05 mmol, 90.24%) as a white solid. MS (m / z) 460.2 (M+H) + .

[0289] Step 9: N-[4-(1-{3-[3-(3,5-difluorophenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl]phenyl}-N-methylformamide)butyl]carbamate tert-butyl (compound 10-1-10) A stirred solution of 6-[3-(3,5-difluorophenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl]pyridine-2-carboxylic acid (compound 10-1-9, 750 mg, 1.63 mmol, 1 equivalent) in DMF (10 ml) is mixed with tert-butyl N-[4-(methylamino)butyl]carbamate (330.22 mg, 1.63 mmol, 1 equivalent) and tripropyl-1,3,5,2λ. 5 ,4λ 5 ,6λ 5-Trioxatriphosfinan-2,4,6-trione (1038.81 mg, 3.26 mmol, 2 equivalents) and ethylbis(propan-2-yl)amine (1054.87 mg, 8.16 mmol, 5 equivalents) were added at 20°C. The reaction mixture was stirred at 20°C for 1 hour. TLC (PE:Â=1:1) indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was diluted with  (100 mL), washed with saturated NaHCO3 (50 mL), dried over Na2SO4, and concentrated to dryness. The residue was purified by column chromatography using silica gel eluted with PE / siRNA (9:1~1:1) to obtain N-[4-(1-{3-[3-(3,5-difluorophenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl]phenyl}-N-methylformamide)butyl]carbamate tert-butyl (compound 10-1-10, 520 mg, 0.81 mmol, 49.62%) as a white solid. MS (m / z) 644.3 (M+H) + .

[0290] Step 10: Synthesis of N-(4-aminobutyl)-6-(3-(3,5-difluorophenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)-N-methylpicolinamide (compound 10-1-11) To a stirred solution of (4-(6-(3-(3,5-difluorophenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)-N-methylpicolinamide)butyl)carbamate tert-butyl (compound 10-1-10, 520 mg, 0.81 mmol, 1 equivalent) in DCM (4 ml, 100.0%), trifluoroacetic acid (1 ml, 8.77 mmol, 10.84 equivalents) was added at 20°C. The reaction mixture was stirred at 20°C for 1 hour. TLC (DCM:MeOH = 10:1) indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain N-(4-aminobutyl)-6-(3-(3,5-difluorophenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)-N-methylpicolinamide (compound 10-1-11, 400 mg, 0.74 mmol, 91.11%) as a white solid. MS(m / z) 543.3(M+H) + .

[0291] Step 11: Synthesis of (Compound 82) To a stirred solution of N-(4-aminobutyl)-6-(3-(3,5-difluorophenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)-N-methylpicolinamide (compound 10-1-11, 97.6714 mg, 0.18 mmol, 1 equivalent) in MeOH (5 ml, 100.0%), titanium(4+)tetrakis(propane-2-oleate) (261.9 mg, 0.92 mmol, 5 equivalents) was added at 20°C. o After stirring in C for 1 hour, the reactants were mixed with sodium-λ. 4 -Trimethyl boranetricarboxylate (388.73 mg, 1.84 mmol, 10 equivalents) was slowly added. The reaction mixture was 20 o The mixture was stirred for another hour in 1C. TLC (DCM:MeOH=10:1) indicated that the reaction was complete. The reaction mixture was quenched with H2O (5 mL) and extracted with DCM (30 mL x 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, and concentrated. The residue was purified by preparative TLC (DCM:MeOH=10:1) to obtain 24-(3,5-difluorophenyl)-11-methyl-2,6,11,22,27-pentazapentacyclo[16.6.2.2]. 2 , 5 .1 13 , 17 .0 21 , 25 Nonacosa-1(24),13(27),14,16,18(26),19,21(25),22-octaen-12-one (compound 82, 26 mg, 0.05 mmol, 27.13%) was obtained as a white solid.

[0292] Compounds 82-86 were synthesized according to the 11-step procedure described in Example 10. The analytical data for compounds 82-86 are provided below. [Table 11-1] [Table 11-2]

[0293] Example 11 [ka] Scheme 11 Step 1: Synthesis of 1-(3-(3-fluoro-5-methylphenyl)-6-(2-hydroxyphenyl)quinoline-4-yl)piperidine-4-one (compound 11-1-2) 1-(3-(3-fluoro-5-methylphenyl)-6-(2-hydroxyphenyl)quinoline-4-yl)piperidine-4-one (compound 11-1-1, 2g, 4.84 mmol, 1.0 equivalent), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1g, 7.26 mmol, 1.5 equivalents), and K2CO3 (1.33g, 9.68 mmol, 2.0 equivalents) were dissolved in 1,4-dioxane (16mL):H2O (4mL) = 4:1, and then Pd(dppf)Cl2 (353mg, 0.484 mmol, 0.1 equivalents) was added to the solution. The reaction mixture was stirred and heated to 90°C for 2 hours under a nitrogen atmosphere. The desired product was detected by LC-MS. The reaction mixture was extracted with ethyl acetate (50 mL x 3), washed with brine, and dried over anhydrous sodium 2SO4. The filtrate was concentrated under vacuum, and the residue was purified by FCC (EA:PE = 1:2) to obtain 1-(3-(3-fluoro-5-methylphenyl)-6-(2-hydroxyphenyl)quinoline-4-yl)piperidine-4-one (compound 11-1-2, 800 mg, 1.87 mmol, 38.6%) as a red solid. MS (m / z) 427.25 (M+H) + .

[0294] Step 2: Synthesis of 2-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)phenyl(4-nitrophenyl)carbonate (compound 11-1-3) 1-(3-(3-fluoro-5-methylphenyl)-6-(2-hydroxyphenyl)quinoline-4-yl)piperidine-4-one (compound 11-1-2, 200 mg, 0.47 mmol, 1.0 equivalent), 4-nitrophenylcarbonochloride (113 mg, 0.564 mmol, 1.2 equivalents), and DIPEA (151 mg, 1.175 mmol, 2.5 equivalents) were dissolved in DCM (5 mL). The reaction mixture was stirred under a nitrogen atmosphere at 25°C for 3 hours. The desired product was detected by LC-MS. The reaction mixture was extracted with CH2Cl2 (20 mL x 3), washed with brine, and dried over anhydrous Na2SO4. The filtrate was concentrated under vacuum, and the residue was purified by FCC (PE:EA=2:1) ​​to obtain 2-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)phenyl(4-nitrophenyl) carbonate (compound 11-1-3, 200 mg, 0.338 mmol, 71.9%) as a white oil. MS(m / z) 592.35(M+H) + .

[0295] Step 3: Synthesis of (2-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)phenyl)ethane-1,2-diyldicarbamate tert-butyl (compound 11-1-4) 2-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)phenyl(4-nitrophenyl) carbonate (compound 11-1-3, 200 mg, 0.338 mmol, 1.0 equivalent) was dissolved in DCM (4 mL), and then (2-aminoethyl)carbamate tert-butyl (64 mg, 0.40 mmol, 1.2 equivalents) was added to the solution. The reaction mixture was stirred at 25°C for 1 hour. The desired product was detected by LC-MS. The reaction mixture was extracted with DCM (20 mL x 3), washed with brine, and dried over anhydrous Na2SO4. The filtrate was concentrated under vacuum, and the residue was purified by FCC (EA:PE=2:1) ​​to obtain (2-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)phenyl)ethane-1,2-diyldicarbamate tert-butyl (compound 11-1-4, 140 mg, 0.229 mmol, 67.7%) as a yellow oil. MS(m / z)613.5(M+H) + .

[0296] Step 4: Synthesis of 2-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)phenyl(2-aminoethyl)carbamate (compound 11-1-5) (2-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)phenyl)ethane-1,2-diyldicarbamate tert-butyl (compound 11-1-4, 70 mg, 0.114 mmol, 1.0 equivalent) was dissolved in a solution of TFA (1 mL):DCM (3 mL) = 1:3. The reaction mixture was stirred at 25°C for 1 hour. The desired product was detected by LC-MS. The reaction mixture was concentrated under vacuum to obtain 2-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)phenyl(2-aminoethyl)carbamate (compound 11-1-5, 58 mg, 0.114 mmol, 100%). MS (m / z) 513.35 (M+H) + .

[0297] Step 5: Synthesis of Compound 87 2-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)phenyl(2-aminoethyl)carbamate (compound 11-1-5, 58 mg, 0.114 mmol, 1.0 equivalent) was dissolved in MeOH (4 mL). Then, Ti(OiPr)4 (321 mg, 1.14 mmol, 10 equivalents) was added to the solution under a nitrogen atmosphere. The reaction mixture was stirred at 25°C for 30 minutes. Then, NaBH(OAc)3 (241 mg, 1.14 mmol, 10 equivalents) was added to the solution. The reaction mixture was stirred at 25°C for 12 hours. The desired product was detected by LC-MS. The reaction mixture was filtered through Celite, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by preparative HPLC (0.1% TFA in water) to obtain 23-(3-fluoro-5-methylphenyl)-4-oxa-6,9-diaza-2(4,6)-quinolina-1(1,4)-piperidinea-3(1,2)-benzenacyclononaphan-5-one (compound 87, 5.0 mg, 0.0084 mmol, 7.4%) as a yellow solid.

[0298] The analytical data for compound 87 is provided below. [Table 12]

[0299] Example 12 [ka] Scheme 12 Step 1: Synthesis of 5-(2-azidoethyl)-2,2-dimethyl-1,3-dioxane (compound 12-1-2) To a solution of 2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl 4-methylbenzenesulfonate (compound 12-1-1, 3.0 g, 9.55 mmol) in DMF (60 ml), sodium azide (1240.39 mg, 19.08 mmol, 2 equivalents) was added, and the solution was stirred at 60°C for 3 hours. After completion, the reaction mixture was extracted with EA (500 mL x 3). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5-(2-azidoethyl)-2,2-dimethyl-1,3-dioxane (compound 12-1-2, 1.74 g, 9.39 mmol) as a colorless oil. MS (m / z) 186 (M+H) + .

[0300] Step 2: Synthesis of 2-(2-azidoethyl)propane-1,3-diol (compound 12-1-3) To a solution of 5-(2-azidoethyl)-2,2-dimethyl-1,3-dioxane (compound 12-1-2, 1.74 g, 9.39 mmol, 1 equivalent) in THF (40 ml), 8 ml of HCl (2 M) was added, and the solution was stirred at 25°C for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure to obtain the crude product in water. The crude product was freeze-dried to obtain 2-(2-azidoethyl)propane-1,3-diol (compound 12-1-3, 1.61 g, 11.09 mmol) as a yellow oil. MS (m / z) 146 (M+H) + .

[0301] Step 3: Synthesis of 2-(4-azido-2-(hydroxymethyl)butoxy)-3-bromobenzonitrile (compound 12-1-4) To a solution of 2-(2-azidoethyl)propane-1,3-diol (compound 12-1-3, 1.61 g, 11.09 mmol) in DMF (12 ml), LiHMDS (11.7 ml, 11.7 mmol, 1.1 equivalents) was added at -60°C. The mixture was stirred at -60°C for 30 minutes, and then 3-bromo-2-fluorobenzonitrile (1.70 g, 8.5 mmol) was added to the mixture at 60°C for 2 hours. After completion, the reaction mixture was extracted with EA (500 mL x 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by flash (DCM:MeOH = 12:1) to obtain 2-(4-azido-2-(hydroxymethyl)butoxy)-3-bromobenzonitrile (compound 12-1-4, 1.29 g, 3.97 mmol) as a white solid. MS(m / z)326(M+H) + .

[0302] Step 4: Synthesis of 2-(4-azido-2-(hydroxymethyl)butoxy)-3-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)benzonitrile (compound 12-1-6) To a solution of 2-(4-azido-2-(hydroxymethyl)butoxy)-3-bromobenzonitrile (compound 12-1-4, 1.29 g, 3.97 mmol) and (3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)boronic acid (compound 12-1-5, 1.50 g, 3.97 mmol, 1 equivalent) in 1,4-dioxane (30 ml) and H2O (6 ml), dipotassium carbonate (1.09 g, 8 mmol, 2 equivalents) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (290 mg, 0.397 mmol, 0.1 equivalent) were added, and the solution was stirred at 100°C for 1 hour. The reaction was monitored by LC-MS and TLC. After completion, the reaction mixture was diluted with water (50 mL) and extracted with EA (100 mL x 2). The combined organic extract was concentrated to obtain the crude product. The crude product was then purified by flush (DCM:MeOH = 10:1) to obtain 2-(4-azido-2-(hydroxymethyl)butoxy)-3-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quin-olin-6-yl)benzonitrile (compound 12-1-6, 800 mg, 1.38 mmol) as a white solid. MS (m / z) 579 (M+H) + .

[0303] Step 5: Synthesis of 2-(4-amino-2-(hydroxymethyl)butoxy)-3-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)benzonitrile (compound 12-1-7) A solution of 2-(4-azido-2-(hydroxymethyl)butoxy)-3-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)benzonitrile (compound 12-1-6, 220 mg, 0.398 mmol, 1 equivalent) in NH4OH (4 ml) was mixed with pyridine (4 ml) and stirred at 25°C for 1 hour. PPh3 (100 mg, 0.398 mmol, 1 equivalent) was added to the mixture and stirred at 25°C for 12 hours. The reaction was monitored by TLC, and after completion, the reaction mixture was diluted with water (50 mL) and extracted with EA (100 mL x 2). The combined organic extracts were concentrated to obtain a crude product. The crude product was then purified by flush (DCM:MeOH = 10:1) to obtain 2-(4-amino-2-(hydroxymethyl)butoxy)-3-(3-(3-fluoro-5-methylphenyl)-4-(4-oxo-piperidine-1-yl)quinoline-6-yl)benzonitrile (compound 12-1-7, 140 mg, 0.253 mmol) as a white solid. MS(m / z)553(M+H) + .

[0304] Step 6: (S)-2 3 -(3-fluoro-5-methylphenyl)-6-(hydroxymethyl)-4-oxa-9-aza-2(4,6)-quinolina-1(1,4)-piperidina-3(1,2)-benzenacyclonononaphane-3 3 -Carbonitrile (compound 88) and (R)-2 3 -(3-fluoro-5-methylphenyl)-6-(hydroxymethyl)-4-oxa-9-aza-2(4,6)-quinolina-1(1,4)-piperidina-3(1,2)-benzenacyclonononaphane-3 3 - Synthesis of carbonitrile (compound 89) A solution of 2-(4-amino-2-(hydroxymethyl)butoxy)-3-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)benzonitrile (compound 12-1-7, 120 mg, 0.223 mmol, 1 equivalent) and Ti(OiPr)4 (308 mg, 1.115 mmol, 5 equivalents) in MeOH (1.8 ml) and DCE (1.8 ml) was stirred at 25°C for 1 hour. Then, NaBH(OAC)3 (460 mg, 2.23 mmol, 10 equivalents) was added to the above mixture and stirred at 25°C for 12 hours. The reaction was monitored by LC-MS and TLC, and after completion, the reaction mixture was diluted with water (100 mL) and extracted with EA (200 mL x 3). The combined organic extracts were concentrated to obtain a crude substance, and the above mixture was purified by preparative HPLC. 3 -(3-fluoro-5-methylphenyl)-6-(hydroxymethyl)-4-oxa-9-aza-2(4,6)-quinolina-1(1,4)-piperidina-3(1,2)-benacyclonononaphane-33-carbonitrile (compound 88, 21.1 mg, 0.039 mmol) and 2 3 -(3-fluoro-5-methylphenyl)-6-(hydroxymethyl)-4-oxa-9-aza-2(4,6)-quinolina-1(1,4)-piperidina-3(1,2)-benacyclonononaphane-33-carbonitrile (compound 89, 4.4 mg, 0.008 mmol) was obtained as a yellow solid. The stereochemistry is arbitrarily defined.

[0305] Compounds 88-93 were synthesized according to the six-step procedure described in Example 12. The analytical data for compounds 88-93 are provided below. [Table 13-1] [Table 13-2] * Stereochemistry can be assigned arbitrarily.

[0306] Example 13 [ka] Scheme 13 Step 1: Synthesis of 3-bromo-2-(buta-3-en-1-yloxy)benzonitrile (compound 13-1-2) 3-Bromo-2-hydroxybenzonitrile (compound 13-1-1, 5 g, 25.51 mmol, 1.0 equivalent) and K2CO3 (7 g, 51 mmol, 2.0 equivalents) were dissolved in MeCN (50 mL), and then 4-bromobuta-1-ene (6.8 g, 51 mmol, 2.0 equivalents) was added to the solution. The reaction mixture was stirred and heated to 90°C for 12 hours under a nitrogen atmosphere. The desired product was detected by LC-MS. The reaction mixture was extracted with ethyl acetate (100 mL * 3), washed with brine, and dried over anhydrous Na2SO4. The filtrate was concentrated under vacuum, and the residue was purified by FCC (EA:PE=1:2) to obtain 3-bromo-2-(buta-3-ene-1-yloxy)benzonitrile (compound 13-1-2, 1.9 g, 7.57 mmol, 29.6%) as a white oil. MS(m / z)250(M-1) - .

[0307] Step 2: Synthesis of 2-(4-amino-3-azidobutoxy)-3-bromobenzonitrile (compound 13-1-3) 3-Bromo-2-(buta-3-en-1-yloxy)benzonitrile (compound 13-1-2, 1 g, 4.0 mmol, 1.0 equivalent) and Fe(OTf)2 (107 mg, 0.4 mmol, 0.1 equivalent) were dissolved in MeOH (10 mL), and then PivONH3OTf (2.67 g, 10 mmol, 2.5 equivalents) and NaN3 (312 mg, 4.8 mmol, 1.2 equivalents) were added to the solution under a nitrogen atmosphere. The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 12 hours. The desired product was detected by LC-MS. The reaction solution was concentrated under vacuum to obtain the crude product 2-(4-amino-3-azidobutoxy)-3-bromobenzonitrile (compound 13-1-3), which is for the next step. MS(m / z)310(M+H) + .

