Somatostatin receptor 2 agonists and uses thereof

Abstract

The subject matter described herein relates to somatostatin receptor activating compounds, methods of making the compounds, pharmaceutical compositions, and the use of the somatostatin receptor activating compounds and the pharmaceutical compositions in the treatment of diseases associated with somatostatin receptors.

Description

[0001] Cross - reference to related applications

[0002] This patent application claims the benefit and priority of PCT application No. PCT / CN2022 / 128301, filed on October 28, 2022, the entire content of which is incorporated herein by reference. Technical field

[0003] The subject matter described herein relates to somatostatin receptor - activating compounds, methods for preparing such compounds, pharmaceutical compositions, and the use of such somatostatin receptor - activating compounds and such pharmaceutical compositions in the treatment of diseases related to somatostatin receptors. Background art

[0004] Somatostatin (SST) is a peptide with many biological functions, including regulation of the secretion of growth hormone, insulin, glucagon, and gastric acid. Additionally, SST exhibits potent anti - proliferative effects.

[0005] The mechanism of action of somatostatin is through high - affinity membrane - associated somatostatin receptors (SSTRs). There are five pharmacologically distinct SSTRs (SSTR1 - 5) with heterogeneous distribution. SSTR2 is of particular interest because it has been shown to mediate the inhibition of growth hormone release from the anterior pituitary and glucagon release from the pancreas. Growth hormone plays a pathogenic role in diabetes - related complications such as diabetic retinopathy. The regulation of glucagon and growth hormone release by somatostatin makes SSTR2 activators or agonists useful for the treatment of diabetes and diabetes - related diseases, including retinopathy, neuropathy, and nephropathy. Additionally, somatostatin and SSTR2 are also involved in a variety of other biological processes, such as nociception, inflammation, and cell proliferation.

[0006] Accordingly, the compounds and methods described herein can also be used to treat 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.

[0007] Accordingly, what is needed in the art but not effectively solved is a compound that acts as an SSTR2 agonist, which can be effectively formulated and administered and has enhanced desired activity of SSTR2. This deficiency is addressed by the subject matter described herein. Summary of the invention

[0008] In certain embodiments, the subject matter described herein relates to a compound of Formula I or a pharmaceutically acceptable salt thereof, said formula 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.

[0009] In certain embodiments, the subject matter described herein relates to a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0010] 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.

[0011] In certain embodiments, the subject matter described herein relates to a method of treating a subject having a disease associated with somatostatin, said method comprising administering to the subject a compound of Formula I or a pharmaceutical composition thereof.

[0012] In certain embodiments, the subject matter described herein relates to a method of activating somatostatin receptors in a subject, said method comprising administering to the subject a compound of Formula I or a pharmaceutical composition thereof.

[0013] Other embodiments are also described. Detailed Description

[0014] The presently disclosed subject matter will now be described more fully hereinafter. However, many modifications and other embodiments of the presently disclosed subject matter will come to mind to those skilled in the art to which the presently disclosed subject matter pertains, having the benefit of the teachings presented in the foregoing description. Therefore, it is to be understood that the presently disclosed 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. In other words, the subject matter described herein covers all alternatives, modifications, and equivalents. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. If one or more of the incorporated documents, patents, and the like materials differ from or contradict this application, including but not limited to defined terms, term usage, described technologies, etc., this application controls.

[0015] I. Definitions

[0016] As used in this specification, the following words, phrases, and symbols are generally intended to have the meanings as set forth below, unless the context in which they are used indicates otherwise.

[0017] A dash (“-”) not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -C(O)NH2 is attached through the carbon atom. Dashes at the front or end of a chemical group are for convenience; the chemical group may be depicted with one or more dashes or without one or more dashes without loss of its general meaning. A wavy or dashed line drawn at the end of a line passing through or perpendicular to the structure indicates the designated point of attachment of the group. Unless chemistry or structure requires it, directionality or stereochemistry is not indicated or implied by the order in which chemical groups are written or named.

[0018] The prefix “C u -C v ” indicates that the following group has u to v carbon atoms. For example, “C1-C6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.

[0019] References herein to “about” values or parameters include (and describe) embodiments that are directed to the value or parameter itself. In certain embodiments, the term “about” includes the indicated amount ±50%. In certain other embodiments, the term “about” includes the indicated amount ±20%. In certain other embodiments, the term “about” includes the indicated amount ±10%. In other embodiments, the term “about” includes the indicated amount ±5%. In certain other embodiments, the term “about” includes the indicated amount ±1%. In certain other embodiments, the term “about” includes the indicated amount ±0.5%, and in some embodiments, 0.1%. Such variations are suitable for performing the disclosed methods or employing the disclosed compositions. Moreover, the term “about x” includes a description of “x”. Also, unless the context clearly dictates otherwise, the singular forms “a” and “the” include plural referents. Thus, for example, reference to “a compound” includes a plurality of such compounds, and reference to “an assay” includes reference to one or more assays known to those skilled in the art and their equivalents.

[0020] “Alkyl” refers to a saturated hydrocarbon chain that is unbranched or branched. As used herein, alkyl has from 1 to 20 carbon atoms (i.e., C1-C 20 alkyl), from 1 to 12 carbon atoms (i.e., C1-C 12alkyl), from 1 to 8 carbon atoms (i.e., C1-C8 alkyl), from 1 to 6 carbon atoms (i.e., C1-C6 alkyl), from 1 to 4 carbon atoms (i.e., C1-C4 alkyl) or from 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 the said number of carbon atoms can be covered; thus, 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).

[0021] The term "alkylene" by itself or as part of another substituent means a divalent group derived from an alkane, such as methylene —CH2—, ethylene —CH2CH2—, etc. For example, "hydroxy-methylene" means HO—CH2—*, where * is the point of attachment of the molecule.

[0022] Unless otherwise expressly stated, when a combination of groups is referred to herein as a moiety, such as arylalkyl or aralkyl, the last-mentioned group contains the atom through which the moiety is attached to the rest of the molecule.

[0023] "Alkoxy" means the group "alkyl-O-". Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy and 1,2-dimethylbutoxy.

[0024] "Amino" means the group -NR y R z where R y and R z are independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl; as defined herein, each of them may optionally be substituted.

[0025] "Aryl" means an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-C 20 aryl), 6 to 12 carbocyclic atoms (i.e., C6-C 12 aryl) or 6 to 10 carbocyclic atoms (i.e., C6-C 10aryl). Examples of aryl include, for example, phenyl, naphthyl, fluorenyl, and anthracenyl. However, aryl does not encompass heteroaryl as defined below or overlap with heteroaryl in any way. If one or more aryl groups are fused to a heteroaryl group, the resulting ring system is heteroaryl. If one or more aryl groups are fused to a heterocyclic group, the resulting ring system is heterocyclic.

[0026] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl (i.e., a cyclic group having at least one double bond) and a carbocyclic fused ring system having at least one sp 3 carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has 3 to 20 ring carbon atoms (i.e., C3-C 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 cycloalkyl), 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 carbon atoms (i.e., C3-C6 cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include, for example, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like. Further, the term cycloalkyl is intended to encompass any non-aromatic ring that may be fused to an aryl ring, regardless of the connectivity of the rest of the molecule. Still further, when there are two substitution positions on the same carbon atom, cycloalkyl also includes "spirocycloalkyl", such as spiro[2.5]octyl, spiro[4.5]decyl, or spiro[5.5]undecyl.

[0027] "Halogen" or "halo" refers to an atom occupying Group VIIA of the periodic table, such as fluorine, chlorine, bromine, or iodine.

[0028] "Halogenoalkyl" means a straight 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 halogen. For example, in the case where the residue is substituted by more than one halogen, it may be referred to by using a prefix corresponding to the number of attached halogen moieties. Dihalogenoalkyl and trihalogenoalkyl mean an alkyl group substituted by two ("di") or three ("tri") halogen groups, which may or may not be the same halogen. Examples of halogenoalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. "C1-C3 halogenoalkyl" and "halogeno-C1-C3 alkyl" are used interchangeably herein and mean an alkyl chain having 1 to 3 carbon atoms, in which one or more hydrogen atoms in the alkyl chain are replaced by halogen. Further, C1-C3 fluoroalkyl (or fluoro-C1-C3 alkyl) means an alkyl chain having 1 to 3 carbon atoms, in which one or more hydrogen atoms in the alkyl chain are replaced by fluorine. Non-limiting examples of halogenoalkyl include -CH2CH2CF3, -CHF2, -CF3, -CH2CHF2, and -CH2CF3.

[0029] "Halogenoalkoxy" means an alkoxy group as defined above, in which one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by halogen. "C1-C3 halogenoalkoxy" and "halogeno-C1-C3 alkoxy" are used interchangeably herein and mean an alkoxy group 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 halogen. Non-limiting examples of halogenoalkoxy include -OCH2CHF2, -OCH2CF3, and -OCF3.

[0030] "Hydroxyalkyl" or "hydroxyalkylene", etc. means an alkyl or alkylene group as defined above, in which one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a hydroxyl group. By way of example, the terms "hydroxy-C1-C3 alkyl", "C1-C3 hydroxyalkyl", or "hydroxy-C1-C3 alkylene" mean an alkyl chain of one to three carbons, in which one or more hydrogens on any carbon are replaced by a hydroxyl group, particularly one hydrogen on one carbon of the chain.

[0031] "Heteroaryl" means an aromatic group having a single ring, multiple rings, or multiple fused rings, in which one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-C 20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-C 12heteroaryl) or 3 to 8 carbocyclic atoms (i.e., C3-C8 heteroaryl) 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, said ring heteroatoms being independently selected from nitrogen, oxygen and sulfur. In certain cases, heteroaryl includes a 9- to 10-membered ring system (9- to 10-membered heteroaryl), a 6- to 10-membered ring system (6- to 10-membered heteroaryl), a 5- to 10-membered ring system (5- to 10-membered heteroaryl), a 5- to 7-membered ring system (5- to 7-membered heteroaryl) or a 5- to 6-membered ring system (5- to 6-membered heteroaryl), 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 include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, 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, isoquinolinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyrazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl and triazinyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]phenylthio, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridyl and imidazo[1,5-a]pyridyl, wherein the heteroaryl may be attached through any one of the rings of the fused system. Any aromatic ring having a single or multiple fused rings and containing at least one heteroatom is considered heteroaryl, regardless of the attachment of the rest of the molecule (i.e., through any one of the fused rings in the fused ring). Heteroaryl does not encompass aryl as defined above or does not overlap with aryl.

[0032] "Heterocycloalkyl" means a saturated or partially unsaturated cyclic alkyl group in which one or more ring heteroatoms are independently selected from nitrogen, oxygen and sulfur. The term "heterocycloalkyl" includes heterocycloalkenyl (i.e., a heterocycloalkyl group having at least one double bond), bridged heterocycloalkyl, fused heterocycloalkyl and spiro heterocycloalkyl. Heterocycloalkyl may be a single ring or multiple rings, wherein the multiple rings may be fused, bridged or spiro and may contain one or more (e.g., 1 to 3) oxo (=O) or N-oxides (-O -) moiety. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclic group regardless of the attachment (i.e., it can be attached through a carbon atom or a heteroatom). Further, the term heterocyclic group is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring can be fused to an aryl ring or a heteroaryl ring regardless of the attachment of the rest of the molecule. As used herein, a heterocyclic group has from 2 to 20 ring carbon atoms (i.e., C2-C 20 heterocyclic group), from 2 to 12 ring carbon atoms (i.e., C2-C 12 heterocyclic group), from 2 to 10 ring carbon atoms (i.e., C2-C 10 heterocyclic group), from 2 to 8 ring carbon atoms (i.e., C2-C8 heterocyclic group), from 3 to 12 ring carbon atoms (i.e., C3-C 12a heterocyclic group), 3 to 8 ring carbon atoms (i.e., C3-C8 heterocyclic group) or 3 to 6 ring carbon atoms (i.e., C3-C6 heterocyclic group); having 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 heterocyclic group ring contains 4 or 6 ring atoms, it is also referred to herein as a 4-membered or 6-membered heterocyclic group. When the heterocyclic group ring contains 5 to 7 ring atoms, it is also referred to herein as a 5- to 7-membered heterocyclic group. When the heterocyclic group ring contains 5 to 10 ring atoms, it is also referred to herein as a 5- to 10-membered heterocyclic group. Examples of heterocyclic groups include, for example, azanyl, azepinyl, benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyrone, benzofuranone, dioxolanyl, dihydropyranyl, hydropyranyl, thieno[1,3]dithiolanyl, decahydroisoquinolinyl, furanone, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, trithienyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), tetrahydropyranyl, thiomorpholinyl, thioxomorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. When there are two substitution positions on the same carbon atom, the term "heterocyclic group" also includes "spiroheterocyclic group". Examples of spiroheterocyclic group 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 fused heterocyclic group rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolyl and isoindolyl, wherein the heterocyclic group can be attached through any ring of the fused system.