[0308] Step 3: Synthesis of (2-azido-4-(2-bromo-6-cyanophenoxy)butyl)carbamate tert-butyl (compound 13-1-4) 2-(4-amino-3-azidobutoxy)-3-bromobenzonitrile (compound 13-1-3, 1 g, 4.0 mmol, 1.0 equivalent) was dissolved in a 1:1 solution of DCM (5 mL):NaHCO3 (aqueous solution) (5 mL), and then (Boc)2O (1.7 g, 8 mmol, 2.0 equivalents) was added to the solution. Reaction mixture 25 o The mixture was stirred in 1C for 12 hours. The desired product was detected by LC-MS. The reaction mixture was extracted with DCM (50 mL x 3), washed with brine, and dried over anhydrous Na2SO4. The filtrate was concentrated under vacuum to obtain the crude product (2-azido-4-(2-bromo-6-cyanophenoxy)butyl)carbamate tert-butyl (compound 13-1-4, 1.2 g, 3.0 mmol, 75%). MS (m / z) 310 / 354 / 356 (M-100 / M-56 / M-56+2) +

[0309] Step 4: Synthesis of (2-azido-4-(2-cyano-6-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)phenoxy)butyl)carbamate tert-butyl (compound 13-1-5) (2-azido-4-(2-bromo-6-cyanophenoxy)butyl)carbamate tert-butyl (compound 13-1-4, 400 mg, 1.0 mmol, 1.0 equivalent), (3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)boronic acid (378 mmol, 1.0 equivalent), and K2CO3 (196 mg, 1.5 mmol, 1.5 equivalents) were dissolved in a solution of 1,4-dioxane (12 mL):H2O (3 mL) = 1:4, and then Pd(dppf)Cl2 (73.01 mg, 0.1 mmol, 0.1 equivalent) was added to the solution. The reaction mixture was heated with stirring to 90°C for 2 hours under a nitrogen atmosphere. The desired product was detected by LC-MS. The reaction solution was extracted with ethyl acetate (30 mL x 3), washed with brine, and dried over anhydrous sodium 2SO4. The filtrate was concentrated under vacuum, and the residue was purified by FCC (PE:EA = 2:1) to obtain (2-azido-4-(2-cyano-6-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)phenoxy)butyl)carbamate tert-butyl (compound 13-1-5, 230 mg, 0.347 mmol, 34.7%) as a yellow solid. MS (m / z) 664.45 (M+H) + .

[0310] Step 5: Synthesis of 2-(4-amino-3-azidobutoxy)-3-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)benzonitrile (compound 13-1-6) (2-azido-4-(2-cyano-6-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)phenoxy)butyl) tert-butyl carbamate (compound 13-1-5, 230 mg, 0.347 mmol, 1.0 equivalent) was dissolved in a solution of TFA (1 mL):DCM (3 mL) = 1:3. The reaction solution was prepared in 25 oThe mixture was stirred in 1°C for 1 hour. The desired product was detected by LC-MS. The reaction solution was concentrated under vacuum to obtain the crude product 2-(4-amino-3-azidobutoxy)-3-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)benzonitrile (compound 13-1-6, 195 mg, 0.347 mmol, 100%). MS (m / z) 564.4 (M+H) + .

[0311] Step 6: Synthesis of Compound 94 2-(4-amino-3-azidobutoxy)-3-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidine-1-yl)quinoline-6-yl)benzonitrile (compound 13-1-6, 195 mg, 0.347 mmol, 1.0 equivalent) was dissolved in MeOH (4 mL). Then, Ti(OiPr)4 (497 mg, 1.75 mmol, 5 equivalents) was added to the solution under a nitrogen atmosphere. The reaction mixture was 25 o The mixture was stirred in C for 30 minutes. Then, NaBH(OAc)3 (742 mg, 3.5 mmol, 10 equivalents) was added to the solution. Reaction mixture 25 o The mixture was stirred in 1C for 12 hours. The desired product was detected by LC-MS. The reaction mixture was filtered through Celite, and the filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by preparative HPLC (0.1% TFA in water) to obtain 7-azide-23-(3-fluoro-5-methylphenyl)-4-oxa-9-aza-2(4,6)-quinolina-1(1,4)-piperidina-3(1,2)-benzenacyclonononaphane-33-carbonitrile (compound 94, 2.0 mg, 0.00366 mmol, 1.0%) as a yellow solid.

[0312] Step 7: Synthesis of Compound 95

[0313] 7-Azide-23-(3-fluoro-5-methylphenyl)-4-oxa-9-aza-2(4,6)-quinolina-1(1,4)-piperidina-3(1,2)-benzenacyclononafane-3 3-Carbonitrile (compound 13-1, 10 mg, 0.0183 mmol, 1.0 equivalent) and PPh3 (7 mg, 0.022 mmol, 1.5 equivalents) were dissolved in pyridine (2 mL). The reaction mixture was heated under a nitrogen atmosphere for 25 minutes. o The mixture was stirred in C for 30 minutes. Then, NH3H2O ​​(2 mL) was added to the solution. The reaction mixture was heated under a nitrogen atmosphere for 25 minutes. o The mixture was stirred in 12°C for 12 hours. The desired product was detected by LC-MS. The reaction solution was concentrated under vacuum, and the residue was purified by preparative HPL (0.1% TFA in water) to obtain 7-amino-23-(3-fluoro-5-methylphenyl)-4-oxa-9-aza-2(4,6)-quinolina-1(1,4)-piperidina-3(1,2)-benzenacyclonononaphane-33-carbonitrile (compound 95, 1.0 mg, 0.00192 mmol, 10%) as a white solid.

[0314] Compounds 94-103 were synthesized according to the six-step procedure described in Example 13. The analytical data for compounds 94-103 are provided below. [Table 14-1] [Table 14-2] [Table 14-3] * Stereochemistry can be assigned arbitrarily.

[0315] Example 14 [ka] Scheme 14 Step 1: Synthesis of (N-[1-(2-chloro-3-formyl-4-pyridyl)-4-piperidyl]carbamate tert-butyl (compound 14-1-2) To a stirred mixture of compound 14-1-1 (10g, 56.82 mmol) and tert-butyl N-(4-piperidyl)carbamate (11.38g, 56.82 mmol) in DMF (100 mL), add DIPEA (36.65 g, 284.09 mmol) for 25 minutes. o The mixture was added in 1C for 2 hours. The reaction was monitored by LC-MS, which indicated that the reaction was complete. The mixture was diluted with water (60 mL), and then a large amount of solid was precipitated from the reaction solution. The solution was filtered to collect the filter cake, which was dissolved in ethyl acetate, then dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain compound 14-1-2 (17.50 g, 51.50 mmol, yield 90.64%) as a yellow solid. MS (m / z) 340 (M+H) + .

[0316] Step 2: Synthesis of N-[1-(5-bromo-2-chloro-3-formyl-4-pyridyl)-4-piperidyl]carbamate tert-butyl (compound 14-1-3) To a solution of compound 14-1-2 (17.5 g, 51.50 mmol) in DMF (100 mL), NBS (9.17 g, 51.50 mmol) was added at 25°C, and the resulting mixture was stirred at 25°C for 16 hours. The reaction was monitored by LC-MS, which indicated that the reaction was complete. The mixture was diluted with water (20 mL), washed with ethyl acetate (3 x 20 mL), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain compound 14-1-3 (7.00 g, crude product) as a yellow solid. MS (m / z) 420 (M+H) + .

[0317] Step 3: Synthesis of N-[1-[5-bromo-2-chloro-3-(5,6-difluoro-1H-benzimidazole-2-yl)-4-pyridyl]-4-piperidyl]carbamate tert-butyl (compound 14-1-4) To a solution of compound 14-1-3 (7.0 g, 16.72 mmol) and 4,5-difluorobenzene-1,2-diamine (2.41 g, 16.72 mmol) in tetrahydrofuran (70 mL), acetic acid (3.01 g, 50.15 mmol) was added, and the mixture was stirred at 60 °C for 2 hours. Then, FeCl3 (8.14 g, 50.15 mmol) was added at 25 °C, and the resulting mixture was stirred at 60 °C for 2 hours. The reaction was monitored by LC-MS and TLC, which indicated that the reaction was complete. The reaction mixture was diluted with water (50 mL). This was then extracted with ethyl acetate (50 mL x 2). All organic phases were combined and dried over anhydrous Na2SO4. The organic phases were concentrated to obtain compound 14-1-4 (6.70 g, crude product) as a brown solid. MS (m / z) 544 (M+H) + .

[0318] Step 4: Synthesis of N-[1-[2-chloro-3-(5,6-difluoro-1H-benzimidazole-2-yl)-5-(3-fluoro-5-methylphenyl)-4-pyridyl]-4-piperidyl]carbamate tert-butyl (compound 14-1-5) To a solution of compound 14-1-4 (6.7 g, 12.34 mmol) and (3-fluoro-5-methylphenyl)boronic acid (1.71 g, 11.11 mmol) in 1,4-dioxane (40 mL) and water (10 mL), NaHCO3 (3.11 g, 37.03 mmol) and PdCl2 (dppf) (905.65 mg, 1.23 mmol) were added at 25 °C, and the resulting mixture was stirred in N2 at 90 °C for 3 hours. The reaction was monitored by LC-MS, which indicated that the reaction was complete. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (EA / PE = 20%~50%) to obtain compound 14-1-5 (2.05 g, 3.58 mmol, yield 28.96%) as a brown solid. MS (m / z) 572.2 (M+H) + .

[0319] Step 5: Synthesis of 1-(2-chloro-3-(5,6-difluoro-1H-benzo[d]imidazole-2-yl)-5-(3-fluoro-5-methylphenyl)pyridine-4-yl)piperidine-4-amine (compound 104) To a stirred solution of compound 14-1-5 (100 mg, 174.82 μmol) in DCM (5 mL), TFA (199.33 mg, 1.75 mmol) was added at 25°C, and the mixture was stirred at room temperature for 16 hours. The reaction was monitored by LC-MS, which indicated that the reaction was complete. The mixture was concentrated under vacuum, the residue was dissolved in methanol (3 mL), treated with NaHCO3 (solid) to adjust the pH to 8, and then filtered. The filtrate was concentrated under vacuum. The contaminated material was purified by preparative HPLC. Lyophilization yielded the desired product compound 104 (11 mg, 23.31 μmol, yield 13.33%) as a white solid.

[0320] The analytical data for compound 104 is provided below. [Table 15]

[0321] Example 15 [ka] Scheme 15 Step 1: Synthesis of (3-((3,5-dibromopyridine-4-yl)aminopropyl)carbamate tert-butyl (compound 15-1-1) A solution of 3,4,5-tribromopyridine (compound 15-1-SM, 350 mg, 1.11 mmol) and tert-butyl N-(3-aminopropyl)carbamate (772.47 mg, 4.43 mmol) in DMSO (0.05 mL) was stirred at 140 °C for 30 minutes. The reaction was monitored by LC-MS. After cooling to room temperature, the solution was poured into ice water (25 mL) and many solids were observed. The solids were collected, washed with H2O (10 mL x 3), and dried under vacuum to obtain the title compound (compound 15-1-1, 400.00 mg, 977.72 μmol, yield 88.21%) as a white solid. MS (m / z) 408.0 (M+H) + .

[0322] Step 2: Synthesis of (3-((3-bromo-5-(1H-indole-2-yl)pyridine-4-yl)amino)propyl)carbamate tert-butyl (compound 15-1-2) To a solution of compound 15-1-1 (350 mg, 855.50 μmol) and (3,5-difluorophenyl)boronic acid (121.58 mg, 769.95 μmol) in a mixed solvent of dioxane (6 mL) and water (0.6 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (94.15 mg, 128.33 μmol) and K2CO3 (181.35 mg, 1.71 mmol) were added at 25°C. The resulting mixture was completely degassed and stirred at 110°C for 2 hours under N2 conditions. The progress of the reaction was monitored by LC-MS. o The mixture was cooled to 1°C and diluted with RINKAN and water. The mixture was separated, and the aqueous phase was extracted twice with RINKAN. The combined organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated to obtain a residue, which was purified by silica gel chromatography eluted in a DCM:MeOH ratio of 8:1 to obtain the title compound (compound 15-1-2, 320.00 mg, 723.50 μmol, yield 84.57%) as a yellow oil. MS(m / z) 442.2(M+H) + .

[0323] Step 3: Synthesis of (3-((3-(3,5-difluorophenyl)-5-(1H-indole-2-yl)pyridine-4-yl)amino)propyl)carbamate tert-butyl (compound 15-1-3) To a solution of compound 15-1-2 (240 mg, 542.62 μmol) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (240 mg, 651.15 μmol) in a mixed solvent of dioxane (3 mL) and water (0.3 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (79.63 mg, 108.52 μmol) and K2CO3 (149.99 mg, 1.09 mmol) were added, and the resulting mixture was then heated under N2 conditions at 110°C. o The mixture was stirred in C for 2 hours. The progress of the reaction was monitored by LC-MS. The reactants were divided into 25 o The mixture was cooled to 1°C and diluted with RINKAN and water. The mixture was separated, and the aqueous phase was extracted twice with RINKAN. The combined organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated to obtain the residue, which was purified by silica gel chromatography eluted in a PE:RINKAN ratio of 1:1 to obtain the title compound (compound 15-1-3, 150.00 mg, 313.46 μmol, yield 57.77%) as a yellow solid. MS(m / z) 479.1(M+H) + .

[0324] Step 4: Synthesis of (3-(4-(3,5-difluorophenyl)-6-oxopyrido[4',3':4,5]pyrimido[1,6-a]indole-5(6H)-yl)propyl)carbamate tert-butyl (compound 15-1-4) To a solution of compound 15-1-3 (75 mg, 145.77 μmol) in DMF (2 mL), sodium hydride (17.49 mg, 437.31 μmol, 60% purity) was added at 0°C, and the resulting mixture was stirred at 0°C for 10 minutes. Methyl carbonochloride (42 mg, 437.31 μmol) was added. The reaction solution was 25 oThe mixture was stirred overnight in 1C. The reaction mixture was quenched with 3 mL of saturated aqueous solution (NH4Cl). The resulting solution was extracted with toluene (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. This residue was purified by silica gel chromatography using PE:toluene = 10:1 elution to obtain the title compound 15-1-4 as a yellow solid (30.00 mg, 55.50 μmol, yield 38.08%). MS (m / z) 505.4 (M+H) + .

[0325] Step 5: Synthesis of 5-(3-aminopropyl)-4-(3,5-difluorophenyl)pyrido[4',3':4,5]pyrimido[1,6-a]indole-6(5H)-one (compound 105) To a solution of compound 15-1-4 (30 mg, 59.46 μmol) in DCM (1.5 mL), TFA (1.25 g, 10.92 mmol, 0.5 mL) was added at 25°C, and the resulting mixture was stirred at 25°C for 10 minutes. The progress of the reaction was monitored by LC-MS. The reaction was successful. The solution was concentrated, and the solvent and TFA were removed until dry. Dilution with MeOH and pH adjusted to 7 using Na2CO3 (solid). The solution was purified by preparative HPLC to obtain the title compound 105 (4.00 mg, 7.93 μmol, yield 13.33%) as a white solid.

[0326] The analytical data for compound 105 is provided below. [Table 16]

[0327] Example 16 [ka] Scheme 16 Step 1: Synthesis of 2-(5-bromo-4-chloropyridine-3-yl)-5,6-difluoro-1H-benzo[d]imidazole (compound 16-1-1) To a solution of compound 16-1-SM (3 g, 13.61 mmol) and 4,5-difluorobenzene-1,2-diamine (1.96 g, 13.61 mmol) in tetrahydrofuran (10 mL), acetic acid (163.44 mg, 2.72 mmol) was added, and the mixture was stirred at 25°C for 16 hours under N2. After adding FeCl3 (331.10 mg, 2.04 mmol) at 55°C, the resulting mixture was stirred at 55°C for 16 hours. The reaction was monitored by LC-MS, which indicated that the reaction was complete. The resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography using PE:siRNA=1:1 elution to obtain 2-(5-bromo-4-chloro-3-pyridyl)-5,6-difluoro-1H-benzimidazole (compound 16-1-1, 2.50 g, 5.80 mmol, yield 42.66%, purity 80%) as a yellow solid. MS(m / z)344.0(M+H) + .

[0328] Step 2: Synthesis of (3-((3-bromo-5-(5,6-difluoro-1H-benzo[d]imidazole-2-yl)pyridine-4-yl)amino)propyl)(methyl)carbamate tert-butyl (compound 16-1-2) To a solution of compound 16-1-1 (813.37 mg, 2.12 mmol) and tert-butyl N-(3-aminopropyl)-N-methylcarbamate (400 mg, 2.12 mmol) in N,N-dimethylformamide (3 mL), N,N-diisopropylethylamine (823.77 mg, 6.37 mmol) was added at 25°C, and the resulting mixture was stirred in N2 at 90°C for 4 hours. The reaction was monitored by LC-MS, which indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate (100 mL). It was then extracted with water (50 mL x 2). The aqueous phase was removed and extracted with ethyl acetate (150 mL). All organic phases were combined and dried over anhydrous Na2SO4. The mixture was concentrated and the organic phase was transferred to obtain the crude product. This was purified by silica gel column chromatography (100-200 mesh) with PE:siRNA = 1:1 elution, yielding N-[3-[[3-bromo-5-(5,6-difluoro-1H-benzimidazole-2-yl)-4-pyridylamino]propyl]N-methylcarbamate tert-butyl (compound 16-1-2, 373.00 mg, 728.95 μmol, yield 34.31%, purity 97%) as a yellow solid. MS (m / z) 496.30 (M+H) + .

[0329] Step 3: Synthesis of (3-(4-bromo-9,10-difluoro-6-oxobenzo[4,5]imidazo[1,2-c]pyrido[3,4-e]pyrimidine-5(6H)-yl)propyl)(methyl)carbamate tert-butyl (compound 16-1-3) To a solution of compound 16-1-2 (150 mg, 302.21 μmol) in N,N-dimethylformamide (3 mL), sodium hydride (21.76 mg, 906.62 μmol) was added and the mixture was stirred at 0°C for 0.5 hours. Then, methyl carbonochloride (57.12 mg, 604.42 μmol) was added at 0°C, and the resulting mixture was stirred in N2 at 0°C for 2 hours. The reaction was monitored by LC-MS, which indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate (150 mL). It was then extracted with water (50 mL x 2). The aqueous phase was extracted with ethyl acetate (150 mL). All organic phases were combined and dried over anhydrous Na2SO4. The organic phase was concentrated to obtain the residue, and the crude product was purified by silica gel column (100-200 mesh) chromatography with elution in a DCM:MeOH ratio of 1:1 to obtain (3-(4-bromo-9,10-difluoro-6-oxobenzo[4,5]imidazo[1,2-c]pyrido[3,4-e]pyrimidine-5(6H)-yl)propyl)(methyl)carbamate tert-butyl (compound 16-1-3, 20.00 mg, 34.46 μmol, yield 11.40%, purity 90%) as a yellow oil. MS(m / z) 522.1(M+H) + .

[0330] Step 4: Synthesis of (3-(4-(3,5-difluorophenyl)-9,10-difluoro-6-oxobenzo[4,5]imidazo[1,2-c]pyrido[3,4-e]pyrimidine-5(6H)-yl)propyl)(methyl)carbamate tert-butyl (compound 16-1-4) To a solution of compound 16-1-3 (20 mg, 38.29 μmol) and (3,5-difluorophenyl)boronic acid (7.86 mg, 49.78 μmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.62 mg, 7.66 μmol) and K2CO3 (15.88 mg, 114.87 μmol) were added at 25 °C, and the resulting mixture was stirred in N2 at 120 °C for 2 hours. The reaction was monitored by LC-MS, which indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate (150 mL). It was then extracted with water (50 mL x 2). The aqueous phase was removed and extracted with ethyl acetate (150 mL). All organic phases were combined and dried over anhydrous Na2SO4. The organic phase was concentrated to obtain a residue, which was purified by silica gel column (100-200 mesh) chromatography using PE:SiO=1:3 elution to obtain (3-(4-(3,5-difluorophenyl)-9,10-difluoro-6-oxobenzo[4,5]imidazo[1,2-c]pyrido[3,4-e]pyrimidine-5(6H)-yl)propyl)(methyl)carbamate tert-butyl (compound 16-1-4, 15.00 mg, 24.30 μmol, yield 63.47%, purity 90%) as a yellow oil. MS(m / z) 556.2(M+H) + .

[0331] Step 5: Synthesis of 4-(3,5-difluorophenyl)-9,10-difluoro-5-(3-(methylamino)propyl)benzo[4,5]imidazo[1,2-c]pyrido[3,4-e]pyrimidine-6(5H)-one (compound 106) To a solution of compound 16-1-4 (15 mg, 27.00 μmol) in dichloromethane (1.5 mL), trifluoroacetic acid (0.5 mL) was added at 25°C, and the resulting mixture was stirred at 25°C for 0.5 hours. The reaction solution was diluted with 20 mL of dichloromethane, the organic phase was concentrated, and the above procedure was repeated three times. The crude product was purified by preparative HPLC (preparative C18, 5 μM OBD, 19 × 250 mm, column, Waters, gradient elution from 30% MeCN in water to 50% MeCN in water over 10 minutes, both solvents containing 10 mmol / L NH4HCO3) to obtain compound 106 (4.30 mg, 6.46 μmol, yield 23.91%, purity 98%) as a white solid.

[0332] The analytical data for compound 106 is provided below. [Table 17]

[0333] Example 17 [ka] Scheme 17 Step 1: Synthesis of (E)-(1-(2-(2-ethoxyvinyl)-3-formylpyridine-4-yl)piperidine-4-yl) tert-butyl carbamate (compound 17-1-1) To a solution of compound 17-1-SM (2 g, 5.89 mmol) and 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.40 g, 7.06 mmol) in 1,4-dioxane (10 mL), add K2CO3 (2.44 g, 17.66 mmol) and X-Phos-Pd-G2 (925.21 mg, 1.18 mmol) for 25 minutes. oThe mixture was added with C and stirred in N2 at 100°C for 5 hours. The reaction was monitored by LC-MS and TLC. LC-MS and TLC showed that the starting materials had disappeared. The reaction mixture was concentrated to dryness and diluted with H2O (100 mL). This was then extracted with ethyl acetate (300 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and dried under vacuum to obtain (E)-(1-(2-(2-ethoxyvinyl)-3-formylpyridine-4-yl)piperidine-4-yl) tert-butyl carbamate (compound 17-1-1, 3.00 g, crude product, purity 50%) as a black solid. The crude product was used directly in the next step without further purification. MS (m / z) 376.2 (M+H) + .

[0334] Step 2: Synthesis of (1-(9,10-difluorobenzo[4,5]imidazo[2,1-f][1,6]naphthyridine-1-yl)piperidine-4-yl)carbamate tert-butyl (compound 17-1-2) To a solution of 4,5-difluorobenzene-1,2-diamine (621.84 mg, 4.31 mmol) and compound 17-1-1 (3 g, 3.60 mmol) in THF (6 mL), add 25 units of FeCl3 (1.79 g, 10.79 mmol, 98% purity). o The reaction was carried out by adding 14C and stirring the resulting mixture in N2 at 55°C for 12 hours. The reaction was monitored by LC-MS. LC-MS indicated the disappearance of the starting materials. The reaction mixture was concentrated to dryness and diluted with H2O (100 mL), then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with DCM:MeOH (99 / 1~10 / 1) to obtain (1-(9,10-difluorobenzo[4,5]imidazo[2,1-f][1,6]naphthyridine-1-yl)piperidine-4-yl) tert-butyl carbamate (compound 17-1-2, 200.00 mg, 352.82 μmol, purity 50%) as a yellow solid. MS (m / z) 454.4 (M+H)+ .

[0335] Step 3: Synthesis of (1-(9,10-difluorobenzo[4,5]imidazo[2,1-f][1,6]naphthyridine-1-yl)piperidine-4-yl)carbamate tert-butyl (compound 17-1-3) To a solution of compound 17-1-2 (200 mg, 352.82 μmol) in MeOH (20 mL), Ni (2.07 mg, 35.28 μmol) was added under N2 conditions. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 50°C for 1 hour under an H2 balloon. The reaction was monitored by LC-MS. LC-MS showed that the starting materials had disappeared and the product was clearly detected. The reaction mixture was filtered, the precipitated solid was washed with ethyl acetate (10 mL x 3), and the filtrate was vacuum-dried to obtain compound 17-1-3 (141.00 mg, crude product, purity 80%) as a yellow solid. The crude product was used directly in the next step. MS (m / z) 456.1 (M+H) + .

[0336] Step 4: Synthesis of (1-(9,10-difluoro-2-(3-fluoro-5-methylphenyl)-5,6-dihydrobenzo[4,5]imidazo[2,1-f][1,6]naphthyridine-1-yl)piperidine-4-yl)carbamate tert-butyl (compound 17-1-4) To a solution of compound 17-1-3 (72 mg, 158.07 μmol) in N,N-dimethylformamide (1 mL), N-chlorosuccinimide (42.21 mg, 316.14 μmol) was added at 25°C, and the resulting mixture was stirred at 40°C for 1 hour. The reaction was monitored by LC-MS. LC-MS indicated the disappearance of the starting materials. The reaction mixture was diluted with water (20 mL) and then extracted with ethyl acetate (20 mL x 2). All organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated to obtain a residue, which was the crude compound 17-1-4 (66.00 mg, crude product, purity 50%) as a yellow solid. MS (m / z) 490.2 (M+H) + .

[0337] Step 5: Synthesis of (1-(9,10-difluoro-2-(3-fluoro-5-methylphenyl)-5,6-dihydrobenzo[4,5]imidazo[2,1-f][1,6]naphthyrizin-1-yl)piperizin-4-yl)carbamate tert-butyl (compound 17-1-5) To a solution of compound 17-1-4 (66 mg, 67.35 μmol) and (3-fluoro-5-methylphenyl)boronic acid (12.44 mg, 80.83 μmol) in 1,4-dioxane (1 mL) and H2O (0.25 mL), K2CO3 (27.93 mg, 202.06 μmol) and X-Phos-Pd-G2 (10.59 mg, 13.47 μmol) were added at 25°C, and the resulting mixture was stirred in N2 at 110°C for 1 hour. The reaction was monitored by LC-MS. LC-MS indicated the disappearance of the starting materials. The reaction products were extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using PE:Â=5:1 elution to obtain compound 17-1-5 (22.00 mg, 37.08 μmol, yield 55.06%, purity 95%) as a yellow solid. MS(m / z)564.3(M+H) + .

[0338] Step 6: Synthesis of 1-(9,10-difluoro-2-(3-fluoro-5-methylphenyl)-5,6-dihydrobenzo[4,5]imidazo[2,1-f][1,6]naphthyridine-1-yl)piperidine-4-amine (compound 107) To a solution of compound 17-1-5 (22 mg, 39.03 μmol) in dichloromethane (1 mL), trifluoroacetic acid (4.45 mg, 39.03 μmol) was added at 25°C, and the resulting mixture was stirred at 25°C for 2 hours. The reaction was monitored by TLC. TLC indicated the disappearance of the starting materials. The reaction solution was diluted with 20 mL of dichloromethane to concentrate the organic phase, and the above procedure was repeated three times. The crude product was purified by preparative HPLC (preparative C18, 5 μM OBD, 19 × 250 mm, column, Waters, gradient elution from 40% MeCN in water to 50% MeCN in water over 9 minutes, both solvents containing 10 mmol / L NH4HCO3) to obtain compound 107 (5.00 mg, 9.71 μmol, yield 24.87%, purity 98.28%) as a white solid.

[0339] The analytical data for compound 107 is provided below. [Table 18]

[0340] Example 18 [ka] Scheme 18 Step 1: Synthesis of Compound 18-1-1 To a solution of compound 18-1-SM (cas: 1060802-24-5, 3g, 13.61 mmol) and 4,5-difluorobenzene-1,2-diamine (1.96g, 13.61 mmol) in THF (10 mL), acetic acid (163.44 mg, 2.72 mmol) was added under N2 conditions at 25°C for 16 hours. After adding ferric trichloride (331.10 mg, 2.04 mmol) at 55°C, the resulting mixture was stirred at 55°C for 16 hours. The reaction mixture was diluted with ethyl acetate (150 mL). It was then extracted with water (50 mL x 2). The aqueous phase was removed and extracted with ethyl acetate (150 mL). All organic phases were combined and dried over anhydrous Na2SO4. The organic phase was concentrated to obtain the crude product. The crude product was purified by chromatography using a silica gel column (100-200 mesh) with PE:siRNA = 1:1 elution, yielding compound 18-1-1 (2.50 g, 5.80 mmol, yield 42.66%, purity 80%) as a yellow solid. MS (m / z) 344.0 (M+H) + .

[0341] Step 2: Synthesis of Compound 18-1-2 To a solution of compound 18-1-1 (1 g, 2.90 mmol) and SEM-Cl (629.06 mg, 3.77 mmol) in N,N-dimethylformamide (10 mL), sodium hydride (208.97 mg, 8.71 mmol) was added at 0°C, and the resulting mixture was stirred in N2 at 0°C for 2 hours. The reaction mixture was diluted with ethyl acetate (50 mL). It was then extracted with water (50 mL x 2). The aqueous phase was detached and extracted with ethyl acetate (150 mL). All organic phases were combined and dried over anhydrous Na2SO4. The organic phase was concentrated to obtain the crude product, which was purified by silica gel column (100-200 mesh) chromatography with PE:siRNA = 3:1 elution to obtain compound 18-1-2 (800.00 mg, 1.65 mmol, yield 56.89%, purity 98%) as a yellow solid. MS (m / z) 474.20 (M+H) + .

[0342] Step 3: Synthesis of Compound 18-1-3 To a solution of compound 18-1-2 (800 mg, 1.68 mmol) and tert-butyl N-(3-aminopropyl)carbamate (440.37 mg, 2.53 mmol) in DMF (6 mL), DIPEA (653.29 mg, 5.05 mmol) was added at 25°C, and the resulting mixture was stirred in N2 at 80°C for 5 hours. The resulting solution was extracted three times with EA (60 mL) and H2O (20 mL). The combined organic layer was dried over Na2SO4 and concentrated. The crude product was purified by silica gel column chromatography (100-200 mesh) with PE:siRNA = 1:1 elution to obtain compound 18-1-3 (780.00 mg, 1.25 mmol, yield 74.06%, purity 98%) as a yellow oil. MS (m / z) 612.40 (M+H) + .

[0343] Step 4: Synthesis of Compound 18-1-4 To a solution of compound 18-1-3 (300 mg, 489.73 μmol) and (5-fluoro-2-formylphenyl)boronic acid (98.69 mg, 587.68 μmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL), Pd(dppf)Cl2 (71.87 mg, 97.95 μmol) and K2CO3 (203.05 mg, 1.47 mmol) were added at 25 °C, and the resulting mixture was stirred at 120 °C for 2 hours under N2 conditions. The reaction mixture was diluted with ethyl acetate (150 mL). It was then extracted with water (50 mL x 2). The aqueous phase was detached and extracted with ethyl acetate (150 mL). All organic phases were combined and dried over anhydrous Na2SO4. The organic phase was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (100-200 mesh) elution with PE:siRNA = 1:4 to obtain compound 18-1-4 (200.00 mg, 297.92 μmol, yield 60.83%, purity 95%) as a yellow solid. MS (m / z) 638.3 (M+H) + .

[0344] Step 5: Synthesis of Compound 18-1-5 To a solution of compound 18-1-4 (100 mg, 156.80 μmol) in methanol (6 mL), Raney Ni (9.20 mg, 156.80 μmol) was added at 25 °C. The resulting mixture was stirred under H2 at 50 °C for 14 hours. The reaction mixture was filtered to remove the solid, which was washed with MeOH (25 mL x 3). The filtrates were combined, and the organic phase was dried under vacuum to obtain compound 18-1-5 (65.00 mg, crude product) as a yellow solid. MS (m / z) 640.2 (M+H) + .

[0345] Step 6: Synthesis of Compound 108 To a solution of compound 18-1-5 (75 mg, 117.60 μmol) in trifluoroacetic acid (8 mL), dichloromethane (5 mL) was added at 25°C, and the resulting mixture was stirred at 25°C for 20 hours. The reaction solution was diluted with 20 mL of dichloromethane to concentrate the organic phase, and the above procedure was repeated three times. The crude product was purified by preparative HPLC (preparative C18, 5 μM OBD, 19 × 250 mm, column, Waters, gradient elution from 20% MeCN in water to 30% MeCN in water over 10 minutes, both solvents containing 10 mmol / L FA) to obtain target compound 108 (25.55 mg, 61.78 μmol, yield 52.54%, purity 99%) as a white solid.

[0346] The analytical data for compound 108 is provided below. [Table 19]

[0347] Example 19 [ka] Scheme 19 Step 1: Synthesis of N-[(Z)-3-[4-[(3,4-difluorophenyl)carbamoyl]-9-fluoro-6H-benzo[c][1,6]naphthyrizin-5-yl]-1-methyl-allyl]carbamate tert-butyl (compound 19-1-1) To a solution of compound 19-1-SM-2 (1 g, 7.75 mmol) and compound 19-1-SM-1 (1.46 g, 9.29 mmol) in DMF (8 mL), HATU (2.95 g, 7.75 mmol) and DIPEA (3.00 g, 23.24 mmol) were added at 25°C. The resulting mixture was then stirred at 25°C for 2 hours. The reaction was monitored by LC-MS. LC-MS indicated the disappearance of the main starting material. Water was added until a large amount of solid was observed. The precipitated solid was collected, washed with H2O (20 mL x 3), and dried under vacuum to obtain 4-chloro-N-(3,4-difluorophenyl)pyridine-3-carboxamide (compound 19-1-1, 1.83 g, 5.45 mmol, yield 70.36%, purity 80%) as a yellow solid. The crude product was used directly in the next step. MS (m / z) 269.1 (M+H) + .

[0348] Step 2: Synthesis of N-[3-[[3-[(3,4-difluorophenyl)carbamoyl]-4-pyridyl]amino]-1-methyl-propyl]carbamate tert-butyl (compound 19-1-2) To a solution of compound 19-1-1 (356.74 mg, 1.06 mmol) and tert-butyl N-(3-amino-1-methyl-propyl)carbamate (200 mg, 1.06 mmol) in dimethyl sulfoxide (1 mL), DIPEA (411.88 mg, 3.19 mmol) was added at 25 °C, and the resulting mixture was stirred at 120 °C for 2.5 hours. Completion of the reaction was detected by LC-MS, which indicated that the reaction had proceeded completely successfully. The reaction mixture was diluted with H₂O (15 mL) and SiO₂ (15 mL). The mixture was extracted with ethyl acetate (25 mL x 2). The combined organic layer was washed with brine (15 mL), dried over Na₂SO₄, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE:SiO(100 / 0~60 / 40) to obtain N-[3-[[3-[(3,4-difluorophenyl)carbamoyl]-4-pyridyl]amino]-1-methyl-propyl]carbamate tert-butyl (compound 19-1-2, 187.00 mg, 435.86 μmol, yield 41.03%, purity 98%) as a yellow solid. MS(m / z)421.2(M+H) + .