[0033] “(C1-C3 alkoxy)-C1-C3 alkyl” means -alkyl-alkoxy, wherein both the alkoxy unit and the alkyl unit each independently contain an alkyl chain having 1 to 3 carbon atoms.

[0034] “(C1-C3 alkoxy)-C1-C3 alkoxy” means -alkoxy-alkoxy, wherein both alkoxy units each independently contain an alkyl chain having 1 to 3 carbon atoms.

[0035] The term "optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and the description includes instances where the described event or circumstance occurs and instances where the described event or circumstance does not occur. Similarly, the term "optionally substituted" means that any one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms on a specified atom or group may be replaced by a moiety other than hydrogen or may not be replaced.

[0036] As used herein, the term "substituted" means any one of the above groups (i.e., alkyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclic, and / or heteroaryl) in which at least one (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms is replaced by a bond to a non-hydrogen atom, the non-hydrogen atom being such as but not limited to alkyl, alkoxy, amino, aryl, aralkyl, carboxyl, carboxyl ester, cyano, cycloalkyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, heteroaryl, heterocyclic, -NHNH2, hydroxy, oxo, nitro, -S(O)OH, -S(O)2OH, N-oxide, or -Si(R y )3, where each R y is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic.

[0037] In certain embodiments, "substituted" includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, where one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are independently replaced by: deuterium, halo, cyano, nitro, oxo, alkyl, haloalkyl, cycloalkyl, heterocyclic, 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 OR g , -NR g S(=O) 1-2 NR g R h , =NSO2R g , =NOR g , -S(=O) 1- 2NR g R h , -SF5, -SCF3 or -OCF3. In certain embodiments, "substituted" also means any of the above groups in which one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are replaced by: -C(=O)R g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g or -CH2SO2NR g R h . As used above, R g and R h are the same or different and independently are hydrogen, alkyl, alkoxy, aryl, cycloalkyl, haloalkyl, heterocyclic, and / or heteroaryl. In certain embodiments, "substituted" also means any of the above groups in which one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are replaced by a bond to an amino, cyano, hydroxy, nitro, oxo, halo, alkyl, alkoxy, alkylamino, aryl, cycloalkyl, haloalkyl, heterocyclic, N - heterocyclic, heteroaryl, or R g and R h and R i together with the atoms to which they are attached form a heterocyclic ring optionally substituted with oxo, halo, or an alkyl - substituted heterocyclic ring optionally substituted with oxo, halo, amino, hydroxy, or alkoxy.

[0038] In certain embodiments described herein, the statement "R 1 and Z together with the rings to which they are respectively attached form a fused bicyclic ring" refers to a compound having the following structure:

[0039]

[0040] In certain embodiments, the statement "R 1 and R C1"Together with the rings to which they are attached form a fused tricyclic ring" refers to a compound having the following structure:

[0041]

[0042] In certain embodiments, the expression "R 2 and R B1 Together with the rings to which they are attached form a fused tricyclic ring" refers to a compound having the following structure:

[0043]

[0044] Polymers or similar indeterminate structures obtained by defining substituents with additional substituents attached infinitely (e.g., a substituted aryl having a substituted alkyl, the substituted alkyl itself being substituted by a substituted aryl substituted by a further substituted heteroalkyl, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of serial substitutions in the compounds described herein is three. For example, the serial substitution of two other substituted aryls for a substituted aryl is limited to (aryl substituted by (substituted aryl)) substituted aryl. Similarly, the above definitions are not intended to include non-permissible substitution patterns (e.g., a methyl group substituted by 5 fluorines or a heteroaryl having two adjacent oxygen ring atoms). Such non-permissible substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups defined herein.

[0045] In certain embodiments, as used herein, the phrase "one or more" means one to five. In certain embodiments, as used herein, the phrase "one or more" means one to four. In certain embodiments, as used herein, the phrase "one or more" means one to three.

[0046] Any compound or structure given herein is intended to represent both the unlabeled form and the isotopically labeled form (isotopomer) of the compound. These forms of the compound may also be referred to as and include "isotope-enriched analogs". The isotopically labeled compound has the structure depicted herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I. Various isotopically labeled compounds of the present disclosure, such as compounds doped with radioactive isotopes such as 3 H, 13 C and 14 C. Such isotopically labeled compounds can be used in metabolic studies, reaction kinetics studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including tissue distribution assays of drugs or substrates, or can be used for radiotherapy of patients.

[0047] 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 carbon atoms. When administered to mammals, especially humans, such compounds exhibit increased metabolic tolerance and can therefore be used to increase the half-life of any compound. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, such as by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0048] The deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, which relate to distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope, such as deuterium, can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life and reduced dose requirements and / or improved therapeutic index. 18 F, 3 H, 11 C-labeled compounds can be used in PET or SPECT or other imaging studies. The isotopically labeled compounds and their prodrugs of the present disclosure can generally be prepared by performing the procedures disclosed in the protocols or examples and as described below, by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents. It should be understood that deuterium in this context is considered a substituent in the compounds described herein.

[0049] The concentration of this heavier isotope, specifically deuterium, can be defined by the isotope enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of said atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen with its natural abundance isotope composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) means deuterium. Further, in some embodiments, corresponding deuterated analogs are provided.

[0050] In many cases, the compounds of the present disclosure are capable of forming acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto.

[0051] Also provided are pharmaceutically acceptable salts, isotope-enriched analogs, deuterated analogs, isomers (such as stereoisomers), mixtures of isomers (such as mixtures of stereoisomers), prodrugs, and metabolites of the compounds described herein.

[0052] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0053] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. Additionally, if a compound described herein is obtained in the form of an acid addition salt, the free base can be obtained by basifying the solution of the acid salt. Conversely, if the product is a free base, an addition salt, specifically a pharmaceutically acceptable addition salt, can be manufactured 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 basic compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic acids and organic acids. Salts derived from inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Salts derived from organic acids include, for example, 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, salicylic acid, etc. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, 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, salts of 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)), bis(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tris(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)), bis(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tris(substituted alkenyl)amines (i.e., N(substituted alkenyl)3), monocyclic, bicyclic, or tricyclic alkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), monoaryl, diaryl, or triarylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. By way of example only, specific examples of suitable amines include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, etc.

[0054] The term "hydrate" refers to a complex formed by combining a compound described herein and water.

[0055] "Solvate" refers to the association or complexation 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, isopropyl alcohol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine.

[0056] Some of the compounds in the compound exist in the form of tautomers. Tautomers are in equilibrium with each other. For example, a compound containing an amide can exist in equilibrium with an imino acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between the tautomers, one of ordinary skill in the art should understand the compound to include both the amide and imino acid tautomers. Thus, a compound containing an amide is understood to include its imino acid tautomers. Similarly, a compound containing an imino acid is understood to include its amide tautomers.

[0057] The compounds of the present disclosure and their pharmaceutically acceptable salts include asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- according to absolute stereochemistry or as (D)- or (L)- for amino acids. The present subject matter is intended to include all such possible isomers and their racemic and optically pure forms. The optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., chromatography and fractional crystallization). Conventional techniques for the preparation / separation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of a racemate (or a racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). When the compounds described herein contain an olefinic double bond or other centers of geometric asymmetry and unless otherwise specified, it is intended that the compounds include both the E geometric isomers and the Z geometric isomers.

[0058] "Stereoisomer" refers to a compound composed of the same atoms connected by the same bonds but having different three-dimensional structures, which are not interchangeable. The present subject matter encompasses various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0059] "Diastereomer" is a stereoisomer having at least two asymmetric atoms but not being a mirror image of each other.

[0060] The relative centers of the compounds depicted herein are indicated diagrammatically using the "thick bond" form (bold line or parallel lines), and the absolute stereochemistry is depicted using wedge bonds (bold line or parallel lines).

[0061] "Prodrug" means any compound which, when administered to a mammalian subject, releases the active parent drug in vivo according to the structures described herein. Prodrugs of the compounds described herein are prepared by modifying the functional groups present in the compounds described herein in such a way that the modification can be cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying the functional groups present in these compounds in such a way that the modifications are cleavable either in conventional operations or in vivo to form these parent compounds. Prodrugs include those described herein in which a hydroxyl, amino, carboxyl or mercapto group in the compounds described herein is bonded to any group which can be cleaved in vivo to regenerate the free hydroxyl, amino or mercapto group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl), etc. of the hydroxyl functional group in the compounds described herein. The preparation, selection and use of prodrugs are discussed in the following references: T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol. 14 of the A.C.S. Symposium Series; "Design of Prodrugs", edited by H. Bundgaard, Elsevier, 1985; and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is hereby incorporated herein by reference in its entirety.

[0062] As used herein, the term "metabolite" refers to the resulting product formed when the compounds disclosed herein are metabolized. As used herein, the term "metabolized" refers to the sum total of the processes by which a particular substance, such as the compounds disclosed herein, is altered by an organism (including, but not limited to, hydrolysis reactions and enzyme-catalyzed reactions). For example, the aldehyde moiety (-C(O)H) of the subject compounds of the invention can be reduced in vivo to the -CH2OH moiety.

[0063] As used herein, terms such as "somatostatin receptor agonist" refer to a compound that activates, increases, or modulates one or more biological activities of a somatostatin receptor. Compared to an appropriate control, the activity can be increased by, for example, at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95%, or 100% of the activity of the somatostatin receptor. The increase can be a statistically significant increase.

[0064] "Treatment" (or "treating") is a method for obtaining a beneficial or desired result, including a clinical result. Beneficial or desired clinical results can include one or more of the following: a) inhibiting a disease or disorder (e.g., reducing one or more symptoms caused by the disease or disorder, and / or reducing the severity of the disease or disorder); b) slowing or inhibiting the progression of one or more clinical symptoms associated with the disease or disorder (e.g., stabilizing the disease or disorder, preventing or delaying the worsening or progression of the disease or disorder, and / or preventing or delaying the spread (e.g., metastasis) of the disease or disorder); and / or c) alleviating the disease, i.e., causing the decline of clinical symptoms (e.g., improving the disease state, providing partial or complete remission of the disease or disorder, enhancing the effect of another drug treatment, delaying the progression of the disease, improving the quality of life, and / or prolonging the survival period).

[0065] "Prevention" (or "preventing") means any treatment of a disease or disorder that results in the non-development of the clinical symptoms of the disease or disorder. In some embodiments, the compound can be administered to a subject (including a human) at risk or having a family history of the disease or disorder.