[0349] Step 3: Synthesis of N-[3-[[3-chloro-5-[(3,4-difluorophenyl)carbamoyl]-4-pyridyl]amino]-1-methyl-propyl]carbamate tert-butyl (compound 19-1-3) To a solution of compound 19-1-2 (120 mg, 279.70 μmol) in N,N-dimethylformamide (0.5 mL), NCS (112.04 mg, 839.10 μmol) was added at 25°C, and the resulting mixture was stirred at 30°C for 8 hours. The reaction was monitored by LC-MS. LC-MS showed that the starting materials had disappeared and the product was clearly detected. The reaction mixture was diluted with H2O (15 mL). This was then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE:SiO(100 / 0~64 / 36) to obtain N-[3-[[3-chloro-5-[(3,4-difluorophenyl)carbamoyl]-4-pyridyl]amino]-1-methyl-propyl]carbamate tert-butyl (compound 19-1-3, 115.00 mg, 247.75 μmol, yield 88.58%, purity 98%) as a yellow solid. MS(m / z)454.9(M+H) + .

[0350] Step 4: Synthesis of N-[(Z)-3-[4-[(3,4-difluorophenyl)carbamoyl]-9-fluoro-6H-benzo[c][1,6]naphthyrizin-5-yl]-1-methyl-allyl]carbamate tert-butyl (compound 19-1-4) To a mixture of compound 19-1-3 (100 mg, 219.83 μmol) and (5-fluoro-2-formylphenyl)boronic acid (44.30 mg, 263.80 μmol) in 1,4-dioxane (2 mL) and water (0.1 mL), XPhosPdG2 (17.27 mg, 21.98 μmol) and K2CO3 (91.01 mg, 659.49 μmol) were added at 25°C. The resulting mixture was degassed and then stirred at 110°C for 3 hours under N2. The reaction mixture was concentrated to dryness. The crude product was purified by silica gel chromatography eluted with PE:SiO(100 / 0~1 / 1) to obtain N-[(Z)-3-[4-[(3,4-difluorophenyl)carbamoyl]-9-fluoro-6H-benzo[c][1,6]naphthyrizin-5-yl]-1-methyl-allyl]carbamate tert-butyl (compound 19-1-4, 67.00 mg, 122.62 μmol, yield 55.78%, purity 96%) as a yellow solid. MS(m / z)525.2(M+H) + .

[0351] Step 5: Synthesis of tert-butyl [3-[4-[(3,4-difluorophenyl)carbamoyl]-N9-fluoro-6H-benzo[c][1,6]naphthyrizin-5-yl]-1-methyl-propyl]carbamate (compound 19-1-5) To a solution of compound 19-1-4 (50 mg, 95.32 μmol) in MeOH (10 mL), Raney Ni (100 mg) was added under N2 conditions, and the suspension was then completely degassed under H2 conditions. The mixture was stirred under an H2 balloon at 50°C for 5 hours. The reaction was monitored by LC-MS. LC-MS indicated that the starting materials had disappeared. The reaction was completely successful. The reaction mixture was filtered, the precipitated solid was washed with MeOH (20 mL x 3), and the filtrate was vacuum-dried to obtain [3-[4-[(3,4-difluorophenyl)carbamoyl]-N9-fluoro-6H-benzo[c][1,6]naphthyrizin-5-yl]-1-methyl-propyl]carbamate tert-butyl (compound 19-1-5, 33.00 mg, crude product) as a white solid. The crude product was used directly in the next step. MS (m / z) 527.3 (M+H) + .

[0352] Step 6: Synthesis of 5-(3-aminobutyl)-N-(3,4-difluorophenyl)-9-fluoro-6H-benzo[c][1,6]naphthyridine-4-carboxamide (compound 109) A solution of compound 19-1-5 (33 mg, 53.90 μmol) in dichloromethane (1 mL) and TFA (0.5 mL) was stirred at 25°C for 2 hours. The reaction was monitored by LC-MS. LC-MS indicated that the starting material had disappeared. Excess dichloromethane was added to a vacuum rotary evaporator. The crude product was purified by preparative HPLC (preparative C18, 5 μM OBD, 19 × 250 mm column, Waters, gradient elution from 40% MeCN in water to 50% MeCN in water over 9 minutes, both solvents containing 10 mmol / L NH4HCO3) to obtain 5-(3-aminobutyl)-N-(3,4-difluorophenyl)-9-fluoro-6H-benzo[c][1,6]naphthyridine-4-carboxamide (compound 109, 15.00 mg, 34.12 μmol, yield 63.31%, purity 97%) as a white solid.

[0353] The analytical data for compound 109 is provided below. [Table 20]

[0354] Example 20 [ka] Scheme 20 Step 1: Synthesis of Compound 20-1-2 To a solution of compound 20-1-1 (2 g, 9.71 mmol) in dimethyl sulfoxide (8 mL), tert-butyl piperidine-4-ylcarbamate (2.92 g, 14.56 mmol) was added at 25 °C, and the resulting mixture was stirred in N2 at 120 °C for 2 hours. The progress of the reaction was monitored by LC-MS. The reaction mixture was diluted with H2O (20 mL) and ethyl acetate (20 mL). The mixture was separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. This residue was purified by silica gel chromatography eluted with 20 / 1 to 4 / 1 PE / siRNA to obtain compound 20-1-2 (2.50 g, 6.08 mmol, yield 62.67%, purity 90%) as a white solid. MS (m / z) 369.9 (M+H) + .

[0355] Step 2: Synthesis of Compound 20-1-3 To a solution of compound 20-1-2 (1 g, 2.70 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (499.72 mg, 3.24 mmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL), potassium carbonate (934.25 mg, 6.76 mmol) and xanthophos Pd G2 (224.08 mg, 270.39 μmol) were added at 25°C, and the resulting mixture was stirred in N2 at 110°C for 2 hours. The progress of the reaction was monitored by LC-MS. After cooling to room temperature, the reaction mixture was quenched with H2O (20 mL). This was then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography with PE / Âxie elution at a ratio of 10 / 1 to 1 / 1 to obtain compound 20-1-3 (500.00 mg, 1.38 mmol, yield 51.16%, purity 100%) as a yellow solid. MS(m / z)362.0(M+H) + .

[0356] Step 3: Synthesis of Compound 20-1-4 Compound 20-1-3 (300 mg, 830.03 μmol) and 3,4-difluoroaniline (535.81 mg, 4.15 mmol) were dissolved in toluene (3 mL) and acetic acid (1 mL) at 25°C, and the resulting mixture was stirred in N2 at 110°C for 4 hours. The progress of the reaction was monitored by LC-MS. LC-MS indicated the disappearance of the starting materials. Reaction mixture 25 o The mixture was cooled to 1°C and quenched with H2O (20 mL). The mixture was then separated, and the aqueous phase was washed twice with ethyl acetate. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to obtain the residue. This residue was purified by silica gel chromatography eluted with 1 / 1 to 1 / 1 PE / siRNA to obtain compound 20-1-4 (45.00 mg, 78.52 μmol, yield 9.46%, purity 80%) as a yellow oil. MS (m / z) 458.9 (M+H) + .

[0357] Step 4: Synthesis of Compound 20-1-5 To a solution of compound 20-1-4 (45 mg, 109.05 μmol) in DMF (1.5 mL), NCS (21.84 mg, 163.58 μmol) was added at 25°C, and the resulting mixture was stirred at 30°C for 2 hours. The progress of the reaction was monitored by LC-MS. LC-MS indicated the disappearance of the starting materials. The reaction mixture was cooled to room temperature and quenched with H2O (20 mL). The mixture was then separated, and the aqueous phase was separated twice with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to obtain a residue. This residue was purified by silica gel chromatography eluted with 30 / 1 to 8 / 1 PE / siRNA to obtain compound 20-1-5 (40.00 mg, 81.14 μmol, yield 74.41%) as a yellow solid. MS (m / z) 469.2 (M+H) + .

[0358] Step 5: Synthesis of Compound 20-1-6 To a solution of compound 20-1-5 (40 mg, 81.14 μmol) and (3,5-difluorophenyl)boronic acid (19.22 mg, 121.72 μmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL), K2CO3 (28.04 mg, 202.86 μmol) and G2-Xphos-Pd (10.09 mg, 12.17 μmol) were added at 25°C, and the resulting mixture was stirred in N2 at 110°C for 2 hours. The progress of the reaction was monitored by LC-MS. LC-MS indicated the disappearance of the starting materials. The reaction mixture was cooled to 25°C and quenched with H2O (20 mL). The mixture was then separated, and the aqueous phase was separated twice with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated to obtain a residue. This residue was purified by silica gel chromatography, where PE / siRNA eluted the compound 20-1-6 (20.00 mg, 35.05 μmol, yield 43.20%) as a yellow oil. MS(m / z) 571.2(M+H) + .

[0359] Step 6: Synthesis of target compound 110 To a solution of compound 20-1-6 (20 mg, 35.05 μmol) in DCM (2.53 mL), TFA (707.63 mg, 6.21 mmol, 474.92 μL) was added at 25°C, and the resulting mixture was stirred at 25°C for 2 hours. The reaction solution was diluted with 20 mL of dichloromethane to concentrate the organic phase, and the above procedure was repeated three times. The crude product was purified by preparative HPLC (preparative C18, 5 μM OBD, 19 × 250 mm, column, Waters, gradient elution from 40% MeCN in water to 50% MeCN in water over 9 minutes, both solvents containing 10 mmol / L NH4HCO3) to obtain compound 110 (7.50 mg, 15.94 μmol, yield 45.48%, purity 100%) as a colorless oil.

[0360] Compounds 110-116 were synthesized according to the six-step procedure described in Example 20. The analytical data for compounds 110-116 are provided below. [Table 21-1] [Table 21-2]

[0361] Example 21 [ka] Scheme 21 Step 1: Synthesis of Compound 21-1-1 To a solution of compound 21-1-SM (1 g, 6.35 mmol) and 3,4-difluoroaniline (901.39 mg, 6.98 mmol) in DMF (5 mL), HATU (2.43 g, 6.35 mmol) and DIPEA (2.46 g, 19.04 mmol) were added at 25°C, and the resulting mixture was stirred in N2 at 25°C for 2 hours. The reaction was monitored by LC-MS, which indicated that the reaction was complete. 20 mL of water was added to the reaction solution, and the solid was collected by filtration. This was the white solid compound 21-1-1 (1.46 g, 4.88 mmol, yield 76.93%, purity 89.84%). MS (m / z) 269.0 (M+H) + .

[0362] Step 2: Synthesis of Compound 21-1-2 To a solution of compound 21-1-1 (800 mg, 2.98 mmol) and tert-butyl N-(3-aminopropyl)-N-methylcarbamate (2.80 g, 14.89 mmol) in DMSO (2 mL), DIPEA (1.92 g, 14.89 mmol) was added at 25 °C, and the resulting mixture was stirred at 120 °C for 2 hours. The reaction was monitored by LC-MS, which indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate (100 mL) and water (50 mL). The aqueous phase was extracted twice with ethyl acetate (100 mL). All organic phases were combined and dried over anhydrous Na₂SO₄. The organic phase was concentrated to obtain the crude product, which was then purified by silica gel column chromatography (100-200 mesh) with elution at PE / siRNA = 4 / 1 to obtain compound 21-1-2 (1.03 g, 2.34 mmol, yield 78.49%, purity 95.14%) as a yellow solid. MS (m / z) 421.2 (M+H) + .

[0363] Step 3: Synthesis of Compound 21-1-3 A solution of compound 21-1-2 (600 mg, 1.43 mmol) and NCS (571.67 mg, 4.28 mmol) in DMF (5 mL) at 25°C was prepared, and the resulting mixture was stirred at 30°C for 12 hours. The reaction was monitored by LC-MS, which indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate (100 mL) and water (50 mL). The aqueous layer was extracted twice with ethyl acetate (60 mL). All organic phases were combined and dried over anhydrous Na₂SO₄. The organic phases were concentrated to obtain the crude product, which was purified by silica gel column chromatography eluted at DCM / MeOH = 1 / 1 to obtain the title compound (compound 21-1-3, 400 mg, 854.35 μmol, yield 59.87%, purity 97.16%) as a brown oil. MS (m / z) 454.9 (M+H) + .

[0364] Step 4: Synthesis of Compound 21-1-4 To a solution of compound 21-1-3 (200 mg, 439.66 μmol) and (3,5-difluorophenyl)boronic acid (104.14 mg, 659.49 μmol) in 1,4-dioxane (10 mL) and water (1 mL), K2CO3 (182.29 mg, 1.32 mmol) and X-Phox-Pd-G2 (34.59 mg, 43.97 μmol) were added at 25 °C, and the resulting mixture was stirred at 110 °C for 1 hour under N2 conditions. The reaction was monitored by LC-MS, which indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate (60 mL). This was then extracted with water (20 mL x 2). The aqueous phase was removed and extracted with ethyl acetate (50 mL). All organic phases were combined and dried over anhydrous Na2SO4. The organic phase was concentrated to obtain the crude product, which was purified by silica gel column chromatography (100-200 mesh) with elution in a DCM:MeOH ratio of 10:1 to obtain the title compound (compound 21-1-4, 186.00 mg, 337.30 μmol, yield 76.72%, purity 96.57%) as a yellow oil. MS (m / z) 533.2 (M+H) + .

[0365] Step 5: Synthesis of Compound 117 Compound 21-1-4 (50 mg, 93.89 μmol) was added to a methanol-hydrochloric acid solution (1 mL) and a solution of compound 21-1-4 in DCM (5 mL) at 25°C, and the resulting mixture was stirred at 40°C for 1 hour. The reaction was monitored by LC-MS, which indicated that the reaction was complete. The organic phase was concentrated to obtain the crude product. The crude product was washed with 5 mL of dichloromethane, and the above procedure was repeated three times. The mixture was concentrated to obtain compound 117 (22.77 mg, 49.85 μmol, yield 53.09%, purity 94.67%) as a gray solid.

[0366] Step 6: Synthesis of Compound 21-1-5 To a solution of compound 21-1-4 (100 mg, 187.78 μmol) and bis(2,5-dioxopyrrolidine-1-yl) carbonate (230.90 mg, 901.36 μmol) in DMF (2 mL), sodium hydride (36.05 mg, 901.36 μmol) was added at 25 °C, and the resulting mixture was stirred in N2 at 60 °C for 6 hours. The reaction was monitored by LC-MS, which indicated that the reaction was complete. The reaction mixture was diluted with ethyl acetate (30 mL). This was then extracted with water (10 mL x 2). The aqueous phase was removed and extracted with ethyl acetate (300 mL). All organic phases were combined, dried over anhydrous Na2SO4, filtered, and the organic phases were concentrated to obtain the crude product. This was purified by silica gel column chromatography using DCM:MeOH=10:1 elution to obtain the title compound (compound 21-1-5, 12.00 mg, 20.85 μmol, yield 11.51%, purity 97.04%) as a white solid. MS(m / z)559.2(M+H) + .

[0367] Step 7: Synthesis of Compound 118 Compound 21-1-5 (12 mg, 21.49 μmol) was added to a methanol hydrochloric acid solution (1 mL) and a solution of compound 21-1-5 in DCM (5 mL) at 25°C, and the resulting mixture was stirred at 40°C for 2 hours. The reaction was monitored by LC-MS, which indicated that the reaction was complete. The reactants were concentrated directly to obtain the crude product. The crude product was washed with 5 mL of dichloromethane, and the above procedure was repeated three times. Concentration yielded compound 118 (9.00 mg, 19.63 μmol, yield 91.38%, purity 100%) as a gray solid.

[0368] The analytical data for compounds 117 and 118 are provided below. [Table 22]

[0369] Example 22 [ka] Scheme 22 Step 1: Synthesis of Compound 22-1-1 To a solution of compounds 22-1-SM-1 (1 g, 4.21 mmol) and 22-1-SM-2 (1.01 g, 5.05 mmol) in THF (10 mL), TEA (1.28 g, 12.63 mmol) was added at 25 °C, and the resulting mixture was stirred at 0 °C for 1 hour. Water (50 mL) and saturated salt solution (15 mL) were added to the reaction mixture, and then extracted with EA (50 mL x 3). The combined organic layer was dried over Na2SO4 and concentrated to obtain the crude product compound 22-1-1 (1.82 g). MS (m / z) 403.0 (M+H) + .

[0370] Step 2: Synthesis of Compound 22-1-2 To a solution of compound 22-1-1 (500 mg, 1.25 mmol) and (3-fluoro-5-methylphenyl)boronic acid (6-5, 230.20 mg, 1.50 mmol) in 1,4-dioxane (2 mL), Pd(dppf)Cl2 (91.43 mg, 124.61 μmol) and K2CO3 (516.65 mg, 3.74 mmol) were added at 25°C, and the resulting mixture was stirred in N2 at 120°C for 2 hours. The crude product was purified by silica gel chromatography (100-200 mesh) eluted with PE:siRNA (100:1-72:28) to obtain compound 22-1-2 (576.00 mg, 1.20 mmol, yield 96.64%, purity 90%) as a yellow solid. MS(m / z)431.3(M+H) + .

[0371] Step 3: Synthesis of Compound 22-1-3 To a solution of compound 22-1-2 (556 mg, 1.29 mmol) in EtOH (15 mL) and saturated NH4Cl (69.09 mg, 1.29 mmol), Fe (721.36 mg, 12.92 mmol) was added at 25°C, and the resulting mixture was stirred at 80°C for 2 hours. Water (50 mL) and saturated salt solution (15 mL) were added to the reaction mixture, and then extracted with EA (50 mL x 3). The combined organic layer was dried over Na2SO4 and then concentrated to obtain the crude product compound 22-1-3 (409 mg). MS (m / z) 401.3 (M+H) + .

[0372] Step 4: Synthesis of Compound 22-1-4 To a solution of compound 22-1-3 (80 mg, 199.76 μmol) in DCM (5 mL), chlorobenzenecarboperoxoic acid (51.71 mg, 299.63 μmol) was added at 25°C, and the resulting mixture was stirred at 0°C for 10 hours. The reaction mixture was diluted with ethyl acetate (150 mL). This was then extracted with water (50 mL x 2). The aqueous phase was detached and extracted with ethyl acetate (150 mL). All organic phases were combined and dried over anhydrous Na₂SO₄. The organic phases were concentrated to obtain the crude product. The crude product was purified by silica gel column (100-200 mesh) chromatography eluted with DCM:MeOH (15:1) to obtain compound 22-1-4 (41.00 mg, 96.67 μmol, yield 48.39%, purity 98.20%) as a yellow solid. MS (m / z) 417.3 (M+H) + .

[0373] Step 5: Synthesis of Compound 22-1-5 To a solution of compound 22-1-4 (41 mg, 98.44 μmol) and 1,3-bis(bromomethyl)benzene (38.98 mg, 147.66 μmol) in tetrahydrofuran (2 mL), NaH (7.09 mg, 295.33 μmol) was added at 25 °C, and the resulting mixture was stirred at 40 °C for 16 hours. The reaction mixture was diluted with ethyl acetate (30 mL). This was then extracted with water (10 mL x 2). The aqueous phase was removed and extracted with ethyl acetate (30 mL). All organic phases were combined and dried over anhydrous Na₂SO₄. The organic phases were concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (100-200 mesh) eluted with DCM:MeOH (30:1) to obtain compound 22-1-5 (10.00 mg, 18.36 μmol, yield 18.65%, purity 92.28%) as a yellow solid. MS (m / z) 503.3 (M+H) + .

[0374] Step 6: Synthesis of Compound 119 To a solution of compound 22-1-5 (10 mg, 19.90 μmol) in DCM (5 mL), methanol hydrochloric acid solution (1 mL) was added at 25°C, and the resulting mixture was stirred at 40°C for 3 hours. The reaction solution was diluted with dichloromethane (20 mL), the organic phase was concentrated, and the above procedure was repeated three times. The crude product was purified with tert-butyl methyl ether to obtain compound 119 (3.02 mg, 7.17 μmol, yield 36.06%, purity 95.62%) as a brown solid.

[0375] The analytical data for compound 119 is provided below. [Table 23]

[0376] Example 23 [ka] Scheme 23 Step 1: Synthesis of Compound 23-1-3 A mixture of compound 23-1-1 (2.12 g, 12 mmol), compound 23-1-2 (1.75 g, 12.00 mmol), and AcOH (3.6 g, 60.00 mmol) in tetrahydrofuran (20 mL) was stirred at 60°C for 2 hours under N2. Then, FeCl3 (7.78 g, 48.00 mmol) was added at 25°C. The mixture was stirred at 60°C under N2. o The mixture was stirred in 1C for 2 hours. Water (10 mL) was added, and the reaction mixture was then extracted with EA (50 mL x 2). The combined organic phase was dried over Na2SO4, filtered, concentrated, and purified by silica gel column (100-200 mesh) chromatography using PE:EA (100:0-3:1) to obtain compound 23-1-3 (2.3 g, 7.69 mmol, yield 64.10%) as a yellow solid. MS (m / z) 300.1 (M+H) + .

[0377] Step 2: Synthesis of Compound 23-1-5 A solution of compound 23-1-3 (2.30 g, 7.69 mmol), compound 23-1-4 (2.00 g, 9.99 mmol), and N,N-diisopropylethylamine (2.48 g, 19.23 mmol) in DMSO (20 mL) was stirred at 120 °C for 2 hours. Water was added, and the mixture was then filtered and washed with PE to obtain crude compound 23-1-5 (2.8 g, yield 78.65%) as a yellow solid. MS (m / z) 464.1 (M+H) + .

[0378] Step 3: Synthesis of Compound 23-1-7 A mixture of compound 23-1-5 (2.8g, 6.05 mmol), compound 23-1-6 (1.24g, 9.07 mmol), Pd2(dba)3 (1.11g, 1.21 mmol), ruphos (1.13g, 2.42 mmol), and sodium 2-methylpropane-2-oleate (1.45g, 15.13 mmol) in DMSO (20 mL) was heated under N2 conditions at 100°C. o Stirred in C for 2 hours. Mixture 25 o Cool to C, then add (Boc)2O (2.64g, 12.1 mmol) and mix 25o The mixture was stirred in C for 1 hour. Water (50 mL) was added, and the reaction mixture was then extracted with EA (80 mL x 2). The combined organic phase was dried over Na2SO4, filtered, concentrated, and purified by silica gel column (100-200 mesh) chromatography using PE:EA (100:0-1:1) to obtain compound 23-1-7 (800 g, 1.21 mmol, yield 20.00%) as a yellow solid. MS (m / z) 664.9 (M+H) + .

[0379] Step 4: Synthesis of Compound 23-1-8 A mixture of compound 23-1-7 (800 mg, 1.21 mmol) and NBS (248.46 mg, 1.45 mmol) in DCM (12 mL) is 0 o The mixture was stirred in C for 1 hour. Water (15 mL) was added, and the reaction mixture was then extracted with EA (20 mL x 2). The combined organic phase was dried over Na2SO4, filtered, concentrated, and purified by silica gel column (100-200 mesh) chromatography using PE:EA (100:0-2:1) to obtain compound 23-1-8 (350 g, 0.47 mmol, yield 38.84%) as a yellow solid. MS (m / z) 743.3 (M+H) + .

[0380] Step 5: Synthesis of Compound 23-1-9 A mixture of compounds 23-1-8 (350 mg, 0.47 mmol) and DDQ (106.69 mg, 0.47 mmol) in DCM (12 mL) is used. o The mixture was stirred in C for 1 hour. The reaction mixture was filtered and purified by silica gel column chromatography (100-200 mesh) eluted with PE:EA (100:0-2:1) to obtain compound 23-1-9 (150 g, 0.24 mmol, yield 51.31%) as a yellow solid. MS (m / z) 623.1 (M+H) + .

[0381] Step 6: Synthesis of Compound 23-1-11 A mixture of compounds 23-1-9 (150 mg, 0.24 mmol), 23-1-10 (80.64 mg, 0.48 mmol), Xphos-Pd-G4 (30.96 mg, 0.036 mmol), and K3PO4 (127.20 mg, 0.60 mmol) in dioxane (10 mL) and water (2 mL) was heated under N2 conditions at 95°C. o The mixture was stirred in 1C for 0.5 hours. The reaction mixture was concentrated and purified by preparative TLC (DCM / MeOH = 20 / 1) to obtain compound 23-1-11 (15 mg, 0.027 mmol, yield 11.41%) as a yellow solid. MS (m / z) 549.2 (M+H) + .

[0382] Step 7: Synthesis of Compound 120 A mixture of compound 23-1-11 (15 mg, 0.027 mmol) in DCM (2 mL) and TFA (2 mL) is prepared. o The mixture was stirred in 1C for 1 hour. The reaction mixture was concentrated and purified by reserved-phase column (MeOH / H2O=3 / 7) and preparative TLC (DCM / MeOH=5 / 1) to obtain compound 120 (4.06 mg, 0.009 mmol, yield 33.33%) as a white solid.

[0383] The analytical data for compound 120 is provided below. [Table 24]

[0384] Example 24 [ka] Scheme 24 Step 1: Synthesis of tert-butyl (1-(2-chloro-5-formylpyridine-4-yl)piperidine-4-yl)carbamate (compound 24-1-2) To a stirred solution of 4,6-dichloronicotinaldehyde (compound 24-1-1, 10 g, 56.8 mmol, 1 equivalent) in MeCN (150 ml), tert-butyl piperidine-4-ylcarbamate (11.36 g, 56.8 mmol, 1 equivalent) and DIPEA (36.64 g, 284 mmol, 5 equivalents) were added at 20°C. The reaction mixture was stirred at 20°C for 16 hours. TLC (PE:siRNA = 1:1) indicated that the reaction was complete. The reaction mixture was diluted with siRNA (700 mL), washed with H2O (500 mL x 3), dried over Na2SO4, and evaporated to obtain the residue. The residue was purified by column chromatography using silica gel eluted with PE / siRNA (100:1~1:1) to obtain tert-butyl (1-(2-chloro-5-formylpyridine-4-yl)piperidine-4-yl)carbamate (compound 24-1-2, 8 g, 23.53 mmol, 42%) as a white solid. MS (m / z) 340.3 (M+H) + .

[0385] Step 2: (1-(5-formyl-2-methoxypyridine-4-yl)piperidine-4-yl) tert-butyl carbamate (compound 24-1-3) To a stirred solution of (1-(2-chloro-5-formylpyridine-4-yl)piperidine-4-yl)carbamate tert-butyl (compound 24-1-2, 8 g, 23.53 mmol, 1 equivalent) in MeOH (150 ml, 100.0%), MeONa (5.08 g, 94.12 mmol, 4 equivalents) was added at 0°C. The reaction mixture was stirred at 60°C for 3 hours. TLC (PE:siRNA = 1:1) indicated that the reaction was complete. The reaction mixture was diluted with siRNA (700 mL), washed with H2O (500 mL x 3), dried over Na2SO4, and evaporated to obtain (1-(5-formyl-2-methoxypyridine-4-yl)piperidine-4-yl)carbamate tert-butyl (7 g, 20.9 mmol, 88%) as a white solid. MS (m / z) 336.3 (M + H) + .

[0386] Step 3: Synthesis of tert-butyl (1-(3-bromo-5-formyl-2-methoxypyridine-4-yl)piperidine-4-yl)carbamate (compound 24-1-4) To a stirred solution of (1-(5-formyl-2-methoxypyridine-4-yl)piperidine-4-yl)carbamate tert-butyl (compound 24-1-3, 7g, 20.9 mmol, 1 equivalent) in MeCN (150 ml, 100.0%), NBS (3.72 g, 20.9 mmol, 1 equivalent) was added at 20°C. The reaction mixture was stirred at 20°C for 1 hour. TLC (PE:siRNA = 3:1) indicated that the reaction was complete. The reaction mixture was diluted with siRNA (700 mL), washed with H2O (500 mL x 3), dried over Na2SO4, and evaporated to obtain the residue. The residue was purified by column chromatography using silica gel eluted with PE / siRNA (100:1~1:1) to obtain tert-butyl (1-(3-bromo-5-formyl-2-methoxypyridine-4-yl)piperidine-4-yl)carbamate (compound 24-1-4, 6g, 14.5 mmol, 69%) as a white solid. MS (m / z) 414.1 / 416.1 (M+H) + .

[0387] Step 4: Synthesis of (1-(3-bromo-5-(5,6-difluoro-1H-benzo[d]imidazole-2-yl)-2-methoxypyridine-4-yl)piperidine-4-yl) tert-butyl carbamate (compound 24-1-6) To a stirred solution of tert-butyl (1-(3-bromo-5-formyl-2-methoxypyridine-4-yl)piperidine-4-yl)carbamate (compound 24-1-4, 6 g, 14.5 mmol, 1 equivalent) in DMA (150 ml, 100.0%), 4,5-difluorobenzene-1,2-diamine (2.09 g, 14.5 mmol, 1 equivalent) and NaHSO3 (6.03 g, 58 mmol, 4 equivalents) were added at 20°C. The reaction mixture was stirred at 120°C for 5 hours. TLC (PE:siRNA = 1:1) indicated that the reaction was complete. The reaction mixture was diluted with siRNA (700 mL), washed with H2O (500 mL x 3), dried over Na2SO4, and evaporated to obtain the residue. The residue was purified by column chromatography on silica gel eluted with PE / siRNA (100:1~1:1) to obtain (1-(3-bromo-5-(5,6-difluoro-1H-benzo[d]imidazole-2-yl)-2-methoxypyridine-4-yl)piperidine-4-yl) tert-butyl carbamate (compound 24-1-6, 6.5 g, 12.1 mmol, 83%) as a white solid. MS (m / z) 538.2 / 540.2 (M+H) + .

[0388] Step 5: (1-(5-(5,6-difluoro-1H-benzo[d]imidazole-2-yl)-3-(5-fluoro-2-formylphenyl)-2-methoxypyridine-4-yl)piperidine-4-yl) tert-butyl carbamate (compound 24-1-8) To a stirred solution of (1-(3-bromo-5-(5,6-difluoro-1H-benzo[d]imidazole-2-yl)-2-methoxypyridine-4-yl)piperidine-4-yl) tert-butyl carbamate (compound 24-1-6, 6.5 g, 12.1 mmol, 1 equivalent) in toluene (60 ml), EtOH (40 ml), and H2O (20 ml), (5-fluoro-2-formylphenyl)boronic acid (2.03 g, 12.1 mmol, 1 equivalent) and K2CO3 (3.34 g, 24.2 mmol, 2 equivalents) were added at 20°C. The reaction mixture was stirred at 90°C for 5 hours. TLC (PE:siRNA = 1:1) indicated that the reaction was complete. The reaction mixture was diluted with toluene (700 mL), washed with H2O (500 mL x 3), dried over Na2SO4, and evaporated to obtain the residue. The residue was purified by column chromatography on silica gel eluted with PE / toluene (100:1~1:1) to obtain (1-(5-(5,6-difluoro-1H-benzo[d]imidazole-2-yl)-3-(5-fluoro-2-formylphenyl)-2-methoxypyridine-4-yl)piperidine-4-yl) tert-butyl (compound 24-1-8, 4 g, 6.87 mmol, 57%) as a white solid. MS (m / z) 582.3 (M+H) + .

[0389] Step 6: (1-(5-(5,6-difluoro-1H-benzo[d]imidazole-2-yl)-3-(5-fluoro-2-(hydroxymethyl)phenyl)-2-methoxypyridine-4-yl)piperidine-4-yl) tert-butyl carbamate (compound 24-1-9) To a solution of (1-(5-(5,6-difluoro-1H-benzo[d]imidazole-2-yl)-3-(5-fluoro-2-formylphenyl)-2-methoxypyridine-4-yl)piperidine-4-yl) tert-butyl carbamate (compound 24-1-8, 4g, 6.87 mmol) in MeOH (20 mL), NaBH4 (522 mg, 13.74 mmol, 2 equivalents) was gradually added at 25°C. The solution was stirred at 25°C for 2 hours. The reaction mixture was quenched with 1N HCl solution and extracted with EA (20 mL x 3). The combined layers were combined and concentrated under reduced pressure to obtain (1-(5-(5,6-difluoro-1H-benzo[d]imidazole-2-yl)-3-(5-fluoro-2-(hydroxymethyl)phenyl)-2-methoxypyridine-4-yl)piperidine-4-yl) tert-butyl carbamate (compound 24-1-9, 3.5 g, crude product) as a colorless oil.

[0390] Step 7: (1-(5-(5,6-difluoro-1H-benzo[d]imidazole-2-yl)-3-(5-fluoro-2-(hydroxymethyl)phenyl)-2-hydroxypyridine-4-yl)piperidine-4-yl) tert-butyl carbamate (compound 24-1-10) A solution of (1-(5-(5,6-difluoro-1H-benzo[d]imidazole-2-yl)-3-(5-fluoro-2-(hydroxymethyl)phenyl)-2-methoxypyridine-4-yl)piperidine-4-yl) tert-butyl carbamate (compound 24-1-9, 3.5 g, crude product) was dissolved in DCE (20 mL), followed by the addition of BBr3 (10 mL), and the solution was heated at 80°C for 4 hours. The reactants were quenched with saturated NaHCO3 solution until the pH was approximately 8-9. The mixture was extracted with DCM (10 mL x 3), and the combined layers were concentrated under reduced pressure to obtain (1-(5-(5,6-difluoro-1H-benzo[d]imidazole-2-yl)-3-(5-fluoro-2-(hydroxymethyl)phenyl)-2-hydroxypyridine-4-yl)piperidine-4-yl)carbamate tert-butyl (compound 24-1-10, 250 mg, 0.44 mmol, yield 10%) as a white solid.

[0391] Step 8: (1-(2-(5,6-difluoro-1H-benzo[d]imidazole-2-yl)-9-fluoro-6H-isochromeno[3,4-b]pyridine-1-yl)piperidine-4-yl) tert-butyl carbamate (compound 24-1-11) To a solution of (1-(5-(5,6-difluoro-1H-benzo[d]imidazole-2-yl)-3-(5-fluoro-2-(hydroxymethyl)phenyl)-2-hydroxypyridine-4-yl)piperidine-4-yl) tert-butyl (compound 24-1-10, 250 mg, 0.44 mmol) in 10 mL of THF at 0°C, DIAD (111 mg, 0.55 mmol, 1.1 equivalents) and PPh3 (144 mg, 0.55 mmol, 1.1 equivalents) were added, respectively. The solutions were then stirred overnight at 25°C. The reaction mixture was extracted with EA (10 mL x 3), and the combined layers were concentrated under reduced pressure to obtain (1-(2-(5,6-difluoro-1H-benzo[d]imidazole-2-yl)-9-fluoro-6H-isochromeno[3,4-b]pyridine-1-yl)piperidine-4-yl)carbamate tert-butyl (compound 24-1-11, 100 mg, white solid).

[0392] Step 9: 1-(2-(5,6-difluoro-1H-benzo[d]imidazole-2-yl)-9-fluoro-6H-isochromeno[3,4-b]pyridine-1-yl)piperidine-4-amine (compound 121) To a solution of (1-(2-(5,6-difluoro-1H-benzo[d]imidazole-2-yl)-9-fluoro-6H-isochromeno[3,4-b]pyridine-1-yl)piperidine-4-yl)carbamate tert-butyl (compound 24-1-11, 100 mg, 0.18 mmol) in DCM (5 mL), TFA (5 mL) was added. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (with 0.5% FA as an additive) to obtain 1-(2-(5,6-difluoro-1H-benzo[d]imidazole-2-yl)-9-fluoro-6H-isochromeno[3,4-b]pyridine-1-yl)piperidine-4-amine (compound 121, 13.8 mg, white solid) as a white solid.