[0066] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation, or experiment. The methods described herein can be used for human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0067] The term "therapeutically effective amount" or "effective amount" of a compound or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogue thereof described herein refers to an amount sufficient to achieve a treatment when administered to a subject to provide a therapeutic benefit, such as improving symptoms or slowing the progression of a disease. For example, a therapeutically effective amount can be an amount sufficient to alleviate the symptoms of pyruvate kinase deficiency (PKD). The therapeutically effective amount can vary depending on the subject, the disease or disorder being treated, the weight and age of the subject, the severity of the disease or disorder, and the mode of administration, which can be readily determined by those skilled in the art.

[0068] Additional definitions may also be provided as appropriate hereinafter.

[0069] II. Compounds

[0070] As described herein, in certain embodiments, the subject matter relates to a compound of Formula I:

[0071]

[0072] or a pharmaceutically acceptable salt thereof; wherein

[0073] g is 1 or 0;

[0074] Z is absent, -N(H)-C(=O)- or -C(=O)-NH-;

[0075] R 1 is hydrogen or halogen; or

[0076] R 1 and Z together with the ring to which each is attached form a fused bicyclic ring, optionally substituted with one or two R 8 substituents; or

[0077] R 1 and R C1 together with the ring to which each is attached form a fused tricyclic ring;

[0078] Ring C is selected from the group consisting of 4- to 10-membered monocyclic or bicyclic fused heterocyclic groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups, each of which is substituted with R C1 , R C2 and R C3 ;

[0079] wherein the 4- to 10-membered monocyclic or bicyclic fused heterocyclic group or 5- to 10-membered heteroaryl group each independently contains 1, 2, 3 or 4 ring heteroatoms selected from N, O and S; and wherein

[0080] R C1 is hydrogen, or may combine with R 1 , R 3 or R 6 ;

[0081] R C2 and R C3 are each independently selected from the group consisting of hydrogen, halogen, cyano, C1-C6 alkyl, hydroxy, -C(=O)NH2, -O-C2-C6 alkenyl, -C1-C6 alkoxy, -NH-(CH2) 1-5 -NH2, -O-piperidinyl, -O-(CH2) qC -O-(CH2) rC-CH3, where qC and rC are each independently an integer from 1 to 4,

[0082] R 2 is hydrogen or a halogen; or

[0083] R 2 and R B1 together with the ring to which each is attached form a fused tricyclic ring;

[0084] R 3 , if present, is a group covalently bonded to R C1 ;

[0085] Ring B is phenyl or pyridyl, each of which is monosubstituted by R B1 or disubstituted by R B1 and R B2 ;

[0086] where R B1 and R B2 are each independently selected from the group consisting of: 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 -CH3, -C(O)-NR Na R Nb , where q2 and r2 are each independently an integer from 1 to 4, where each R Na and R Nb are each independently selected from the group consisting of: hydrogen and C1-C6 alkyl;

[0087] and

[0088] A is selected from the group consisting of:

[0089] i. -NR 4 R 5 , where

[0090] R 4 is optionally substituted C1-C6 alkyl, -NH-C1-C6 alkyl-NHR 4a and -C1-C6 alkyl-NHR 4a , where R 4a is hydrogen or methyl; and

[0091] R 5 is hydrogen or optionally substituted C1-C6 alkyl;

[0092] where the optional substituents are selected from the group consisting of: halogen and hydroxy;

[0093] or

[0094] R 5 and R B1 with R 5 The N and R connected to B1 together with the linked ring B form a fused heterocyclic group;

[0095] or

[0096] R 5 and R C1 with R 5 The N and R connected to C1 together with the linked ring C form a fused heterocyclic group;

[0097] or

[0098] R 5 and R 8 with R 5 The N and R connected to 8 together with the linked ring form a fused heterocyclic group;

[0099] ii. A spiro ring substituted by -NH-R 6 or R S wherein

[0100] R S is hydrogen or -C(=O)-C1-C6 alkyl;

[0101] and

[0102] iii. -O-(C3-C8 cycloalkyl), a 5- to 11-membered heterocyclic group or a 5- to 6-membered heteroaryl group, each of which is substituted by -NH-R 6 substituted, or substituted by R F and R G wherein

[0103] R F is selected from the group consisting of: hydroxy, 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 wherein

[0104] x is 0 or 1; and

[0105] R F1 and R F2Each is independently H, -(C═O)-O-C1-C6 alkyl, and C1-C6 alkyl;

[0106] R G is hydrogen or -C1-C6 alkoxy; or

[0107] R G together with R C1 forms -O-(CH2) k -O-, where k is an integer from 1 to 5; or

[0108] R F and R G together form a carboxyl group; and

[0109] R 6 together with R C1 forms:

[0110]

[0111] where

[0112] represents the point of attachment of R 6 to A;

[0113] p is an integer from 1 to 4;

[0114] 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 , where R a and R b are each independently H or C1-C6 alkyl;

[0115] When E is absent, it is -O- or -N(R b )-, where R b is H or optionally substituted C1-C6 alkyl;

[0116] J is -C(O)- or -C(R 7a R 7b )-; and

[0117] When L is absent, it is -O- or -N(H)-,

[0118] where the optional substituent is selected from the group consisting of: halogen, -NH2, and hydroxyl;

[0119] provided that the compound is not one of the following:

[0120]

[0121] In certain of the above embodiments, useful compounds are those in which Z is absent.

[0122] 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.

[0123] In certain of the above embodiments, useful compounds are those in which g is 0.

[0124] In certain of the above embodiments, useful compounds are those having the structure of formula Ia or Ib, wherein Z and R 1 together with the rings to which they are attached form a fused:

[0125]

[0126] wherein X 1 and X 2 are each independently selected from the group consisting of: O, N, N-R 8 , S and C-R 8 ;

[0127] wherein R 8 is selected from the group consisting of: hydrogen, optionally substituted C1-C6 alkyl, and -C(=O)OR 8a , wherein R 8a is hydrogen or C1-C6 alkyl, and wherein the optional substituent is selected from the group consisting of: halogen, -NH2, and hydroxy.

[0128] In certain of the above embodiments, useful compounds are those having the structure of formula Ia-1:

[0129]

[0130] In certain of the above embodiments, useful compounds are those having the structure of formula Ia-2:

[0131]

[0132] In certain of the above embodiments, useful compounds are those having the structure of formula Ia-3:

[0133]

[0134] In certain of the above embodiments, useful compounds are those having the structure of formula Ib-1:

[0135]

[0136] In certain of the above embodiments, useful compounds are those compounds having the structures of Formulae Ib-1a to Ib-1e:

[0137]

[0138] and

[0139]

[0140] In certain of the above embodiments, useful compounds are those in which R B1 and R B2 in each of Ib-1a to Ib-1e are in the following positions:

[0141]

[0142] In certain of the above embodiments, useful compounds are those in which R B1 and R B2 are each independently selected from the group consisting of: C1-C6 alkyl, halogen, and C1-C6 alkoxy.

[0143] In certain of the above embodiments, useful compounds are those in which the C1-C6 alkyl is methyl, the halogen is fluorine, and the C1-C6 alkoxy is methoxy.

[0144] In certain of the above embodiments, useful compounds are those in which at least one of R B1 and R B2 is fluorine.

[0145] In certain of the above embodiments, useful compounds are those in which both R B1 and R B2 are fluorine.

[0146] In certain of the above embodiments, useful compounds are those in which R C1 is hydrogen, and the positions of R C2 and R C3 are as follows:

[0147]

[0148] In certain of the above embodiments, useful compounds are those compounds in which

[0149] R C2 is selected from the group consisting of: hydroxy, C1-C6 alkoxy, -O-piperidinyl, -N-(CH2)3-NH2, -O-C2-C6 alkenyl, -O-(CH2) q1 -O-(CH2) r1-CH3, where q1 and r1 are each independently an integer from 1 to 4; and

[0150] R C3 is selected from the group consisting of: cyano and halogen.

[0151] In certain of the above embodiments, useful compounds are those compounds wherein

[0152] R C2 is selected from the group consisting of: hydroxy, methoxy, -O-CH2-CH=CH2, and -O-CH2-O-CH3, and

[0153] R C3 is selected from the group consisting of: cyano and bromine.

[0154] In certain of the above embodiments, useful compounds are those wherein R C1 is hydrogen, and the positions of R C2 and R C3 are those as follows:

[0155]

[0156] In certain of the above embodiments, useful compounds are those compounds wherein

[0157] R C2 and R C3 are each halogen.

[0158] In certain of the above embodiments, useful compounds are those wherein the halogen is fluorine.

[0159] In certain of the above embodiments, useful compounds are those wherein R C1 is hydrogen, and the positions of R C2 and R C3 are those as follows:

[0160]

[0161] In certain of the above embodiments, useful compounds are those compounds wherein

[0162] R C2 and R C3 are each independently selected from the group consisting of: hydroxy, C1-C6 alkoxy, halogen, -(C=O)-NH2, -O-C2-C6 alkenyl, and C1-C6 alkyl.

[0163] In certain of the above embodiments, useful compounds are those compounds wherein

[0164] R C2 and RC3 Each independently selected from the group consisting of: -(C=O)-NH2, methoxy, fluorine, and methyl.

[0165] In certain of the above embodiments, useful compounds are those compounds wherein

[0166] Ring B is a phenyl group disubstituted by R B1 and R B2 ; and

[0167] Ring C is a 4- to 10-membered monocyclic or bicyclic heterocyclic group.

[0168] In certain of the above embodiments, useful compounds are those compounds wherein Ring C is a 9- to 10-membered bicyclic lactam or cyclic urea.

[0169] In certain of the above embodiments, useful compounds are those compounds wherein Ring C is selected from the group consisting of:

[0170] and

[0171]

[0172] In certain of the above embodiments, useful compounds are those compounds having the structure of Formula Ic, wherein Z is absent, and R 1 and R C1 together with the ring to which R 1 is attached and the ring to which R C1 is attached form a fused ring substituted by R 8 :

[0173]

[0174] In certain of the above embodiments, useful compounds are those compounds wherein R 8 is hydrogen.

[0175] In certain of the above embodiments, useful compounds are those compounds wherein Ring C is an 8- to 10-membered heteroaryl group substituted by R C2 and R C3 .

[0176] In certain of the above embodiments, useful compounds are those compounds wherein Ring C is the following:

[0177]

[0178] In certain of the above embodiments, useful compounds are those compounds wherein each of R C2 and R C3 is fluorine.

[0179] In certain of the above embodiments, useful compounds are those in which ring B is a phenyl group disubstituted by R B1 and R B2 .

[0180] In certain of the above embodiments, useful compounds are those in which R B1 is halogen and R B2 is halogen or C1-C6 alkyl

[0181] In certain of the above embodiments, useful compounds are those in which R B1 is fluorine and R B2 is fluorine or methyl

[0182] In certain of the above embodiments, useful compounds are those in which the positions of R B1 and R B2 in the benzene ring are as follows

[0183]

[0184] In certain of the above embodiments, useful compounds are those having the structure of formula Id, in which Z and R 1 together with the rings to which they are attached form a fused ring

[0185]

[0186] In certain of the above embodiments, useful compounds are those in which R 8 is hydrogen

[0187] In certain of the above embodiments, useful compounds are those in which ring C is a phenyl group substituted by R C1 , R C2 and R C3 .

[0188] In certain of the above embodiments, useful compounds are those in which R C1 is hydrogen and the positions of R C2 and R C3 are as follows

[0189]

[0190] In certain of the above embodiments, useful compounds are those in which R C2 and R C3 are each independently selected from the group consisting of C1-C6 alkyl and halogen

[0191] In certain of the above embodiments, useful compounds are those in which said C1-C6 alkyl is methyl and said halogen is fluorine.

[0192] In certain of the above embodiments, useful compounds are those in which ring B is phenyl disubstituted by R B1 and R B2 double-substituted phenyl.