[0393] The analytical data for compound 121 is provided below. [Table 25]

[0394] Example 25 [ka] Scheme 25 Step 1: Synthesis of 6-bromo-3-iodoquinoline-4-ol (compound 25-1-2) A mixture of compound 25-1-1 (3000 mg, 13.389 mmol, 1 equivalent) was dissolved in AcOH (50 mL), and NIS (3012 mg, 13.389 mmol, 1 equivalent) was added. The mixture was stirred at 60°C for 3 hours. The mixture was cooled to zero degrees, and many solids were observed. LC-MS showed that the solid was the title compound with good purity. After filtration, 6-bromo-3-iodoquinoline-4-ol (compound 25-1-2, 4.4 g, yield 94%) was obtained as a white solid. MS (m / z) 349.9 (M+H) + .

[0395] Step 2: Synthesis of 6-bromo-4-chloro-3-iodoquinoline (compound 25-1-3) A solution of compound 25-1-2 (4.4 g, crude product) in POCl3 (45 mL) is prepared by 100 o The mixture was stirred at 16 hours. The mixture was cooled to zero degrees Celsius, then poured into ice-NaHCO3 (aqueous solution), and NaHCO3 solid was continuously added until the pH reached 7. The solution was extracted with EA (50 mL x 4). The combined organic extracts were concentrated to obtain the crude product. The crude product was purified by silica gel chromatography eluted with PE:siRNA (100:1~5:1) to obtain the product 6-bromo-4-chloro-3-iodoquinoline (compound 25-1-3, 4.4 g) as a white solid. MS (m / z) 367.8 (M+H) + .

[0396] Step 3: Synthesis of 6-bromo-4-chloro-3-(3,5-difluorophenyl)quinoline (compound 25-1-4) To a solution of compound 25-1-3 (4.4 g, crude product), (3,5-difluorophenyl)boronic acid (1.16 g, 7.36 mmol, 1.1 equivalents), and K2CO3 (3.05 g, 22.08 mmol, 3 equivalents) in a mixture of dioxane (40 mL), PdCl2 (dppf) (600 mg, 0.74 mmol, 0.1 equivalents) was added under N2. The suspension was degassed under vacuum and purged several times with N2. The reaction mixture was then stirred at 90°C for 4 hours. The reaction mixture was filtered and washed with EA (200 mL x 3). The combined organic extracts were concentrated to obtain a crude substance. This crude substance was purified by silica gel chromatography eluted with PE:siRNA (100:1~5:1) to obtain the product 6-bromo-4-chloro-3-iodoquinoline (compound 25-1-4, 2.3 g) as a white solid. MS (m / z) 354.0 (M+H) + .

[0397] Step 4: Synthesis of 3-(4-chloro-3-(3,5-difluorophenyl)quinoline-6-yl)-2-(methoxymethoxy)benzonitrile (compound 25-1-5) A mixture of compound 25-1-4 (300 mg, 0.85 mmol, 1 equivalent) and 2-(methoxymethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (400 mg, 0.85 mmol, 1 equivalent) was dissolved in dioxane (10 mL), and PdCl2 (dppf) (73 mg, 0.056 mmol, 0.1 equivalent) and K2CO3 (352 mg, 2.25 mmol, 3 equivalents) were added. The mixture was stirred at 90°C for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with  (20 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, and filtered. The organic layer was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (PE: 10 / 1 to 1 / 1 EA) to obtain compound 25-1-5 as a yellow solid (200 mg, yield 53.95%). MS (m / z) 437.1 (M+H) + .

[0398] Step 5: Synthesis of (4-(6-(3-cyano-2-(methoxymethoxy)phenyl)-3-(3,5-difluorophenyl)quinoline-4-yl)phenyl)carbamate tert-butyl (compound 25-1-6) A mixture of compound 25-1-5 (100 mg, 0.23 mmol, 1 equivalent) and (4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (112 mg, 0.47 mmol, 2 equivalents) was dissolved in THF (6 mL) and H2O (0.5 mL), and Pd(PPh3)4 (58 mg, 0.05 mmol, 0.2 equivalents) and K2CO3 (96 mg, 0.69 mmol, 3 equivalents) were added. The mixture was stirred at 70°C for 4 hours. The reaction was monitored by LC-MS, which indicated that the reaction was successful. The reaction mixture was diluted with H2O (20 mL) and extracted with ELISA (20 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, and filtered. The organic layer was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (PE:EA10 / 1~1 / 1) to obtain compound 25-1-6 as a yellow solid (70 mg, yield 51.31%). MS (m / z) 594.2 (M+H) + .

[0399] Step 6: Synthesis of 3-(4-(4-aminophenyl)-3-(3,5-difluorophenyl)quinoline-6-yl)-2-hydroxybenzonitrile (compound 122) A mixture of compound 25-1-6 (70 mg, 0.12 mmol, 1 equivalent) dissolved in DCM (2 mL) was mixed with TFA (2 mL). The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated and purified by preparative HPLC to obtain compound 122 (11.4 mg, yield 21.15%) as a yellow solid.

[0400] Compounds 122-125 were synthesized according to the six-step procedure described in Example 25. The analytical data for compounds 122-125 are provided below. [Table 26]

[0401] Example 26 [ka] Scheme 26 Step 1: Synthesis of 5-chloro-2-iodopyridine-3-ol (compound 26-1-2) 5-chloropyridine-3-ol (compound 26-1-1, 3.0 g, 23.16 mmol) and I2 (6.0 g, 23.16 mmol) were added at 25°C to a solution of sodium carbonate (4.8 g, 46.41 mmol) in water (45 mL). The resulting mixture was stirred at 25°C for 5 hours. The mixture was treated with hydrochloric acid solution (90 mL, 2 M), and the formed precipitate was collected by filtration and redissolved in ethyl acetate (200 mL). The mixture was washed with brine (100 mL x 2), and the organic phase was dried over sodium sulfate. The solvent was removed under reduced pressure to obtain 5-chloro-2-iodopyridine-3-ol as a yellow solid (compound 26-1-2, 5.7 g, 96%). LCMS: m / z: 255.9 (M + H + ) In 1.49 minutes.

[0402] Step 2: Synthesis of 6-chloro-2-(trimethylsilyl)fl[3,2-b]pyridine (compound 26-1-3) To a solution of compound 26-1-2 (5.7 g, 22.3 mmol) in dioxane (91.2 mL, 1.076 mol), ethynyltrimethylsilane (4.75 g, 48.38 mmol), Pd(PPh3)2Cl2 (1.695 g, 2.42 mmol), CuI (57 mg, 0.285 mmol), and triethylamine (12.1 g, 119.7 mmol) were added at 25°C. The resulting mixture was stirred at 120°C for 6 hours. The mixture was cooled to 25°C and treated with water (350 mL). The resulting mixture was extracted with ethyl acetate (350 mL x 3). The organic phases were combined, washed with brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography using ethyl acetate in hexane (0% to 5% gradient) to obtain 6-chloro-2-(trimethylsilyl)fl[3,2-b]pyridine (compound 26-1-3, 1.5 g, 70%) as a brown solid. MS(m / z) 226.0(M+H) + .

[0403] Step 3: Synthesis of 6-chloro-2-(trimethylsilyl)fl[3,2-b]pyridine-4 oxide (compound 26-1-4) To a solution of compound 26-1-3 (1.5 g, 6.64 mmol, 1.00 equivalent) in dichloromethane (50 mL), m-CPBA (1.71 g, 9.96 mmol) was gradually added at 0°C. The resulting solution was stirred at 0°C for 30 minutes, then heated to room temperature, and stirred further at 25°C for 16 hours. The reaction mixture was treated with water (100 mL) and adjusted to pH=8 using a saturated solution of sodium bicarbonate. The resulting mixture was then extracted with dichloromethane (100 mL x 2), the organic phases were combined, washed with brine, and dried over sodium sulfate. The solvent was removed under reduced pressure to obtain compound 26-1-4 (1.9 g, crude product). MS(m / z)242.1(M+H) + .

[0404] Step 4: Synthesis of 6,7-dichloro-2-(trimethylsilyl)fl[3,2-b]pyridine (compound 26-1-5) To a solution of compound 26-1-4 (1.9 g, crude product) in toluene (50 mL), POCl3 (2 g, 13.07 mmol) was added at 25°C. The resulting solution was then stirred at 95°C for 3 hours. After cooling to 25°C, the reaction mixture was concentrated under reduced pressure, and the resulting residue was poured into ice water (70 mL). The pH of the mixture was adjusted to 9 with a saturated sodium carbonate solution. The resulting mixture was then extracted with dichloromethane (70 mL x 3). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography using ethyl acetate in hexane (0% to 2% gradient) to obtain compound 26-1-5 (800 mg, 47% in 2 steps). MS(m / z)260.0(M+H) + .

[0405] Step 5: Synthesis of (1-(6-chloro-2-(trimethylsilyl)fl[3,2-b]pyridine-7-yl)piperidine-4-yl)carbamate tert-butyl (compound 26-1-6) To a solution of compound 26-1-5 (300 mg, 1.2 mmol, 1 equivalent) in DMSO (0.05 mL), tert-butyl piperidine-4-ylcarbamate (2317 mg, 11.6 mmol, 10 equivalents) was added. The reaction mixture was stirred at 140°C for 2 hours. The reaction mixture was diluted with water (40 mL) and extracted with EA (100 mL x 3). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography using ethyl acetate in hexane (0%~2% gradient) to obtain compound 26-1-6 as a yellow solid (400 mg, 81.7%). MS (m / z) 424.4 (M+H) + .

[0406] Step 6: Synthesis of (1-(6-(3,5-difluorophenyl)-2-(trimethylsilyl)fluoro[3,2-b]pyridine-7-yl)piperidine-4-yl)carbamate tert-butyl (compound 26-1-7) To a solution of compound 26-1-6 (400 mg, 0.243 mmol, 1 equivalent) and (3,5-difluorophenyl)boronic acid (46 mg, 0.84 mmol, 1.2 equivalents) in a mixture of dioxane:H2O=10:1 (6 mL), K2CO3 (67 mg, 0.487 mmol, 2 equivalents) and Pd-G2 (19 mg, 0.024 mmol, 0.1 equivalent) were added. The reaction mixture was stirred at 110°C for 2 hours. The reaction mixture was cooled, diluted with water (30 mL), and extracted with EA (50 mL x 3). The combined organic extract was concentrated to obtain the crude substance, which was purified by chromatography through a pre-packed silica gel column (12 g) with elution under a gradient of 0% to 10% MeOH in DCM to obtain compound 26-1-7 (300 mg) as a gray solid. MS(m / z)502.1(M+H) + .

[0407] Step 7: Synthesis of (1-(6-(3,5-difluorophenyl)-2-iodofluoro[3,2-b]pyridine-7-yl)piperidine-4-yl) tert-butyl carbamate (compound 26-1-8) To a solution of compound 26-1-7 (300 mg, 0.92 mmol, 1 equivalent) in CH3CN (10 mL), potassium fluoride (161 mg, 2.7 mmol) and NIS (621 mg, 3 equivalents) were added at 25°C. The resulting solution was stirred at 55°C for 3 hours. The reaction mixture was cooled to 25°C and treated with NaHSO3 solution (100 mL, 4 M). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine, and dried over sodium sulfate. The solvent was removed under reduced pressure to obtain compound 26-1-8 (190 mg) as a yellow solid. MS (m / z) 556.0 (M+H) + .

[0408] Step 8: Synthesis of (1-(2-(3-cyano-2-hydroxyphenyl)-6-(3,5-difluorophenyl)fluoro[3,2-b]pyridine-7-yl)piperidine-4-yl)carbamate tert-butyl (compound 26-1-9) Compound 26-1-8 (190 mg, 0.342 mmol, 1 equivalent), 2-(3-bromopropoxy)-3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)benzonitrile (81 mg, 0.513 mmol, 1.5 equivalents), and K2CO3 (142 mg, 1.027 mmol, 3 equivalents) were dissolved in a mixed solvent of dioxane (8 mL) and H2O (0.8 mL). Pd(dppf)Cl2 (25 mg, 0.034 mmol, 0.1 equivalents) was added to this solution. The reaction mixture was stirred at 110°C for 2 hours under N2 conditions. The reaction mixture was diluted with water (30 mL) and extracted with EA (50 mL x 3). The combined organic extracts were concentrated to obtain a crude substance, which was purified by chromatography through a pre-packed silica gel column (12g) with Redi-Sep elution under a gradient of 0% to 30% EA in PE to obtain compound 26-1-9 (45mg) as a yellow oil. MS (m / z) 547.1 (M+H) + .

[0409] Step 9: Synthesis of 3-(7-(4-aminopiperidine-1-yl)-6-(3,5-difluorophenyl)fl[3,2-b]pyridine-2-yl)-2-hydroxybenzonitrile (compound 127) To a solution of compound 26-1-9 (45 mg, 0.076 mmol, 1 equivalent) in DCM (2 mL), TFA (1 mL) was added. The reaction mixture was stirred at 25°C for 2 hours. Completion of the reaction was detected by LC-MS. The mixture was then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain compound 127 (13.3 mg).

[0410] Compounds 127-131 were synthesized according to the nine-step procedure described in Example 26. The analytical data for compounds 127-131 are provided below. [Table 27]

[0411] Example 27 [ka] Scheme 27 Step 1: Synthesis of Compound 27-1-1 To a solution of compound 27-1-SM (5 g, 33.07 mmol) in acetonitrile (100 mL), NBS (7.65 g, 42.99 mmol) was added, and the resulting mixture was stirred at 100°C for 3 hours. The reaction mixture was concentrated to dryness and used as a yellow solid in the next step without further compound 27-1-1 (12.30 g, crude product). MS (m / z) 229.9 (M+H) + .

[0412] Step 2: Synthesis of Compound 27-1-2 A solution of compound 27-1-1 (12.3 g, 53.46 mmol) in POCl3 (164.50 g, 1.07 mol, 100 mL) was prepared, and the resulting mixture was stirred at 110°C for 2 hours. The reaction mixture was cooled to 25°C, then concentrated to remove POCl3, and subsequently diluted with DCM. The concentration was repeated. The residue was diluted with DCM (100 mL) and then slowly poured into ice water. The resulting mixture was extracted with CH2Cl2 (200 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluted with PE:siRNA = 10:1 to obtain compound 27-1-2 (7.28 g, 24.90 mmol, yield 46.58%, purity 85%) as a pale red solid. MS (m / z) 248.9 (M+H) + .

[0413] Step 3: Synthesis of Compound 27-1-3 To a solution of compound 27-1-2 (1.00 g, 3.82 mmol) in acetic acid (10 mL), NCS (1.53 g, 11.47 mmol) was added at 25°C, and the resulting mixture was stirred in N2 at 120°C for 12 hours. The reaction mixture was diluted with ethyl acetate (20 mL). This was then extracted with water (20 mL x 2). The aqueous phase was detached and extracted with ethyl acetate (20 mL). All organic phases were combined and dried over anhydrous Na2SO4. The organic phases were concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography eluted with PE:siRNA in a 98:2-95:5 ratio to obtain compound 27-1-3 (470.00 mg, 1.25 mmol, yield 32.75%, purity 75.38%) as a white solid. MS (m / z) 282.00 (M+H) + .

[0414] Step 4: Synthesis of Compound 27-1- To a solution of compound 27-1-3 (350 mg, 932.35 μmol) and tert-butyl piperidine-4-ylcarbamate (186.73 mg, 932.35 μmol) in dimethyl sulfoxide (4 mL), DIPEA (361.50 mg, 2.80 mmol) was added at 25°C, and the resulting mixture was stirred at 150°C for 4 hours. The reaction mixture was diluted with ethyl acetate (20 mL). This was then extracted with water (20 mL x 2). The aqueous phase was removed and extracted with ethyl acetate (20 mL). All organic phases were combined and dried over anhydrous Na₂SO₄. The organic phases were concentrated to obtain the crude product. The crude product was purified by silica gel chromatography using PE:siRNA (V / V: 90 / 10~75 / 25) to obtain compound 27-1-4 (200.00 mg, 348.62 μmol, yield 37.39%, purity 77.88%) as a yellow solid. MS (m / z) 446.0 (M+H) + .

[0415] Step 5: Synthesis of Compound 27-1-5 To a solution of compound 27-1-4 (80 mg, 179.06 μmol) and (3,5-difluorophenyl)boronic acid (33.93 mg, 214.87 μmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL), K2CO3 (49.49 mg, 358.11 μmol) and Pd(dppf)Cl2 (26.28 mg, 35.81 μmol) were added at 25°C, and the resulting mixture was stirred in N2 at 100°C for 16 hours. The resulting mixture was then extracted with dichloromethane (100 mL x 2), the organic phases were combined, washed with brine, and dried over sodium sulfate. The crude product was purified by silica gel chromatography eluted with 15 / 1 to 5 / 1 PE / Â to obtain compound 27-1-5 (65.00 mg, 135.43 μmol, yield 75.63%) as a yellow oil. MS(m / z)480.2(M+H) + .

[0416] Step 6: Synthesis of Compound 27-1-6 To a solution of compound 27-1-5 (65 mg, 135.43 μmol) and (3-cyano-2-hydroxyphenyl)boronic acid (32.08 mg, 203.14 μmol) in 1,4-dioxane (2 mL) and H2O (0.2 mL), K2CO3 (37.43 mg, 270.85 μmol) and G2-XPhos-Pd (15.96 mg, 20.31 μmol) were added at 25°C, and the resulting mixture was stirred in N2 at 100°C for 16 hours. The reaction solution was directly concentrated to obtain a residue, which was purified by silica gel chromatography eluted with 15 / 1 to 1 / 1 PE / Âde to obtain compound 27-1-6 (50.00 mg, 89.67 μmol, yield 66.21%) as a yellow solid. MS (m / z) 558.2 (M+H) + .

[0417] Step 7: Synthesis of Compound 132 To a solution of compound 27-1-6 (50 mg, 73.81 μmol) in dichloromethane (2 mL), TFA (1.49 g, 13.07 mmol, 1 mL) was added at 25°C, and the resulting mixture was stirred at 25°C for 2 hours. The reaction solution was concentrated to dryness and then diluted with dichloromethane (20 mL). The concentration was repeated three times. The crude product was dissolved in MeOH, and then NaHCO3 solid was added until the pH reached 6. The methanol liquid was directly purified by preparative HPLC (preparative C18, 5 μM OBD, 19 × 250 mm, column, Waters, gradient elution from 40% MeCN in water to 50% MeCN in water over 9 minutes, both solvents containing 10 mmol / L NH4HCO3) to obtain compound 132 (5.00 mg, 10.93 μmol, yield 14.81%, purity 100%) as a white solid.