[0193] In certain of the above embodiments, useful compounds are those in which R B1 is halogen and R B2 is halogen or C1-C6 alkyl.

[0194] In certain of the above embodiments, useful compounds are those in which R B1 is fluorine and R B2 is fluorine or methyl.

[0195] In certain of the above embodiments, useful compounds are those in which the positions of R B1 and R B2 in the phenyl are as follows:

[0196]

[0197] In certain of the above embodiments, useful compounds are those having the structure of formula Ie, wherein R 2 and R B1 together with the ring to which R 2 is attached and the ring to which R B1 is attached form a fused ring:

[0198]

[0199] wherein

[0200] Q is O or CH2, and is a single bond; or Q is N, and is a double bond;

[0201] R 1 is hydrogen or halogen; and

[0202] ring B is phenyl substituted by R B2 substituted phenyl.

[0203] In certain of the above embodiments, useful compounds are those in which R 1 is hydrogen.

[0204] In certain of the above embodiments, useful compounds are those in which ring C is substituted by R C1 、R C2 and R C3Those compounds of a substituted 8- to 10-membered heteroaryl.

[0205] In certain of the above embodiments, useful compounds are those in which R C1 is hydrogen and ring C is as follows:

[0206]

[0207] In certain of the above embodiments, useful compounds are those in which R B2 is halogen.

[0208] In certain of the above embodiments, useful compounds are those in which R B2 is fluorine.

[0209] In certain of the above embodiments, useful compounds are those in which Q is N and is a double bond.

[0210] In certain of the above embodiments, useful compounds are those in which Q is O and is a single bond.

[0211] In certain of the above embodiments, useful compounds are those in which A is each substituted by -NH-R 6 ; or by R F and R G substituted 5- to 11-membered heterocyclic group or 5- to 6-membered heteroaryl.

[0212] In certain of the above embodiments, useful compounds are those in which A has the following structure:

[0213]

[0214] wherein

[0215] ring A1 is a 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclic group.

[0216] In certain of the above embodiments, useful compounds are those in which A has the following structure:

[0217] i.

[0218] wherein

[0219] G is N; D is CH2; y is 0 or 1; and each is a single bond;

[0220] G is C; D is CH2; y is 1; and is a double bond, and the other are each single bonds;

[0221] G is N, D is CH2; y is 0; and and each is a double bond, and the others each is a single bond;

[0222] G is C; D is N or C-H; y is 1; and each is a double bond.

[0223] In certain of the above embodiments, useful compounds are those in which A is selected from the group consisting of:

[0224]

[0225] In certain of the above embodiments, useful compounds are those in which A is a spiro ring having the following structure:

[0226]

[0227] wherein t, t1, u and u1 are each independently 1 or 2.

[0228] In certain of the above embodiments, useful compounds are those in which A is selected from the group consisting of:

[0229]

[0230] In certain of the above embodiments, useful compounds are those in which A is -NH-R 6 substituted or -O-(C3-C8 cycloalkyl) substituted by R F and R G substituted.

[0231] In certain of the above embodiments, useful compounds are those in which A has the following structure:

[0232]

[0233] wherein

[0234] ring A2 is C4-C6 cycloalkyl.

[0235] In certain of the above embodiments, useful compounds are those in which A is selected from the group consisting of:

[0236]

[0237] In certain of the above embodiments, useful compounds are those compounds wherein

[0238] R 6 is associated with RC1 Together form:

[0239]

[0240] wherein

[0241] represents the point of attachment of R 6 to A;

[0242] p is an integer from 1 to 4;

[0243] R 7a and R 7b are each independently selected from the group consisting of: hydroxy, optionally substituted -C1-C6 alkyl, -N3, -NR a R b wherein R a and R b are each independently H or C1-C6 alkyl;

[0244] E is absent, is -O- or -N(R b )-, wherein R b is H or optionally substituted C1-C6 alkyl;

[0245] J is -C(O)- or -C(R 7a R 7b )-; and

[0246] L is absent, is -O- or -N(H)-.

[0247] In certain of the above embodiments, useful compounds are those in which R 6 together with R C1 form the following:

[0248]

[0249]

[0250] In certain of the above embodiments, useful compounds are those having the structure of formula Ia-4:

[0251]

[0252] In certain of the above embodiments, useful compounds are those having the structure of formula Ia-4A:

[0253]

[0254] In certain of the above embodiments, useful compounds are those in which the ring C to which R C1 is attached has the following structure:

[0255]

[0256] In certain of the above embodiments, useful compounds are those in which R C1 is attached to a ring C having the following structure:

[0257]

[0258] In certain of the above embodiments, useful compounds are those in which R C2 is cyano or -(C=O)-NH2.

[0259] In certain of the above embodiments, useful compounds are those having the structures of formulas Ia-6, Ia-7, Ib-2, and Ib-3:

[0260]

[0261]

[0262] In certain of the above embodiments, useful compounds are those in which R B1 and R B2 in each of Ia-6, Ia-7, Ib-2, and Ib-3 is in the following positions:

[0263]

[0264] In certain of the above embodiments, useful compounds are those in which R B1 and R B2 are each independently selected from the group consisting of: C1-C6 alkyl, halogen, and C1-C6 alkoxy.

[0265] In certain of the above embodiments, useful compounds are those in which the C1-C6 alkyl is methyl, the halogen is fluorine, and the C1-C6 alkoxy is methoxy.

[0266] In certain of the above embodiments, useful compounds are those in which at least one of R B1 and R B2 is fluorine.

[0267] In certain of the above embodiments, useful compounds are those in which R B1 and R B2 are both fluorine.

[0268] In certain of the above embodiments, useful compounds are those in which R C2 and R C3The positions are those compounds as follows:

[0269]

[0270] In certain of the above embodiments, useful compounds are those compounds in which

[0271] R C2 is selected from the group consisting of: hydroxy, C1-C6 alkoxy, -O-piperidinyl, -N-(CH2)3-NH2, -O-C2-C6 alkenyl, -O-(CH2) q1 -O-(CH2) r1 -CH3, where q1 and r1 are each independently an integer from 1 to 4; and

[0272] R C3 is selected from the group consisting of: cyano and halogen.

[0273] In certain of the above embodiments, useful compounds are those compounds in which

[0274] R C2 is selected from the group consisting of: hydroxy, methoxy, -O-CH2-CH=CH2, and -O-CH2-O-CH3, and

[0275] R C3 is selected from the group consisting of: cyano and bromine.

[0276] In certain of the above embodiments, useful compounds are those in which R C1 is hydrogen, and the positions of R C2 and R C3 are those as follows:

[0277]

[0278] In certain of the above embodiments, useful compounds are those compounds in which

[0279] R C2 and R C3 are each halogen.

[0280] In certain of the above embodiments, useful compounds are those in which the halogen is fluorine.

[0281] In certain of the above embodiments, useful compounds are those in which R C1 is hydrogen, and the positions of R C2 and R C3 are those as follows:

[0282]

[0283] In certain of the above embodiments, useful compounds are those wherein

[0284] R C2 and R C3 are each independently selected from the group consisting of: hydroxy, C1-C6 alkoxy, halogen, -(C=O)-NH2, -O-C2-C6 alkenyl, and C1-C6 alkyl.

[0285] In certain of the above embodiments, useful compounds are those wherein

[0286] R C2 and R C3 are each independently selected from the group consisting of: -(C=O)-NH2, methoxy, fluorine, and methyl.

[0287] In certain of the above embodiments, useful compounds are those wherein A is -NR 4 R 5 of those compounds.

[0288] In certain of the above embodiments, useful compounds are those wherein

[0289] R 4 is optionally substituted C1-C6 alkyl, -C1-C6 alkyl-NH-CH3, C1-C6 alkyl-NH2, -NH-C1-C6 alkyl-NH-CH3, -NH-C1-C6 alkyl-NH2, and

[0290] R 5 is hydrogen or optionally substituted C1-C6 alkyl.

[0291] In certain of the above embodiments, useful compounds are those wherein R 4 is -(CH2)3-NH-CH3; and R 5 is hydrogen of those compounds.

[0292] In certain of the above embodiments, useful compounds are those having the structure of formula If, wherein R 5 and R B1 together with the N to which R 5 is attached and the ring B to which R B1 is attached form a fused ring:

[0293]

[0294] wherein

[0295] M is a carbonyl or C-R M1 R M2 wherein R M1 and R M2Each independently is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, and C1-C6 alkyl-NH2, wherein said optional substituent is selected from the group consisting of halogen and hydroxy.

[0296] In certain of the above embodiments, useful compounds are those compounds wherein

[0297] M is CH2;

[0298] R 1 and R 2 are each hydrogen, and

[0299] R 4 is C1-C6 alkyl-NHR 4a .

[0300] In certain of the above embodiments, useful compounds are those compounds wherein Z is -C(=O)-NH-.

[0301] In certain of the above embodiments, useful compounds are those compounds wherein

[0302] ring B is phenyl monosubstituted by R B1 or disubstituted by R B1 and R B2 .

[0303] In certain of the above embodiments, useful compounds are those compounds wherein R B1 and R B2 are each fluorine.

[0304] In certain of the above embodiments, useful compounds are those compounds wherein ring C is a 4- to 10-membered monocyclic or bicyclic fused heterocyclic group or a 5- to 10-membered heteroaryl group each substituted by R C1 , R C2 and R C3 .

[0305] In certain of the above embodiments, useful compounds are those compounds wherein ring C is a 6- to 10-membered aryl group substituted by R C1 , R C2 and R C3 .

[0306] In certain of the above embodiments, useful compounds are those compounds having the structure of formula Ig, wherein Z is absent, and R 5 and R C1 together with the N to which R 5 is attached and the ring C to which R C1 is attached form a fused ring:

[0307]

[0308] wherein

[0309] M is a carbonyl or C-R M1 R M2 , where R M1 and R M2 are each independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, and C1-C6 alkyl-NH2, wherein the optional substituent is halogen or hydroxy.

[0310] In certain of the above embodiments, useful compounds are those wherein

[0311] M is a carbonyl;

[0312] R 1 and R 2 are each hydrogen, and

[0313] R 4 is C1-C6 alkyl-NHR 4a .

[0314] In certain of the above embodiments, useful compounds are those wherein

[0315] ring B is phenyl mono-substituted by R B1 or di-substituted by R B1 and R B2 .

[0316] In certain of the above embodiments, useful compounds are those wherein R B1 and R B2 are each fluorine.

[0317] In certain of the above embodiments, useful compounds are those wherein ring C is a 4- to 10-membered monocyclic or bicyclic fused heterocyclic group or a 5- to 10-membered heteroaryl group each substituted by R C1 , R C2 and R C3 .

[0318] In certain of the above embodiments, useful compounds are those wherein g is 1. These compounds will have a counterion, such as a halide.

[0319] In certain of the above embodiments, useful compounds are those wherein R C1 and R 3 together form the following:

[0320]

[0321] wherein

[0322] represents R6 The connection point with A;

[0323] p is an integer from 1 to 4;

[0324] R 7a and R 7b In each case, independently selected from the group consisting of: hydroxyl, optionally substituted -C1-C6 alkyl, -N3, -NR a R b , where R a and R b are each independently H or C1-C6 alkyl;

[0325] E is absent, is -O- or -N(R b ), where R b is H or optionally substituted C1-C6 alkyl;

[0326] J is -C(O)- or -C(R 7a R 7b ); and

[0327] L is absent, is -O- or -N(H)-.

[0328] In certain of the above embodiments, useful compounds are those compounds having the structure of formula I-2:

[0329]

[0330] In certain of the above embodiments, useful compounds are those in which -L-J-E-(CR 7a R 7b ) p - forms the following:

[0331]

[0332]

[0333]

[0334] In certain of the above embodiments, useful compounds are those in which ring B is a phenyl group disubstituted by R B1 and R B2 .

[0335] In certain of the above embodiments, useful compounds are those in which R B1 is halogen, and R B2 is halogen or C1-C6 alkyl.

[0336] In certain of the above embodiments, useful compounds are those in which R B1is fluorine and R B2 Those compounds in which it is fluorine or methyl.

[0337] In certain of the above embodiments, useful compounds are those in which R B1 and R B2 are in the following positions in the benzene ring:

[0338]

[0339] In certain of the above embodiments, useful compounds are those in which R C1 is attached to a ring C having the following structure:

[0340]

[0341] In certain of the above embodiments, useful compounds are those in which R C2 is cyano.

[0342] In certain of the above embodiments, useful compounds are those in which A has the following structure:

[0343]

[0344] Wherein

[0345] G is N; D is CH2; y is 0 or 1; and each is a single bond;

[0346] G is C; D is CH2; y is 1; and is a double bond, and the other are each single bonds;

[0347] G is N, D is CH2; y is 0; and and are each double bonds, and the other are each single bonds;

[0348] G is C; D is N or C-H; y is 1; and each is a double bond.

[0349] In certain of the above embodiments, useful compounds are those in which A is selected from the group consisting of:

[0350]

[0351] And

[0352] In certain of the above embodiments, useful compounds are those in which A has the following structure:

[0353]

[0354] Wherein ring A2 is a C4-C6 cycloalkyl group.

[0355] In certain of the above embodiments, useful compounds are those in which A is selected from the group consisting of:

[0356]

[0357] In certain of the above embodiments, useful compounds are those shown in Table 1 or a pharmaceutically acceptable salt thereof.

[0358] In certain embodiments, the subject matter described herein relates to a pharmaceutical composition comprising a compound of any of the above embodiments or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0359] In certain embodiments, the subject matter described herein relates to a method of treating a subject having a somatostatin-related disease, the method comprising administering to the subject a compound of any of the above embodiments or a pharmaceutical composition thereof.

[0360] In certain embodiments, the subject matter described herein relates to a method of treating a subject having a disease 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 tumor (NET), and pain.

[0361] In certain embodiments, the subject matter described herein relates to a method of activating a somatostatin receptor in a subject, the method comprising administering to the subject a compound of any of the above embodiments or a pharmaceutical composition thereof.

[0362] In certain embodiments, the subject matter described herein relates to the compounds shown in Table 1.

[0363] Table 1.

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378] *Indicates that the stereochemistry is arbitrarily assigned III. Pharmaceutical Compositions and Modes of Administration

[0379] The compounds provided herein are generally administered in the form of pharmaceutical compositions. Accordingly, the present invention also provides pharmaceutical compositions that comprise one or more of the compounds described herein or pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers thereof, and one or more pharmaceutically acceptable media selected from carriers, adjuvants, and excipients. Suitable pharmaceutically acceptable media can include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, 17th ed. (1985), Mace Publishing Co., Philadelphia, Pa.; and Modern Pharmaceutics, 3rd ed. (G.S. Banker and C.T. Rhodes eds.), Marcel Dekker, Inc.

[0380] The pharmaceutical compositions can be administered in single-dose or multi-dose forms. The pharmaceutical compositions can be administered by a variety of methods, including, for example, rectal, buccal, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical compositions can be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0381] One mode of administration is parenteral, for example, by injection. Forms that can be incorporated into the pharmaceutical compositions described herein for administration by injection include, for example, aqueous or oily suspensions or emulsions with sesame oil, corn oil, cottonseed oil or peanut oil, and elixirs, mannitol, glucose or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0382] Oral administration can be another route for administering the compounds described herein. The administration can be by, for example, capsules or enteric-coated tablets. In the preparation of pharmaceutical compositions comprising at least one compound or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers described herein, the active ingredient is usually diluted with excipients and / or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid or liquid material which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

[0383] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate; sweetening agents; and flavoring agents.

[0384] Compositions comprising at least one compound or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof described herein can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a subject by procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods disclosed herein employs a transdermal delivery device (“patch”). Such transdermal patches can be used to provide continuous or intermittent infusion of the compounds described herein in a controlled amount. The construction and use of transdermal patches for delivering agents are well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches can be constructed for continuous, pulsatile or on-demand delivery of the agent.

[0385] For preparing solid compositions such as tablets, the principal active ingredient can be admixed with a pharmaceutical excipient to form a solid preformulation composition that is a homogeneous mixture containing the compound or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof described herein. When these preformulation compositions are said to be homogeneous, the active ingredient is uniformly dispersed throughout the composition so that the composition can be readily re-divided into equally effective unit dosage forms such as tablets, pills and capsules.

[0386] Tablets or pills of the compounds described herein can be coated or otherwise compounded to provide dosage forms having the advantage of a long duration of action or protection against the acidic conditions of the stomach. For example, a tablet or pill can comprise an inner dosage component and an outer dosage component in the form of a coating over the former. The two components can be separated by an enteric layer that is resistant to disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be released therein in a delayed manner. A variety of materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

[0387] Compositions for inhalation or insufflation may include solutions and suspensions or mixtures thereof in pharmaceutically acceptable aqueous or organic solvents, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered by the oral or nasal respiratory route to produce a local or systemic effect. In other embodiments, the composition in a pharmaceutically acceptable solvent may be nebulized using an inert gas. The nebulized solution may be inhaled directly from the nebulizer device, or the nebulizer device may be connected to a face mask holder or an intermittent positive pressure ventilator. Solutions, suspensions or powder compositions may preferably be administered by mouth or nose in a suitable manner from a device that delivers the formulation.

[0388] The specific dosage level of the compounds of the present application for any particular subject will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination, and the severity of the particular disease being treated. For example, the dosage may be expressed as the number of milligrams of the compound described herein per kilogram of the subject's body weight (mg / kg). Dosages between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments, dosages between 0.5 mg / kg and 60 mg / kg may be appropriate. Normalizing according to the subject's body weight may be particularly useful when adjusting dosages between subjects of widely different sizes, such as occurs when using a drug in both children and adult humans or when converting an effective dosage in a non-human subject (such as a dog) to a dosage suitable for a human subject. The dosage may be administered once a day (QID), twice a day (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties of the particular compound, including absorption, distribution, metabolism, and excretion. Additionally, toxicity factors may affect the dosage and administration regimen. When administered orally, pills, capsules, or tablets may be taken daily or less frequently over a specific period of time. The regimen may be repeated for multiple treatment cycles.

[0389] IV. Methods of Treatment

[0390] The methods described herein can be applied to in vivo or ex vivo cell populations. "In vivo" means within a living individual, such as in an animal or human. In this context, the methods described herein can be used therapeutically in an individual. "Ex vivo" means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples can 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 can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used ex vivo for a given indication, cell type, individual, and other parameters to determine the optimal schedule and / or dose of administration of the compounds of the present disclosure. Information gathered from such use can be used for experimental purposes or in the clinic to set a protocol for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suitable are described below or will be apparent to those skilled in the art. The selected compounds can be further characterized to examine the safe or tolerated dose in a human or non-human subject. Such characterization can be examined using methods generally known to those skilled in the art.

[0391] In certain embodiments, the administration and treatment methods described herein further comprise co-administering one or more additional pharmaceutically active compounds.

[0392] In combination therapy, the pharmaceutically active compounds can be administered at the same time, in the same formulation, or at different times. Such combination therapy comprises co-administering a compound of Formula I or a pharmaceutically acceptable salt thereof with at least one additional pharmaceutically active compound. Combination therapy in the form of a fixed-dose combination therapy comprises co-administering a compound of Formula I or a pharmaceutically acceptable salt thereof with at least one additional pharmaceutically active compound in a fixed-dose formulation. Combination therapy in the form of a free-dose combination therapy comprises co-administering a compound of Formula I or a pharmaceutically acceptable salt thereof with at least one additional pharmaceutically active compound at the free doses of the respective compounds, either by co-administering the individual compounds simultaneously or by using the individual compounds sequentially over a period of time.

[0393] V. Methods for Preparing Compounds of Formula I and Their Pharmaceutically Acceptable Salts

[0394] The starting materials and reagents for preparing the compounds described herein are available from commercial suppliers such as Sigma-Aldrich Chemical Co. (Milwaukee, Wis.), Bachem (Torrance, Calif.), or can be prepared by methods known to those skilled in the art according to 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 Supplements (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, 1989). These schemes merely illustrate some of the ways in which the compounds of the present disclosure can be synthesized, and various modifications to these schemes can be made and will be apparent to those skilled in the art upon reading this disclosure. If desired, conventional techniques including, but not limited to, filtration, distillation, crystallization, chromatography, etc. can be used to separate and purify the starting materials and intermediates of the reaction as well as the final product. Such materials can be characterized using conventional means including physical constants and spectral data.

[0395] Synthetic chemical transformations and protecting group methods (protection and deprotection) useful for synthesizing compounds and necessary reagents and intermediates are known in the art and include, for example, those described in: R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and its subsequent editions.

[0396] Compounds can be prepared individually or as a library of compounds comprising at least 2 (e.g., 5 to 1,000 compounds or 10 to 100 compounds). Libraries of compounds of Formula I can be prepared by combinatorial'split and mix' methods or by multiple parallel synthesis using solution-phase or solid-phase chemistry, by procedures known to those skilled in the art. Accordingly, on the other hand, there is provided a library of compounds comprising at least 2 compounds or pharmaceutically acceptable salts thereof.

[0397] Unless otherwise indicated, the reactions described herein are carried out at atmospheric pressure in the temperature range of about -78 °C to about 150 °C (e.g., about 0 °C to about 125 °C, and further, e.g., at about room temperature (or ambient temperature), such as about 20 °C). The routes shown and described herein are merely illustrative and are not intended nor should they be construed to limit the scope of the claims in any way. Those skilled in the art will be able to identify modifications to the disclosed syntheses and design alternative routes based on the disclosure herein; all such modifications and alternative routes are within the scope of the claims.

[0398] The following examples are provided in an illustrative rather than a limiting manner.

[0399] Examples

[0400] I. Synthetic Examples

[0401] Example A

[0402] Synthesis of Common Intermediate Compounds 1 - 3 (6 - Bromo - 4 - chloro - 3 - iodoquinoline)

[0403]

[0404] Step 1: Synthesis of 6-bromo-3-iodoquinolin-4-ol (Compound 1-1-1-2)

[0405]

[0406] A mixture of Compound 1-1-1-1 (8 g, 35.71 mmol) and 2-iodocyclopentane-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 h. The reaction was monitored by LCMS, which showed completion of the reaction. The reaction mixture was filtered, and the precipitated solid was washed with PE (50 mL × 3) and dried under vacuum to give the title compound 6-bromo-3-iodoquinolin-4-ol (Compound 1-1-1-2, 11.20 g, 32.00 mmol, 89.63% yield) as a white solid. MS (m / z) 349.9 (M+H) + 。

[0407] Step 2: Synthesis of 6-bromo-4-chloro-3-iodoquinoline (Compound 1-1-1)

[0408]

[0409] A solution of Compound 1-1-1-2 (10 g, 28.58 mmol) in phosphoryl chloride (20 mL) was stirred at 100 °C for 2 h. The reaction mixture was concentrated to dryness. Dichloromethane (100 mL) was added to the residue, and a large amount of solid was observed, then filtered. The filter cake was washed with 20 mL of dichloromethane and dried in vacuo to give Compound 1-1-1 (6.00 g, 15.39 mmol, 53.87% yield, 94.52% purity) as a yellow solid. MS (m / z) 367.90 (M+H) + 。

[0410] Example 1

[0411]

[0412] Scheme 1

[0413] Step 1: tert-Butyl ((1S,3S)-3-((6-bromo-3-iodoquinolin-4-yl)oxy)cyclopentyl)carbamate (Compound 1-1-2)