[0418] Compounds 132-134 were synthesized according to the seven-step procedure described in Example 27. Analytical data for compounds 132-134 are provided below. [Table 28]

[0419] Example 28 [ka] Step 1: Synthesis of 4-(6-bromo-3-chloroquinoline-4-yl)piperazine-1-carboxylate tert-butyl (compound 28-1-2) To a stirred solution of 6-bromo-3,4-dichloroquinoline (compound 28-1-1, 2 g, 7.22 mmol, 1 equivalent) in DMF (20 ml, 100.0%), piperazine-1-carboxylate tert-butyl (1345.06 mg, 7.22 mmol, 1 equivalent) and dipotassium carbonate (2 g, 14.44 mmol, 2 equivalents) were added at 20°C. The reaction mixture was stirred at 100°C for 16 hours. TLC (PE:siRNA = 5:1) indicated that the reaction was complete. The reaction mixture was poured into H2O (100 mL), filtered, and concentrated to obtain 4-(6-bromo-3-chloroquinoline-4-yl)piperazine-1-carboxylate tert-butyl (compound 28-1-2, 2.3 g, 5.39 mmol, 74.63%). MS (m / z) 426.1 / 428.1 (M+H) + .

[0420] Step 2: 4-[3-chloro-6-(3-cyano-2-hydroxyphenyl)quinoline-4-yl]piperazine-1-carboxylate tert-butyl (compound 28-1-3) To a stirred solution of 4-(6-bromo-3-chloroquinoline-4-yl)piperazine-1-carboxylate tert-butyl (compound 28-1-2, 900 mg, 2.11 mmol, 1 equivalent) in 1,4-dioxane (12 ml, 100.0%), water (3 ml, 166.53 mmol, 78.96 equivalents), 2-hydroxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (516.88 mg, 2.11 mmol, 1 equivalent), dipotassium carbonate (582.97 mg, 4.22 mmol, 2 equivalents), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (160.88 mg, 0.21 mmol, 0.1 equivalent) were added at 20°C. The reaction mixture was stirred at 90°C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was diluted with toluene (300 mL), washed with saturated NaHCO3 (50 mL), dried over Na2SO4, and evaporated to obtain the residue. The residue was purified by column chromatography on silica gel eluted with PE / toluene (9:1~1:1) to obtain 4-[3-chloro-6-(3-cyano-2-hydroxyphenyl)quinoline-4-yl]piperazine-1-carboxylate tert-butyl (compound 28-1-3, 500 mg, 1.08 mmol, 50.99%) as a white solid. MS (m / z) 465.2 (M+H) + .

[0421] Step 3: Synthesis of 4-[6-(3-cyano-2-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)quinoline-4-yl]piperazine-1-carboxylate tert-butyl (compound 28-1-4) To a stirred solution of 4-[3-chloro-6-(3-cyano-2-hydroxyphenyl)quinoline-4-yl]piperazine-1-carboxylate tert-butyl (compound 28-1-3, 500 mg, 1.08 mmol, 1 equivalent) in 1,4-dioxane (10 ml, 100.0%), water (2.5 ml, 138.78 mmol, 129.04 equivalents), (3-fluoro-5-methylphenyl)boronic acid (165.56 mg, 1.08 mmol, 1 equivalent), dipotassium carbonate (297.26 mg, 2.15 mmol, 2 equivalents), and dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (76.15 mg, 0.11 mmol, 0.1 equivalent) were added at 20°C. The reaction mixture was stirred at 100°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with toluene (300 mL), washed with saturated NaHCO3 (50 mL), dried over Na2SO4, and evaporated to obtain the residue. The residue was purified by column chromatography on silica gel eluted with PE / toluene (9:1~1:1) to obtain 4-[6-(3-cyano-2-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)quinoline-4-yl]piperazine-1-carboxylate tert-butyl (compound 28-1-4, 400 mg, 0.74 mmol, 69.06%) as a white solid. MS (m / z) 539.3 (M+H) + .

[0422] Step 4: Synthesis of 3-[3-(3-fluoro-5-methylphenyl)-4-(piperazin-1-yl)quinoline-6-yl]-2-hydroxybenzonitrile (compound 28-1-5) To a stirred solution of 4-[6-(3-cyano-2-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)quinoline-4-yl]piperazine-1-carboxylate tert-butyl (compound 28-1-4, 100 mg, 0.19 mmol, 1 equivalent) in DCM (3 ml), trifluoroacetic acid (1 ml, 8.77 mmol, 47.24 equivalents) was added at 20°C. The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated and evaporated to obtain 3-[3-(3-fluoro-5-methylphenyl)-4-(piperazine-1-yl)quinoline-6-yl]-2-hydroxybenzonitrile (compound 28-1-5, 80 mg, 0.18 mmol, 98.26%) as a white solid. MS (m / z) 439.3 (M+H) + .

[0423] Step 5: Synthesis of Compound 135 To a stirred solution of 3-[3-(3-fluoro-5-methylphenyl)-4-(piperazin-1-yl)quinoline-6-yl]-2-hydroxybenzonitrile (compound 28-1-5, 80 mg, 0.18 mmol, 1 equivalent) in DMF (2 ml, 0%), pyrazole-1-carboxymidamide (40.18 mg, 0.36 mmol, 2 equivalents) and ethylbis(propan-2-yl)amine (235.79 mg, 1.82 mmol, 10 equivalents) were added at 20°C. The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with  (50 mL), washed with H₂O (50 mL x 3), dried over Na₂SO₄, and evaporated to obtain the residue. The residue was purified by HPLC to obtain 4-[6-(3-cyano-2-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)quinoline-4-yl]piperazine-1-carboxymidoamide (compound 135, 3.8 mg, 0.01 mmol, 4.33%) as a white solid.

[0424] Compounds 135 and 136 were synthesized according to the five-step procedure described in Example 28. Analytical data for compounds 135 and 136 are provided below. [Table 29]

[0425] II. Biological Examples Example 29 Biochemical assay for activation of somatostatin receptor 2 (SSTR2) SSTR agonist activation leads to increased intracellular cAMP production. cAMP concentrations were measured in a high-throughput format using Cisbio's homogeneous time-resolved fluorescence (HTRF) cAMP assay. Increases in intracellular cAMP concentration were measured using stably transfected cell lines expressing SSTR2. The test compound was dissolved in DMSO. Cells were incubated with the compound for 1–2 hours, and then competitive binding of cAMP produced due to SSTR2 activation by the test compound was measured using the Cisbio cAMP Gs dynamic assay system (Perkin Elmer, Bedford, MA).

[0426] For the test compound, the average pEC 50 This decision was made. The data is provided in Table 2 below. [Table 30-1] [Table 30-2] [Table 30-3] [Table 30-4] [Table 30-5] [Table 30-6] [Table 30-7] [Table 30-8] [Table 30-9] [Table 30-10] [Table 30-11] [Table 30-12] [Table 30-13] [Table 30-14] * Indicates that stereochemistry is assigned arbitrarily.

[0427] While efforts have been made to ensure accuracy regarding the numbers used (e.g., quantity, temperature, etc.), some experimental errors and deviations should be taken into account.

[0428] Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein that may be used in carrying out the subject matter described herein. This disclosure is by no means limited to the methods and materials described herein.

[0429] Unless otherwise defined, the technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in the field to which this subject belongs, and are consistent with Singleton et al (1994) Dictionary of Microbiology and Molecular Biology, 2nd Ed., J. Wiley & Sons, New York, NY; and Janeway, C., Travers, P., Walport, M., Shlomchik (2001) Immunobiology, 5th Ed., Garland Publishing, New York.

[0430] Throughout this specification and the claims, unless the context requires a different understanding, the terms “include,” “contain,” and “contain.” Embodiments described herein are understood to include embodiments that “consist of” and / or “essentially consist of.”

[0431] Where a range of values ​​is provided, unless the context explicitly indicates otherwise, it is understood that the range between its upper and lower limits, and any other listed or intervening values ​​within that range, encompasses values ​​up to one-tenth of the lower limit of the unit. The upper and lower limits of these smaller ranges, which may independently be contained within smaller ranges, are also encompassed, subject to any specifically excluded restrictions within the specified range. If the listed range includes one or both of the restrictions, it also includes the range that excludes one or both of those included limits.

[0432] Many modifications and other embodiments described herein will be apparent to those skilled in the art, who benefit from the teachings presented in the preceding description and the accompanying drawings. It should be understood that the subject matter is not limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Certain terms are used herein, but they are used only in a general and descriptive sense, and not for limiting purposes.

Claims

1. Compound of formula I: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, g is either 1 or 0. Z either does not exist, or is -N(H)-C(=O)-, or -C(=O)-NH-, R １ is either hydrogen or a halogen, or R １ And Z, along with the ring to which each is joined, one or two R ８ It forms a condensed bicyclic ring that can be substituted as desired, or R １ and R Ｃ１ Each of these, along with the rings to which they are bonded, forms a fused tricyclic ring. Ring C is such that each of them is R Ｃ１ , R Ｃ２ , and R Ｃ３ The substitution is made by selecting from the group consisting of 4-10 member monocyclic or bicyclic condensed heterocyclines, 6-10 member aryls, and 5-10 member heteroaryls, Here, the 4-10 member monocyclic or bicyclic condensed heterocyclyl or 5-10 member heteroaryl each independently contains 1, 2, 3, or 4 ring heteroatoms selected from N, O, and S, and, R Ｃ１ is hydrogen or R １ , R ３ , or R ６ can combine with R Ｃ２ and R Ｃ３ These are, independently, hydrogen, halogen, cyano, and C. １ -C ６ Alkyl, hydroxy, -C(=O)NH ２ , -O-C ２ -C ６ Alkenyl, -C １ -C ６ Alkoxy, -NH-(CH ２ ) １‐５ -NH ２ -O-piperidinyl, -O-(CH ２ ) ｑＣ -O-(CH ２ ) ｒＣ -CH ３ Selected from the group consisting of, qC and rC are each independent integers from 1 to 4. R ２ is either hydrogen or a halogen, or R ２ and R Ｂ１ Each of these, along with the rings to which they are bonded, forms a fused tricyclic ring. R ３ If present, R Ｃ１ It is a group covalently bonded to it, Ring B is either phenyl or pyridinyl, and each is R Ｂ１ It is either replaced by R Ｂ１ and R Ｂ２ It is replaced twice, Here, R Ｂ１ and R Ｂ２ Each of these is independently hydrogen, cyano, and C. １ -C ６ Alkyl, halogen, halo-C １ -C ６ Alkyl, hydroxy-C １ -C ６ Alkyl, hydroxy, C １ -C ６ Alkoxy, -O-C ２ -C ６ Alkenyl, -NH-(CH ２ ) １－５ -NH ２ ,-O-(CH ２ ) ｑ２ -O-(CH ２ ) ｒ２ -CH ３ Selected from the group consisting of, q2 and r2 are each independently integers from 1 to 4, -C(O)-NR Ｎａ R Ｎｂ And each R Ｎａ and R Ｎｂ These are, independently, hydrogen and C １ -C ６ Selected from the group consisting of alkyl groups, Furthermore, A is selected from the following group: i. -NR ４ R ５ Here, R ４ C can be substituted at will. １ -C ６ Alkyl, -NH-C １ -C ６ Alkyl-NHR ４ａ , or -C １ -C ６ Alkyl-NHR ４ａ And R ４ａ is hydrogen or methyl, and R ５ C is either hydrogen or optionally substituted. １ -C ６ It is alkyl, The optional substituents are selected from the group consisting of halogens and hydroxyls. or R ５ and R Ｂ１ R ５ N and R that bind together Ｂ１ Together with ring B to which it is attached, it forms a condensed heterocycline. or R ５ and R Ｃ１ R ５ N and R that bind together Ｃ１ Together with the ring C to which it is attached, it forms a condensed heterocycline. or R ５ and R ８ are, together with N to which R ５ is attached and the ring to which R ８ is attached, form a fused heterocyclyl, ii. -NH-R ６ Or R Ｓ A spiro ring is substituted by, where, R Ｓ is hydrogen or -C(=O)-C １ -C ６ It is alkyl, Furthermore, iii. each independently being -NH-R ６ substituted with, or R Ｆ and R Ｇ substituted with, -O-(C ３ -C ８ cycloalkyl), 5-11 member heterocyclyl, or 5-6 member heteroaryl, wherein R Ｆ is hydroxyl, hydroxy-C １ -C ６ Alkyl, nitro, -C(=O)H, -C １ -C ６ Alkoxy, -C(=NH)-NH ２ , -NH-C(=NH)-NH ２ , -C (=O) -C １ -C ６ Alkyl, -(C=O)-O-C １ -C ６ Alkyl, and -(C １ -C ６ Alkyl) ｘ -NR Ｆ１ R Ｆ２ Selected from the group consisting of, x is 0 or 1, and R Ｆ１ and R Ｆ２ These are H, -(C=O)-O-C, and H, -(C=O)-O-C, respectively, independently. １ -C ６ Alkyl and C １ -C ６ It is alkyl, R Ｇ is hydrogen or -C １ -C ６ It is alkoxy, or R Ｇ R Ｃ１ Along with, -O-(CH ２ ) ｋ It forms -O-, where k is an integer from 1 to 5, or R Ｆ and R Ｇ They together form a carboxyl group, and R ６ R Ｃ１ Together with the following, 【Chemistry 2】 During the ceremony, 【Transformation 3】 R ６ This represents the connection point to A, p is an integer between 1 and 4. R ７ａ and R ７ｂ In each case, hydroxyl is optionally substituted with -C. １ -C ６ Alkyl, -N ３ ,-NR ａ R ｂ Independently selected from the group consisting of, R ａ and R ｂ These are, independently, H or C １ -C ６ It is alkyl, E does not exist, or -O- or -N(R) ｂ ) - and R ｂ C can be substituted with H or as desired. １ -C ６ It is alkyl, J is -C(O)- or -C(R ７ａ R ７ｂ ) - and L either does not exist, or is -O- or -N(H)-. Optional substituents include halogens and -NH ２ Selected from the group consisting of , and hydroxyl, However, the compound is a compound of formula I or a pharmaceutically acceptable salt thereof, except for one of the following: 【Chemistry 4】

2. The compound according to claim 1, wherein g is 0.

3. Having the structure of formula Ia or Ib, where Z and R １ These, along with the rings to which they are joined, are condensed: 【Transformation 5】 Forming, In the formula, X １ and X ２ These are, independently, O, N, and N-R. ８ , S, and CR ８ Selected from the group consisting of, R ８ C is a hydrogen atom that can be optionally substituted. １ -C ６ Alkyl and -C(=O)OR ８ａ Selected from the group consisting of R ８ａ is hydrogen or C １ -C ６ It is an alkyl group, and optional substituents include halogens and -NH. ２ The compound according to claim 2, selected from the group consisting of , and hydroxyl.

4. The compound according to claim 3, having the structure of formula Ia-1. 【Transformation 6】

5. The compound according to claim 4, having the structure of formula Ia-2. 【Transformation 7】

6. The compound according to claim 5, having the structure of formula Ia-3. 【Transformation 8】

7. The compound according to claim 3, having the structure of formula Ib-1. 【Chemistry 9】

8. The compound according to claim 7, having the structure of formulas Ib-1a to Ib-1e. 【Chemistry 10】

9. R in each of Ib-1a to Ib-1e Ｂ１ and R Ｂ２ The compound according to claim 8, wherein the position is as follows. 【Chemistry 11】

10. R Ｂ１ and R Ｂ２ Each of them operates independently, C １ -C ６ Alkyl, halogen, and C １ -C ６ A compound according to any one of claims 1 to 9, selected from the group consisting of alkoxys.

11. Said C １ -C ６ The alkyl is methyl, the halogen is fluoro, and the C １ -C ６ The compound according to claim 10, wherein the alkoxy is methoxy.

12. R Ｂ１ and R Ｂ２ The compound according to any one of claims 1 to 11, wherein at least one of the elements is fluoro.

13. R Ｂ１ and R Ｂ２ The compound according to claim 12, wherein both are fluoro.

14. R Ｃ１ is hydrogen, R Ｃ２ and R Ｃ３ The compound according to any one of claims 5 to 13, wherein the position is as follows. 【Chemistry 12】

15. R Ｃ２ However, hydroxy, C １ -C ６ Alkoxy, -O-piperidinyl, -N-(CH ２ ) ３ -NH ２ , -O-C ２ -C ６ Alkenyl, -O-(CH ２ ) ｑ１ -O-(CH ２ ) ｒ１ -CH ３ Selected from the group consisting of, where q1 and r1 are each independently integers from 1 to 4, and R Ｃ３ The compound according to claim 14, selected from the group consisting of cyano and halogen.

16. R Ｃ２ However, hydroxy, methoxy, -O-CH ２ -CH=CH ２ and -O-CH ２ -O-CH ３ Selected from the group consisting of, R Ｃ３ The compound according to claim 15, selected from the group consisting of cyano and bromine.

17. R Ｃ１ is hydrogen, R Ｃ２ and R Ｃ３ The compound according to any one of claims 5 to 13, wherein the position is as follows. 【Chemistry 13】

18. R Ｃ２ and R Ｃ３ The compound according to claim 17, wherein each of them is a halogen.

19. The compound according to claim 18, wherein the halogen is fluoro.

20. R Ｃ１ is hydrogen, R Ｃ２ and R Ｃ３ The compound according to any one of claims 5 to 13, wherein the position is as follows. 【Chemistry 14】

21. R Ｃ２ and R Ｃ３ Each of them independently forms hydroxy, C １ -C ６ Alkoxy, Halogen, -(C=O)-NH ２ , -O-C ２ -C ６ Alkenyl and C １ -C ６ A compound according to claim 20, selected from alkyl groups.