[0414]

[0415] At 25 °C, N-[(1S,3S)-3-hydroxycyclopentyl]carbamic acid tert-butyl ester (98.34 mg, 488.60 μmol) was added 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), 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. Then it was separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 2). All the organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column (100 - 200 mesh) chromatography, eluted with PE:EtOAc = 4:1, to give tert-butyl ((1S,3S)-3-((6-bromo-3-iodoquinolin-4-yl)oxy)cyclopentyl)carbamate (Compound 1-1-2, 150.00 mg) as a white solid. Note that the product was not pure enough after purification and could not be used in the next step without further purification. MS (m / z) 349.9 (M+H) + 。

[0416] Step 2: tert-butyl ((1S,3S)-3-((6-bromo-3-(3-fluoro-5-methylphenyl)quinolin-4-yl)oxy)cyclopentyl)carbamate (Compound 1-1-3)

[0417]

[0418] At 25 °C, PdCl2(dppf) (102.66 mg, 139.91 μmol) and K2CO3 (290.05 mg, 2.10 mmol) were added 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), and the resulting mixture was stirred at 120 °C for 3 hours under N2. The progress of the reaction was monitored by LCMS and showed that the reaction was effective. The reaction mixture was diluted with water and ethyl acetate. Then it was 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 give a residue, which was purified by chromatography with PE:EtOAc = 3 / 2 to give the title compound 1-1-3 (70 mg) as a yellow oil. MS (m / z) 352.3 (M+H) + 。

[0419] Step 3: tert-Butyl ((1S,3S)-3-((6-(3-carbamoyl-5-fluorophenyl)-3-(3-fluoro-5-methylphenyl)quinolin-4-yl)oxy)cyclopentyl)carbamate (Compound 1-1-4)

[0420]

[0421] 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) was added PdCl2(dppf) (19.93 mg, 27.16 μmol) and K2CO3 (56.31 mg, 407.44 μmol), and then the resulting mixture was degassed with N2 and then stirred at 120 °C under N2 for 2 h. The progress of the reaction was monitored by LCMS and showed that the reaction was effective. The reaction mixture was diluted with water and ethyl acetate. Then it was 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 give a residue, which was purified by chromatography with PE / EtOAc from 5 / 1 to 1 / 1 to give Compound 1-1-4 (40.00 mg) as a yellow oil. MS (m / z) 391.1 (M+H) + 。

[0422] Step 4: 3-(4-(((1S,3S)-3-aminocyclopentyl)oxy)-3-(3-fluoro-5-methylphenyl)quinolin-6-yl)-5-fluorobenzamide (Compound 1)

[0423]

[0424] At 25 °C, trifluoroacetic acid (1 mL) was added to a solution of Compound 1-1-4 (40 mg, 69.73 μmol) in dichloromethane (3 mL), and then the resulting mixture was stirred at 25 °C for 0.5 h. The reaction solution was diluted with 20 mL of dichloromethane, and then the organic phase was concentrated to remove the solvent. The above operation was repeated three times to ensure that the excess TFA disappeared. The crude product was purified by preparative HPLC (preparative C18, 5 μM OBD, 19×250 mm column, Waters; gradient elution from 40% MeCN / water to 55% MeCN / water over an 11-minute period, where both solvents contained 10 mmol / L NH4HCO3) to give Compound 1 (4.10 mg, 12.15% yield) as a white solid.

[0425] Compound 1-11 was synthesized according to the 4-step procedure described in Example 1. The analytical data of Compound 1-11 are provided below.

[0426]

[0427]

[0428]

[0429]

[0430] Example 2

[0431]

[0432] Scheme 2

[0433] Step 1: Synthesis of 6-bromo-4-chloro-3-(3,5-difluorophenyl)quinoline (Compound 2-1-2)

[0434]

[0435] At 25 °C, PdCl2(dppf) (39.83 mg, 54.29 μmol) and K2CO3 (2.25 g, 16.29 mmol) were added 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), and the resulting mixture was degassed and stirred at 120 °C under N2 for 16 h. The reaction was monitored by LCMS and TLC, which showed completion of the reaction. The reaction mixture was diluted with water (30 mL) and then extracted with EA (50 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude material. The crude product was purified by silica gel column (100-200 mesh) chromatography, eluting with petroleum ether:ethyl acetate (100:0 to 95:5), to afford Compound 2-1-2 as a white solid (1.40 g, 2.70 mmol, 49.68% yield, 68.31% purity). MS (m / z) 356.10 (M+H) + 。

[0436] Step 2: Synthesis of tert-butyl ((1R,3S)-3-((6-bromo-3-(3,5-difluorophenyl)quinolin-4-yl)oxy)cyclopentyl)carbamate (Compound 2-1-3)

[0437]

[0438] At 25 °C, potassium tert-butoxide (167.26 mg, 1.49 mmol) was added 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), and the resulting mixture was stirred at 25 °C for 3 h. Water (50 mL) was added to the reaction mixture, and then the mixture was extracted with EA (50 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel column (100-200 mesh) chromatography, eluting with petroleum ether:ethyl acetate (100:0 to 80:20) to obtain compound 2-1-3 as a white oil (42.00 mg, 63.37 μmol, 12.75% yield, 78.37% purity). MS (m / z) 519.1 (M+H) + 。

[0439] Synthesis of tert-butyl ((2-hydroxycyclohexyl)methyl)carbamate (Compound 2-9-amine):

[0440]

[0441] Raney nickel (185.87 mg) and Boc2O (230.38 mg, 1.06 mmol) were added to a solution of compound SM (130 mg, 1.06 mmol) in methanol (4 mL), and then the resulting mixture was degassed completely with hydrogen. After degassing, the reaction mixture was stirred at 50 °C under H2 for 2 h. The reaction solution was filtered to collect the reaction liquid, and the reaction liquid was concentrated to obtain a crude material (Compound 2-9-amine, 150 mg, crude product), which was used in the next step without purification.

[0442] Step 3: Synthesis of tert-butyl ((1R,3S)-3-((3,6-bis(3,5-difluorophenyl)quinolin-4-yl)oxy)cyclopentyl)carbamate (Compound 2-1-4)

[0443]

[0444] At 25 °C, cyclopent-1,3-dien-1-yl(diphenyl)phosphane; iron; palladium(2+); dichloride (29.67 mg, 40.43 μmol) and potassium carbonate (33.53 mg, 242.60 μmol) were added 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), and the resulting mixture was stirred in N2 at 120 °C for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel column (100-200 mesh) chromatography, eluting with petroleum ether:ethyl acetate (100:0 to 70:30) to give compound 2-1-4 as a yellow solid (20 mg, 11.60 μmol, 14.34% yield). MS (m / z) 553.3 (M+H) + 。

[0445] Step 4: Synthesis of (1R,3S)-3-((3,6-bis(3,5-difluorophenyl)quinolin-4-yl)oxy)cyclopentanamine (Compound 12).

[0446]

[0447] At 25 °C, trifluoroacetic acid (1 mL) was added to a solution of compound 2-1-4 (20 mg, 0.036 mmol) in dichloromethane (3 mL), and the resulting mixture was stirred at 25 °C for 0.5 h. LCMS showed completion of the reaction. The mixture was distilled under reduced pressure to remove the solvent and purified by preparative HPLC to give compound 12 as a white solid (9.3 mg, 55% yield).

[0448] Compound 12-22 was synthesized according to the 4-step procedure described in Example 2. The analytical data for compound 12-22 are provided below.

[0449]

[0450]

[0451]

[0452] Example 3

[0453]

[0454] Scheme 3

[0455] Step 1: Synthesis of tert-butyl (5-bromo-4-chloro-3-nitropyridin-2-yl)carbamate (Compound 3-1-2)

[0456]

[0457] At 0 °C, NaH 60% (576 mg, 14.4 mmol) was added to a solution of Compound 3-1-1 (3000 mg, 12.0 mmol) in THF (30.0 mL), and then the reaction mixture was stirred at 0 °C for 1 h. Boc2O (3140 mg, 2.4 mmol) was added to the reaction mixture. The reaction solution was stirred for 1 h and detected by LCMS, and 80% of the product was detected in LCMS. The reaction mixture was poured into water and extracted with EA (200 mL × 2). The organic phases were combined, dried, concentrated and purified by flash chromatography (PE:EA = 3:1) to obtain Compound 3-1-2 (3680 mg) as a yellow solid. MS (m / z) 295.9 (M+H-55) + 。

[0458] Step 2: Synthesis of tert-butyl (5-bromo-4-chloro-3-nitropyridin-2-yl)(methyl)carbamate (Compound 3-1-3)

[0459]

[0460] At 0 °C, NaH 60% (480 mg, 12.0 mmol) was added to a solution of Compound 3-1-2 (216 mg, 8.0 mmol) in DMF (20.0 mL), and then the reaction mixture was stirred at 0 °C for 1 h. MeI (1704 mg, 3.0 mmol) was added to the reaction mixture. The reaction solution was stirred for 1 h and detected by LCMS, and 80% of the product was detected in LCMS. The reaction mixture was poured into water and extracted with EA (100 mL × 2). The organic phases were combined, dried, concentrated and purified by flash chromatography (PE:EA = 3:1) to obtain Compound 3-1-3 (2400 mg) as a yellow solid. MS (m / z) 309.9 (M+H-55) + 。

[0461] 1H NMR (400 MHz, DMSO-d6): 9.05 (s, 1H), 3.21 (s, 3H), 1.35 (s, 9H).

[0462] Step 3: Synthesis of tert-butyl (4-chloro-5-(3-fluoro-5-methylphenyl)-3-nitropyridin-2-yl)(methyl)carbamate (Compound 3-1-4)

[0463]

[0464] 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 potassium carbonate (1.07 g, 7.73 mmol) were added to the solution. The solid was completely dissolved by sonication, and 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 at 110 °C with an N2 balloon for 5 hours. The resulting solution was rotary evaporated to dryness, 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:EtOAc = 93:7 to give two peaks, and the product compound 3-1-4 (425.00 mg, 1.01 mmol, 39.18% yield) was obtained. MS (m / z) 344.0 (M+H) + 。

[0465] Step 4: Synthesis of 4-chloro-5-(3-fluoro-5-methylphenyl)-N-methyl-3-nitropyridin-2-amine (Compound 3-1-5)

[0466]

[0467] At 25 °C, 2,2,2-trifluoroacetic acid (4.25 g, 37.30 mmol, 2.86 mL) was added to a solution of Compound 3-1-4 (2400 mg, 5.5 mmol) in dichloromethane (15 mL). 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 operation was repeated three times. The crude product was used in the next step without further purification. Compound 3-1-5 (2.00 g, crude) was obtained as a yellow oil. MS (m / z) 300.0 (M+H) + 。

[0468] Step 5: Synthesis of tert-butyl ((3R,4R)-1-(5-(3,5-difluorophenyl)-2-(methylamino)-3-nitropyridin-4-yl)-3-methoxypiperidin-4-yl)carbamate (Compound 3-1-6)

[0469]

[0470] At 25 °C, a solution of compound 3-1-5 (2000 mg, 4.7 mmol) and tert-butyl N-[(3R,4R)-3-methoxy-4-piperidinyl]carbamate (1285.4 mg, 5.6 mmol) in 1,4-dioxane (16 mL) was added with DIPEA (1800 mg, 14 mmol), and the resulting mixture was stirred at 100 °C in N2 for 5 h. Water (50 mL) was added to the reaction mixture. And then it was extracted with ethyl acetate (50 mL * 2). All the 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 chromatography, eluting with PE:EtOAc = 5:1 to give compound 3-1-6 as a yellow solid (1500.00 mg, 2.5 mmol, 74.10% yield, 82.76% purity). MS (m / z) 494.3 (M+H) + 。