22. R Ｃ２ and R Ｃ３ However, each independently, -(C=O)-NH ２ The compound according to claim 21, selected from the group consisting of methoxy, fluoro, and methyl.

23. Ring B is R Ｂ１ and R Ｂ２ It is a disubstituted phenyl, and also, The compound according to claim 3, wherein ring C is a monocyclic or bicyclic heterocycline with 4 to 10 members.

24. The compound according to claim 23, wherein ring C is a 9-10 membered bicyclic lactam or cyclic urea.

25. The compound according to claim 24, wherein ring C is selected from the group consisting of the following. 【Chemistry 15】

26. It has the structure of formula Ic, in which Z does not exist, and R １ and R Ｃ１ R １ The ring to which it is bonded and R Ｃ１ Along with the ring to which it is bonded, R ８ The compound according to claim 2, which forms a fused ring that is substituted with 【Chemistry 16】

27. R ８ The compound according to claim 26, wherein the compound is hydrogen.

28. Ring C is R Ｃ２ and R Ｃ３ The compound according to claim 26 or 27, wherein the compound is an 8- to 10-membered heteroaryl substituted with .

29. The compound according to claim 28, wherein ring C is as follows. 【Chemistry 17】

30. R Ｃ２ and R Ｃ３ The compound according to claim 28, wherein each of them is fluoro.

31. Ring B is R Ｂ１ and R Ｂ２ The compound according to any one of claims 26 to 30, wherein the compound is a phenyl compound that is disubstituted with phenyl.

32. R Ｂ１ is halogen, R Ｂ２ is halogen or C １ -C ６ The compound according to claim 31, wherein it is alkyl.

33. R Ｂ１ is fluoro, R Ｂ２ The compound according to claim 32, wherein is fluoro or methyl.

34. R in the phenyl ring Ｂ１ and R Ｂ２ The compound according to any one of claims 31 to 33, wherein the position is as follows. [Chemistry 18]

35. It has the structure of formula Id, where Z and R １ The compound according to claim 2, wherein each ring, together with the ring to which it is bonded, forms a fused ring. 【Chemistry 19】

36. R ８ The compound according to claim 34, wherein the compound is hydrogen.

37. Ring C is R Ｃ１ , R Ｃ２ , and R Ｃ３ The compound according to claim 36, wherein the compound is a phenyl substituted with [the specified compound].

38. R Ｃ１ is hydrogen, R Ｃ２ and R Ｃ３ The compound according to claim 37, wherein the position is as follows. 【Chemistry 20】

39. R Ｃ２ and R Ｃ３ However, each is independent of C １ -C ６ The compound according to claim 38, selected from the group consisting of alkyl and halogen.

40. Said C １ -C ６ The compound according to claim 39, wherein the alkyl group is methyl and the halogen group is fluoro.

41. Ring B is R Ｂ１ and R Ｂ２ The compound according to any one of claims 36 to 40, wherein the compound is a phenyl compound that is disubstituted with phenyl.

42. R Ｂ１ is halogen, R Ｂ２ is halogen or C １ -C ６ The compound according to claim 41, wherein it is alkyl.

43. R Ｂ１ is fluoro, R Ｂ２ The compound according to claim 42, wherein is fluoro or methyl.

44. R in the phenyl Ｂ１ and R Ｂ２ The compound according to claim 43, wherein the position is as follows. 【Chemistry 21】

45. It has the structure of formula Ie, where R ２ and R Ｂ１ R ２ The ring to which it is bonded and R Ｂ１ Together with the ring to which it is bonded, it forms a fused ring. 【Chemistry 22】 During the ceremony, Q is O or CH ２ And, 【Chemistry 23】 is a single bond, or Q is N, 【Chemistry 24】 It is a double bond, R １ is hydrogen or halogen, and Ring B is R Ｂ２ The compound according to claim 2, wherein the compound is a phenyl substituted with [the specified compound].

46. R １ The compound according to claim 45, wherein the compound is hydrogen.

47. Ring C is R Ｃ１ , R Ｃ２ , and R Ｃ３ The compound according to claim 45 or 46, wherein the compound is an 8- to 10-membered heteroaryl substituted with .

48. R Ｃ１ The compound according to claim 47, wherein is hydrogen and ring C is as follows. 【Chemistry 25】

49. R Ｂ２ The compound according to any one of claims 45 to 48, wherein the compound is a halogen.

50. R Ｂ２ The compound according to claim 49, wherein it is fluoro.

51. Q is N, 【Chemistry 26】 The compound according to any one of claims 45 to 50, wherein the bond is a double bond.

52. Q is O, 【Chemistry 27】 The compound according to any one of claims 45 to 50, wherein the bond is a single bond.

53. A is -NH-R ６ It is replaced by or R Ｆ and R Ｇ The compound according to any one of claims 1 to 52, which is a 5- to 11-membered heterocyclyl or a 5- to 6-membered heteroaryl substituted with

54. A has the following structure: 【Chemistry 28】 During the ceremony, The compound according to claim 53, wherein ring A1 is a 5-6 membered heteroaryl or a 5-6 membered heterocyclyl.

55. A has the following structure: i. 【Chemistry 29】 During the ceremony, G is N, and D is CH ２ And y is 0 or 1, each 【Transformation 30】 It is a single bond, G is C, and D is CH ２ And y is 1, 【Chemistry 31】 It is a double bond, and the other 【Chemistry 32】 Each is a single bond, G is N, and D is CH ２ And y is 0, 【Transformation 33】 Each of them is a double bond, and the other 【Transformation 34】 Each is a single bond, G is C, D is N or C-H, y is 1, each 【Chemistry 35】 The compound according to claim 54, wherein is a double bond.

56. The compound according to claim 55, wherein A is selected from the group consisting of the following. 【Transformation 36】

57. A is a spirocyclic structure having the following structure: 【Chemistry 37】 The compound according to any one of claims 1 to 52, wherein t, t1, u, and u1 are each independently 1 or 2.

58. The compound according to claim 57, wherein A is selected from the group consisting of the following. 【Transformation 38】

59. A is -NH-R ６ Replaced by, or R Ｆ and R Ｇ Substituted by -O-(C ３ -C ８ A compound according to any one of claims 1 to 52, wherein it is a cycloalkyl compound.

60. A has the following structure, 【Chemistry 39】 During the ceremony, Ring A2 is C ４ -C ６ The compound according to claim 59, which is a cycloalkyl compound.

61. The compound according to claim 60, wherein A is selected from the group consisting of the following. 【Chemistry 40】

62. R ６ R Ｃ１ Together with the following, 【Chemistry 41】 During the ceremony, 【Chemistry 42】 R ６ This represents the aforementioned connection point to A, p is an integer between 1 and 4. R ７ａ and R ７ｂ In each case, hydroxyl is optionally substituted with -C. １ -C ６ Alkyl, -N ３ ,-NR ａ R ｂ Independently selected from the group consisting of, R ａ and R ｂ These are, independently, H or C １ -C ６ It is alkyl, E does not exist, or -O- or -N(R) ｂ ) - and R ｂ C can be substituted with H or as desired. １ -C ６ It is alkyl, J is -C(O)- or -C(R ７ａ R ７ｂ ) - and The compound according to any one of claims 53 to 61, wherein L is absent or -O- or -N(H)-.

63. R ６ However, R Ｃ１ The compound according to claim 62, which together forms the following. 【Chemistry 43】 【Chemistry 44】

64. The compound according to claim 62 or 63, having the structure of formula Ia-4. 【Chemistry 45】

65. The compound according to claim 64, having the structure of formula Ia-4A. 【Chemistry 46】

66. R Ｃ１ The compound according to claim 65, wherein the ring C to which is bonded has the following structure. 【Chemistry 47】

67. R Ｃ１ The compound according to claim 66, wherein the ring C to which is bonded has the following structure. 【Chemistry 48】

68. R Ｃ２ However, cyano or -(C=O)-NH ２ The compound according to claim 67.

69. A compound according to any one of claims 53 to 61, having the structures of formulas Ia-6, Ia-7, Ib-2, and Ib-3. 【Chemistry 49】

70. R in Ia-6, Ia-7, Ib-2, and Ib-3 respectively Ｂ１ and R Ｂ２ The compound according to claim 69, wherein the position is as follows. [Transformation 50]

71. R Ｂ１ and R Ｂ２ Each of them operates independently, C １ -C ６ Alkyl, halogen, and C １ -C ６ A compound according to claim 69 or 70, selected from the group consisting of alkoxys.

72. Said C １ -C ６ The alkyl is methyl, the halogen is fluoro, and the C １ -C ６ The compound described in 71, wherein the alkoxy is methoxy.

73. R Ｂ１ and R Ｂ２ The compound according to any one of claims 69 to 72, wherein at least one of them is fluoro.

74. R Ｂ１ and R Ｂ２ The compound according to claim 73, wherein both are fluoro.

75. R Ｃ２ and R Ｃ３ The compound according to any one of claims 69 to 74, wherein the position is as follows. 【Chemistry 51】

76. R Ｃ２ However, hydroxy, C １ -C ６ Alkoxy, -O-piperidinyl, -N-(CH ２ ) ３ -NH ２ , -O-C ２ -C ６ Alkenyl, -O-(CH ２ ) ｑ１ -O-(CH ２ ) ｒ１ -CH ３ Selected from the group consisting of, where q1 and r1 are each independently integers from 1 to 4, and R Ｃ３ The compound according to claim 75, which is selected from the group consisting of cyano and halogen.

77. R Ｃ２ However, hydroxy, methoxy, -O-CH ２ -CH=CH ２ and -O-CH ２ -O-CH ３ Selected from the group consisting of, R Ｃ３ The compound according to claim 76, selected from the group consisting of cyano and bromine.

78. R Ｃ１ is hydrogen, R Ｃ２ and R Ｃ３ The compound according to any one of claims 69 to 74, wherein the position is as follows. 【Chemistry 52】

79. R Ｃ２ and R Ｃ３ The compound according to claim 78, wherein each of them is a halogen.

80. The compound according to claim 79, wherein the halogen is fluoro.

81. R Ｃ１ is hydrogen, R Ｃ２ and R Ｃ３ The compound according to any one of claims 69 to 74, wherein the position is as follows. 【Chemistry 53】

82. R Ｃ２ and R Ｃ３ However, each independently, hydroxy, C １ -C ６ Alkoxy, halogen, -(C=O)-NH ２ , -O-C ２ -C ６ Alkenyl and C １ -C ６ A compound according to claim 81, selected from the group consisting of alkyl groups.

83. R Ｃ２ and R Ｃ３ However, each independently, -(C=O)-NH ２ The compound according to claim 82, selected from the group consisting of methoxy, fluoro, and methyl.

84. A is -NR ４ R ５ The compound according to any one of claims 1 to 52.

85. R ４ However, C can be substituted at will. １ -C ６ Alkyl, -C １ -C ６ Alkyl-NH-CH ３ , C １ -C ６ Alkyl-NH ２ , -NH-C １ -C ６ Alkyl-NH-CH ３ , -NH-C １ -C ６ Alkyl-NH ２ And, R ５ However, C is substituted with hydrogen or as desired. １ -C ６ The compound according to claim 84, wherein it is alkyl.

86. R ４ ga- (CH ２ ) ３ -NH-CH ３ And R ５ The compound according to claim 85, wherein is hydrogen.

87. It has the structure of formula If, where R ５ and R Ｂ１ R ５ N and R are bonded to each other. Ｂ１ Together with ring B to which it is bonded, it forms a fused ring. 【Chemistry 54】 During the ceremony, M is carbonyl or C-R Ｍ１ R Ｍ２ And R Ｍ１ and R Ｍ２ Each of these is independently of hydrogen, and C is optionally substituted. １ -C ６ Alkyl and C １ -C ６ Alkyl-NH ２ The compound according to claim 84, wherein the optional substituent is selected from the group consisting of halogens and hydroxyls.

88. M is CH ２ And, R １ and R ２ However, each is hydrogen, and R ４ However, C １ -C ６ Alkyl-NHR ４ａ The compound according to claim 87.

89. The compound according to claim 88, wherein Z is -C(=O)-NH-.

90. Ring B is R Ｂ１ It is a monosubstituted phenyl, or R Ｂ１ and R Ｂ２ The compound according to any one of claims 87 to 89, wherein the compound is a phenyl compound that is disubstituted with phenyl.

91. R Ｂ１ and R Ｂ２ The compound according to claim 90, wherein each is a fluoropolymer.

92. Ring C is a 4-10 member monocyclic or bicyclic condensed heterocyclyl, or a 5-10 member heteroaryl, and each is R Ｃ１ , R Ｃ２ , and R Ｃ３ The compound according to claim 90 or 91, which is substituted with

93. Ring C is R Ｃ１ , R Ｃ２ , and R Ｃ３ The compound according to claim 92, wherein the compound is a 6- to 10-membered aryl substituted with

94. It has the structure of formula Ig, where Z is absent and R ５ and R Ｃ１ R ５ N and R are bonded to each other. Ｃ１ Together with the bonded ring C, it forms a fused ring. 【Transformation 55】 During the ceremony, M stands for carbonyl, or C-R Ｍ１ R Ｍ２ And R Ｍ１ and R Ｍ２ Each of these is independently of hydrogen, and C is optionally substituted. １ -C ６ Alkyl and C １ -C ６ Alkyl-NH ２ The compound according to claim 84, selected from the group consisting of the following, wherein the optional substituent is a halogen or a hydroxyl group.

95. M is a carbonyl group, R １ and R ２ However, each is hydrogen, and R ４ However, C １ -C ６ Alkyl-NHR ４ａ The compound according to claim 94.

96. Ring B is R Ｂ１ It is a monosubstituted phenyl, or R Ｂ１ and R Ｂ２ The compound according to claim 94 or 95, which is a phenyl compound that is disubstituted with phenyl.

97. R Ｂ１ and R Ｂ２ The compound according to claim 96, wherein each is a fluoropolymer.

98. Ring C is a 4-10 member monocyclic or bicyclic condensed heterocyclyl, or a 5-10 member heteroaryl, and each is R Ｃ１ , R Ｃ２ , and R Ｃ３ The compound according to claim 90 or 91, which is substituted with

99. The compound according to claim 1, wherein g is 1.

100. R Ｃ１ However, R ３ Together, the following are formed: 【Transformation 56】 During the ceremony, 【Chemistry 57】 R ６ This represents the aforementioned connection point to A, p is an integer between 1 and 4. R ７ａ and R ７ｂ In each case, hydroxyl is optionally substituted with -C. １ -C ６ Alkyl, -N ３ ,-NR ａ R ｂ Independently selected from the group consisting of, R ａ and R ｂ These are, independently, H or C １ -C ６ It is alkyl, E does not exist, or -O- or -N(R) ｂ ) - and R ｂ C can be substituted with H or as desired. １ -C ６ It is alkyl, J is -C(O)- or -C(R ７ａ R ７ｂ ) - and The compound according to claim 99, wherein L is absent or -O- or -N(H)-.

101. A compound according to claim 99 or 100, having the structure of formula I-2. 【Chemistry 58】

102. -L-J-E-(CR ７ａ R ７ｂ ) ｐ - The compound according to claim 100 or 101, wherein it forms the following: 【Chemistry 59】 【Transformation 60】

103. Ring B is R Ｂ１ and R Ｂ２ The compound according to any one of claims 99 to 102, wherein the compound is a phenyl compound that is disubstituted with phenyl.

104. R Ｂ１ is halogen, R Ｂ２ is halogen or C １ -C ６ The compound according to claim 103, wherein it is alkyl.

105. R Ｂ１ is fluoro, R Ｂ２ The compound according to claim 104, wherein is fluoro or methyl.

106. R in the phenyl ring Ｂ１ and R Ｂ２ The compound according to any one of claims 103 to 105, wherein the position is as follows. 【Chemistry 61】

107. R Ｃ１ The compound according to any one of claims 99 to 106, wherein the ring C to which is bonded has the following structure. 【Transformation 62】

108. R Ｃ２ The compound according to claim 107, wherein it is cyano.

109. A has the following structure, 【Transformation 63】 During the ceremony, G is N, and D is CH ２ And y is 0 or 1, each 【Chemistry 64】 It is a single bond, G is C, and D is CH ２ And y is 1, 【Transformation 65】 It is a double bond, and the other 【Chemical Formula 66】 Each is a single bond, G is N, and D is CH ２ And y is 0, 【Transformation 67】 Each of them is a double bond, and the other 【Transformation 68】 Each is a single bond, G is C, D is N or C-H, y is 1, each 【Transformation 69】 The compound according to any one of claims 99 to 108, wherein is a double bond.

110. The compound according to claim 109, wherein A is selected from the group consisting of the following. 【Transformation 70】

111. A has the following structure, 【Chemistry 71】 In the formula, ring A2 is C ４ -C ６ A compound according to any one of claims 99 to 108, wherein it is a cycloalkyl compound.

112. The compound according to claim 111, wherein A is selected from the group consisting of the following. 【Chemistry 72】

113. The compounds shown in Table 1, or their pharmaceutically acceptable salts.

114. A pharmaceutical composition comprising a compound according to any one of claims 1 to 113, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

115. A method for treating a subject suffering from a somatostatin-related disease, comprising administering to the subject a compound according to any one of claims 1 to 113 or a pharmaceutical composition according to claim 114.

116. The method according to claim 115, wherein the disease is selected from the group consisting of diabetes mellitus, diarrhea, inflammatory bowel disease, irritable bowel syndrome, cancer, acromegaly, depression, chronic atrophic gastritis, Crohn's disease, ulcerative colitis, retinopathy, arthritis, restenosis, neuroendocrine tumors (NETs), and pain.

117. A method for activating somatostatin receptors in a subject, comprising administering to the subject a compound according to any one of claims 1 to 113 or a pharmaceutical composition according to claim 114.

Images