[0471] Step 6: Synthesis of tert-butyl ((3R,4R)-1-(3-amino-5-(3,5-difluorophenyl)-2-(methylamino)pyridin-4-yl)-3-methoxypiperidin-4-yl)carbamate (Compound 3-1-7)

[0472]

[0473] Under N2, Pd / C (320.00 mg, 131.74 μmol, 312.19 μL, 5% purity) was added to a solution of compound 3-1-6 (tert-butyl N-[(3R,4R)-1-[5-(3-fluoro-5-methoxyphenyl)-2-(methylamino)-3-nitropyridin-4-yl]-3-methoxy-4-piperidinyl]carbamate) (740 mg, 1.32 mmol) in methanol (15 mL). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 25 °C under a H2 balloon for 1 h. The suspension was filtered through Celite, and the filter cake was washed with MeOH (10 mL × 2). The combined filtrates were concentrated to dryness to give the product compound 3-1-7 (tert-butyl N-[(3R,4R)-1-[3-amino-5-(3-fluoro-5-methoxyphenyl)-2-(methylamino)pyridin-4-yl]-3-methoxy-4-piperidinyl]carbamate) as a purple solid (510.00 mg, 1.07 mmol, 81.40% yield). MS (m / z) 464.3 (M+H) + 。

[0474] Step 7: Synthesis of 3-(7-((3R,4R)-4-amino-3-methoxypiperidin-1-yl)-6-(3,5-difluorophenyl)-3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)-2-hydroxybenzonitrile (Compound 23)

[0475] At 25 °C, iron(III) chloride (97.21 mg, 599.30 μmol) and acetic acid (3.60 mg, 59.93 μmol) were added to a solution of Compound 3-1-7 (tert-butyl N-[(3R,4R)-1-[3-amino-5-(3-fluoro-5-methoxyphenyl)-2-(methylamino)-4-pyridinyl]-3-methoxypiperidin-4-yl]carbamate) (100 mg, 199.77 μmol) and 3-formyl-2-hydroxybenzonitrile (35.27 mg, 239.72 μmol) in tetrahydrofuran (4 mL). The resulting mixture was stirred at 60 °C for 2 h. Completion of the reaction was detected by TLC and LC-MS. TLC and LCMS showed completion of the reaction. Then it was concentrated to obtain the crude material, and the crude product was purified by preparative HPLC to obtain the product Compound 23 (38.10 mg).

[0476] Compound 23-34 was synthesized according to the 7-step procedure described in Example 3. The analytical data of Compound 23-34 are provided below.

[0477]

[0478]

[0479]

[0480]

[0481] Example 4

[0482]

[0483] Scheme 4

[0484] Step 1: Synthesis of tert-butyl (5-bromo-4-chloro-3-nitropyridin-2-yl)carbamate (Compound 4-1-2)

[0485] At 0 °C, 60% NaH (950 mg, 14.26 mmol) was added to a solution of compound 4-1-1 (3 g, 11.88 mmol) in THF (40 mL), and then the reaction mixture was stirred at 0 °C for 1 hour. Di-tert-butyl dicarbonate ((Boc)2O) (3.11 g, 14.26 mmol) was added to the reaction mixture. The reaction solution was stirred for 1 hour and monitored by LCMS. The reaction mixture was poured into water and extracted with EA (200 mL × 3). The combined organic phases were dried, concentrated and purified by flash column chromatography (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) + 。

[0486] Step 2: Synthesis of tert-butyl (5-bromo-4-chloro-3-nitropyridin-2-yl)(methyl)carbamate (Compound 4-1-3)

[0487] At 0 °C, 60% NaH (544 mg, 3.0 mmol) was added to a solution of compound 4-1-2 (3.2 g, 9.07 mmol) in DMF (30.0 mL), and then the reaction mixture was stirred at 0 °C for 1 hour. Methyl iodide (MeI) (1.9 g, 3.0 mmol) was added to the reaction mixture. The reaction solution was stirred for 1 hour and monitored by LCMS. The reaction mixture was poured into water and extracted with EA (100 mL × 3). The combined organic phases were dried, concentrated and purified by flash column chromatography (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) + 。

[0488] Step 3: Synthesis of 5-bromo-4-chloro-N-methyl-3-nitropyridin-2-amine (Compound 4-1-4)

[0489] At 25 °C, trifluoroacetic acid (TFA) (5 mL) was added to a solution of compound 4-1-3 (1.5 g, 4.09 mmol) in DCM (15 mL), and then the reaction mixture was stirred at 25 °C for 1 hour and monitored by LCMS. 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) + 。

[0490] Step 4: Synthesis of tert-butyl (1-(5-bromo-2-(methylamino)-3-nitropyridin-4-yl)piperidin-4-yl)carbamate (Compound 4-1-5)

[0491] At 25 °C, to a solution of compound 4-1-4 (1 g, 3.75 mmol) in 1,4-dioxane (10.0 mL) was added tert-butyl piperidin-4-ylcarbamate (0.9 g, 4.5 mmol) and DIPEA (1.45 g, 11.25 mmol). The reaction mixture was warmed to 80 °C and stirred for 2 h. The reaction was monitored by LCMS and was normal. LCMS showed that the reaction was complete. The solution was cooled to 0 °C and a large amount of solid was observed. After filtration, compound 4-1-5 as a yellow solid (1.5 g, 93% yield) was obtained. MS (m / z) 430.0 (M+H) + 。

[0492] Step 5: Synthesis of tert-butyl (1-(5-(3-fluoro-5-methylphenyl)-2-(methylamino)-3-nitropyridin-4-yl)piperidin-4-yl)carbamate (Compound 4-1-6)

[0493] Under N2, to a solution of compound 4-1-5 (700 mg, 1.63 mmol, 1 equiv), (3-fluoro-5-methylphenyl)boronic acid (377 mg, 2.45 mmol, 1.5 equiv) and K2CO3 (676 mg, 4.89 mmol, 3 equiv) in a mixture of dioxane (15 mL) and H2O (1 mL) was added PdCl2 (117 mg, 0.16 mmol). The suspension was degassed under vacuum and purged with N2 several times. Then the reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (40 mL × 3). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated to give a crude material, which was purified by chromatography on a Redi-Sep pre-packed silica gel column (12 g) with a gradient elution of 0% to 10% MeOH in DCM to give compound 4-1-6 as a white solid (545 mg, 72.9% yield). MS (m / z) 460.2 (M+H) + 。

[0494] Step 6: Synthesis of tert-butyl (1-(3-amino-5-(3-fluoro-5-methylphenyl)-2-(methylamino)pyridin-4-yl)piperidin-4-yl)carbamate (Compound 4-1-7)

[0495] To a solution of compound 4-1-6 (545 mg, 1.19 mmol, 1 equiv) in THF (20 mL) was added Pd / C (126.3 mg, 1.19 mmol). The suspension was degassed under vacuum and purged with H2 several times. Then the reaction mixture was stirred at room temperature for 2 h. TLC and LCMS showed completion of the reaction. The reaction mixture was filtered and concentrated to give compound 4-1-7 as an oil (420 mg, 82.4% yield). MS (m / z) 430.2 (M+H) + 。

[0496] Step 7: Synthesis of 3-(7-(4-aminopiperidin-1-yl)-6-(3-fluoro-5-methylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)-5-fluorobenzamide (Compound 35)

[0497] To a solution of compound 4-1-7 (100 mg, 0.233 mmol, 1 equiv) and 3-fluoro-5-formylbenzamide (47 mg, 0.280 mmol, 1.2 equiv) in THF (10 mL) was added AcOH (0.05 mL). The reaction mixture was stirred at 60 °C for 2 h. After 1 h, FeCl3 (37.3 mg, 0.233 mmol, 1 equiv) was added. The reaction mixture was stirred at 60 °C for 2 h. TLC and LCMS showed completion of the reaction. The reaction mixture was diluted with water (30 mL) and extracted with EA (50 mL×4). The combined organic extracts were concentrated to give a crude material, which was purified by silica gel chromatography, eluting with DCM:MeOH (100:1 to 1:1), to give a crude product. Then the crude material was purified by preparative HPLC to give compound 35 as a white solid (19.8 mg).

[0498] Synthesis of Compound 42 and Compound 43

[0499]

[0500] Under N2 protection, compound 40 (61 mg, 0.10 mmol, 1.0 equiv), Zn(CN)2 (26 mg, 0.22 mmol, 2.2 equiv), Pd(PPh3)4 (14 mg, 0.02 mmol, 20 mol%) were suspended in DMF (2.0 mL), and the reaction mixture was stirred at 120 °C for 5 h. The reaction mixture was purified by HPLC to give compound 42 as a white solid (27 mg).

[0501] At 25 °C, TFA (0.5 mL) was added to a solution of compound 42 (22 mg, 0.06 mmol) in DCM (2.0 mL), and then the reaction mixture was stirred at 25 °C for 2 h and monitored by LCMS, where 100% product was observed. The reaction mixture was concentrated and lyophilized to afford compound 43 (16.5 mg) as a white solid of the two TFA salts.

[0502] Synthesis of 3-Fluoro-5-formylbenzamide (Compound 4-1-aldehyde)

[0503]

[0504] To a solution of 3-fluoro-5-formylbenzoic acid (Compound 4-1-SM, 100 mg, 0.60 mmol, 1.0 equiv) and NH4Cl (65 mg, 1.19 mmol, 1.2 equiv) in DMF (2 mL) were added DIPEA (230 mg, 1.79 mmol, 3.0 equiv) and HATU (270 mg, 0.71 mmol, 1.2 equiv). The mixture was stirred at 25 °C for 2 h. The mixture was extracted with water and ethyl acetate, the aqueous phase was extracted with ethyl acetate, the combined organic layers were washed with brine, dried over Na2SO4, and the organic layer was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography with DCM:MeOH from 0% to 11% to afford the product 3-fluoro-5-formylbenzamide (Compound 4-1-aldehyde, 35 mg) as a white solid. MS (m / z) 168.1 (M+H) + 。

[0505] Compound 35-43 was synthesized according to the 7-step procedure described in Example 4. The analytical data for Compound 35-43 are provided below.

[0506]

[0507]

[0508]

[0509] Example 5

[0510]

[0511] Scheme 5

[0512] Step 1: Synthesis of Compound 5-1-2

[0513] At 0 °C, 60% NaH (144 mg, 3.6 mmol) was added to a solution of compound 5-1-1 (750 mg, 3.0 mmol) in THF (15.0 mL), and then 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 solution was stirred for 1 hour and detected by LCMS, and 80% of the product was detected by LCMS. The reaction mixture was poured into water and extracted with EA (50 mL × 2). The organic phases were combined, dried, concentrated and purified by flash column chromatography (PE:EA = 3:1) to obtain compound 5-1-2 (510 mg) as a yellow solid. MS (m / z) 386.1 (M+H) + 。

[0514] Step 2: Synthesis of compound 5-1-3

[0515] Compound 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 room temperature. The reaction solution was warmed to 80 °C and stirred for 2 hours. LCMS showed that the reaction was complete. The reaction mixture was concentrated and purified by flash column chromatography (PE:EA = 1:1) to obtain compound 5-1-3 (280 mg) as a yellow solid. MS (m / z) 550.2 (M+H) + 。

[0516] Step 3: Synthesis of compound 5-1-4

[0517] Under N2 protection, compound 5-1-3 (200 mg, 0.36 mmol, 1.0 equiv), SM-3 (68 mg, 0.44 mmol, 1.2 equiv), Na2CO3 (134 mg, 1.08 mmol, 3.0 equiv), PdCl2[dppf] (52 mg, 0.07 mmol, 20 mol%) were suspended in 1,4-dioxane (6.0 mL) and water (2.0 mL), and the reaction mixture was stirred at 110 °C for 5 hours. The reaction solution was detected by LCMS, and 70% of the product was detected. The reaction mixture was purified by flash column chromatography (PE:EA = 3:1 - 1:1) to obtain compound 5-1-4 (140 mg) as a yellow solid. MS (m / z) 584.2 (M+H) + 。

[0518] Step 4: Synthesis of compound 5-1-5

[0519] At 25 °C, it was added to a mixture of compound 5-1-4 (58 mg, 0.10 mmol), Zn (50 mg) in EtOH (3.0 mL) and aqueous NH4Cl solution (1.0 mL). The reaction mixture was stirred at 50 °C for 3 hours. The mixture was detected by LCMS, and the reaction was 95% complete. The reaction solution was poured into water, extracted with EA (20 mL × 2), the organic phases were combined, dried, concentrated to obtain compound 5-1-5 (74 mg) as a gray solid. MS (m / z) 554.2 (M+H) + 。

[0520] Step 5: Synthesis of compound 5-1-6

[0521] At 0 °C, 60% NaH (5.2 mg, 0.13 mmol) was added to a solution of compound 5-1-5 (74 mg, 0.13 mmol) in DMF (3.0 mL), and then the reaction mixture was stirred at 0 °C for 1 hour. MeI (19 mg, 0.13 mmol) was added to the reaction mixture. The reaction solution was stirred for 1 hour and detected by LCMS, and 80% of the product was detected in LCMS. The reaction mixture was poured into water and extracted with EA (50 mL × 2), the organic phases were combined, dried, concentrated and purified by flash chromatography (PE:EA = 3:1) to obtain compound 5-1-6 (52 mg) as a yellow solid. MS (m / z) 568.2 (M+H) + 。

[0522] Step 6: Synthesis of compound 5-1-7

[0523] At 25 °C, it was added to a mixture of compound 5-1-6 (52 mg) in MeOH (5 mL). Pd / C (100 mg) was added to the reaction mixture. The reaction mixture was stirred under H2 protection at 25 °C for 3 hours. The mixture was detected by LCMS, and the reaction was 95% complete. The reaction solution was filtered, concentrated and purified by flash chromatography to obtain compound 5-1-7 (42 mg) as a gray solid. MS (m / z) 434.2 (M+H) + 。

[0524] Step 7: Synthesis of compound 44

[0525] At 25 °C, compound 5-1-7 (42 mg, 0.10 mmol), SM-4 (24 mg, 0.12 mmol), and AcOH (15 mg, catalytic amount) were dissolved in THF (5.0 mL). The reaction solution was warmed to 60 °C and stirred for 16 h. The reaction was monitored by LCMS and was normal. The reaction mixture was concentrated and purified by HPLC (0.5% FA) to afford compound 44 (21 mg) as a white solid. 7.3 mg was delivered.

[0526] Step 8: Synthesis of compound 45

[0527] Compound 44 (ca. 20 mg) was dissolved in DCM (2.0 mL) at 25 °C. TFA (0.5 mL) was added to the reaction solution, and then the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated and lyophilized to afford compound 45 (18.3 mg) as a white solid of a TFA salt.

[0528] Compounds 44 and 45 were synthesized according to the 7-step or 8-step procedure described in Example 5. The analytical data for compounds 44 and 45 are provided below.

[0529]

[0530] Example 6

[0531]

[0532] Scheme 6

[0533] Step 1: Synthesis of tert-butyl (5-bromo-4-chloro-3-nitropyridin-2-yl)carbamate (compound 6-1-2)

[0534] At 25 °C, compound 6-1-1 (3 g, 11.88 mmol) was dissolved in THF (40 mL). The reaction solution was cooled to 0 °C. NaH 60% (950 mg, 14.26 mmol) was added to the reaction solution, and then the reaction mixture was stirred at 0 °C for 1 h. (Boc)2O (3.11 g, 14.26 mmol) was added to the reaction mixture. The reaction solution was stirred for 1 h. The reaction mixture was poured into water and extracted with EA (200 mL × 3). The combined organic phases were dried, concentrated, and purified by flash chromatography (PE:EA = 3:1) to afford compound 6-1-2 (3.2 g) as a yellow solid. MS (m / z) 295.9 (M+H-55) + .

[0535] Step 2: Synthesis of tert-butyl (4-chloro-5-(3,5-difluorophenyl)-3-nitropyridin-2-yl)carbamate (compound 6-1-3)

[0536] To a solution of compound 6-1-2 (1500 mg, 4.27 mmol, 1 equiv), (3,5-difluorophenyl)boronic acid (740 mg, 4.70 mmol, 1.1 equiv) and K2CO3 (1770 mg, 12.82 mmol, 3 equiv) in a mixture of 1,4-dioxane (20 mL) and water (2 mL) was added PdCl2(dppf) (310 mg, 0.43 mmol, 0.1 equiv). The suspension was degassed under vacuum and purged with nitrogen several times. The mixture was stirred at 80 °C under nitrogen for 2 h. The reaction was monitored by LC-MS and TLC, which showed completion of the reaction. The reaction liquid was extracted with water (10 mL) and ethyl acetate (10 mL × 3), and the combined organic phases were dried over Na2SO4. The organic phase was dried over silica gel by rotary evaporator and purified by flash chromatography with 0% to 10% petroleum ether:ethyl acetate to obtain a liquid product, which was dried by rotary evaporator to obtain crude tert-butyl (4-chloro-5-(3,5-difluorophenyl)-3-nitropyridin-2-yl)carbamate (compound 6-1-3, 1216 mg). MS (m / z) 408.1 (M+Na) + ,330.0 (M+H-55) + 。

[0537] Step 3: Synthesis of 4-chloro-5-(3,5-difluorophenyl)-3-nitropyridin-2-amine (Compound 6-1-4)

[0538] To a solution of compound 6-1-3 (600 mg, 1.56 mmol, 1 equiv) in dichloromethane (2.00 mL) was added trifluoroacetic acid (4 mL). The mixture was stirred at 25 °C for 2 h. The reaction was monitored by LCMS and TLC, which showed completion of the reaction. The reaction liquid was dried by rotary evaporator to obtain the product as a yellow oil in the form of trifluoroacetate, which was dried over dichloromethane by rotary evaporator to obtain crude 4-chloro-5-(3,5-difluorophenyl)-3-nitropyridin-2-amine (Compound 6-1-4). MS (m / z) 286.0 (M+H) + 。

[0539] Step 4: Synthesis of ((3R,4R)-1-(2-amino-5-(3,5-difluorophenyl)-3-nitropyridin-4-yl)-3-methoxypiperidin-4-yl)carbamic acid tert-butyl ester (Compound 6-1-5)

[0540] To a solution of compound 6-1-4 (350 mg, 1.23 mmol, 1 equiv) in 1,4-dioxane (3.00 mL) was added tert-butyl ((3R,4R)-3-methoxypiperidin-4-yl)carbamate (283 mg, 1.23 mmol, 1 equiv) and DIPEA (476 mg, 3.68 mmol, 3 equiv). The mixture was stirred at 80 °C for 16 h. The reaction was monitored by LCMS and TLC, which showed completion of the reaction. The reaction liquid was extracted with water (10 mL) and ethyl acetate (10 mL * 3), and the organic phase was dried over Na2SO4. The organic phase was dried over silica gel by rotary evaporator and purified by flash chromatography with 0% to 20% petroleum ether:ethyl acetate to obtain a liquid product, which was dried by rotary evaporator to obtain crude tert-butyl ((3R,4R)-1-(2-amino-5-(3,5-difluorophenyl)-3-nitropyridin-4-yl)-3-methoxypiperidin-4-yl)carbamate (Compound 6-1-5, 336 mg). MS (m / z) 480.2 (M + H) + ,502.2 (M + Na) + .

[0541] Step 5: Synthesis of tert-butyl ((3R,4R)-1-(2,3-diamino-5-(3,5-difluorophenyl)pyridin-4-yl)-3-methoxypiperidin-4-yl)carbamate (Compound 6-1-6)

[0542] To a solution of compound 6-1-5 (336 mg, 0.70 mmol, 1 equiv) in methanol (5.00 mL) was added Pd / C (15 mg, 0.14 mmol, 0.2 equiv). The mixture was stirred under hydrogen at 25 °C for 2 h. The reaction was monitored by LCMS and TLC, which showed completion of the reaction. The reaction liquid was filtered to obtain a filtrate, which was dried by rotary evaporator to obtain crude tert-butyl ((3R,4R)-1-(2,3-diamino-5-(3,5-difluorophenyl)pyridin-4-yl)-3-methoxypiperidin-4-yl)carbamate (Compound 6-1-6, 122 mg). MS (m / z) 450.2 (M + H) + .

[0543] Step 6: Synthesis of 5-(7-((3R,4R)-4-amino-3-methoxypiperidin-1-yl)-6-(3,5-difluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1,3-dihydro-2H-benzimidazol-2-one (Compound 46)

[0544] To a solution of compound 6-1-6 (60 mg, 0.13 mmol, 1 equiv) and 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (26 mg, 0.16 mmol, 1.2 equiv) in THF (2.00 mL) was added AcOH (0.80 mL), and the solution was stirred at 60 °C for 2 h. Then, FeCl3 (32 mg, 0.20 mmol, 1.5 equiv) was added to the mixture, and it was stirred at 60 °C for 2 h. The reaction was monitored by LCMS and TLC, which showed completion of the reaction. The reaction liquid was dried over silica gel using a rotary evaporator and purified by flash chromatography with 0% to 20% DCM:methanol to obtain a liquid product, and the liquid product was dried by rotary evaporator to obtain a crude product. The crude product was purified by PREP-HPLC to obtain 5-(7-((3R,4R)-4-amino-3-methoxypiperidin-1-yl)-6-(3,5-difluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (Compound 46, 22.9 mg, 35% yield) as a white solid.

[0545] Compounds 46-66 were synthesized according to the 6-step procedure described in Example 6. The analytical data of compounds 46-66 are provided below.

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552] Example 7

[0553]

[0554] Scheme 7

[0555] Step 1: Synthesis of 6-bromo-3-iodoquinolin-4-ol (Compound 7-1-2)

[0556] To a solution of compound 7-1-1 (3000 mg, 13.389 mmol, 1 equiv) in AcOH (50 mL) was added NIS (3012 mg, 13.389 mmol, 1 equiv). The mixture was stirred at 60 °C for 3 h. The reaction was monitored by LCMS, which showed that the reaction was going well. The solution was cooled to zero degree, and a large amount of solid was observed. After filtration, 6-bromo-3-iodoquinolin-4-ol (compound 7-1-2, 4.4 g, 94% yield) as a white solid was obtained. MS (m / z) 349.9 (M+H) + 。

[0557] Step 2: Synthesis of 6-bromo-4-chloro-3-iodoquinoline (compound 7-1-3)

[0558] A solution of compound 7-1-2 (2500 mg, 7.144 mmol, 1 equiv) in POCl3 (15 mL) was stirred at 100 °C for 3 h. The completion of the reaction was detected by TLC and LCMS. LCMS showed that the reaction had been completed. NaHCO3 (aqueous solution) was added to the solution to adjust the pH to 7, then the reaction mixture was diluted with water (50 mL) and extracted with EA (80 mL×4). The combined organic extracts were concentrated to give a crude material, which was then purified by silica gel chromatography, eluting with PE:EtOAc (100:1 to 5:1) to give the product compound 7-1-3 (1.5 g) as a pale yellow solid. MS (m / z) 367.8 (M+H) + 。

[0559] Step 3: Synthesis of tert-butyl (1-(6-bromo-3-iodoquinolin-4-yl)piperidin-4-yl)carbamate (compound 7-1-4)

[0560] To a solution of compound 7-1-3 (1000 mg, 2.714 mmol, 1 equiv) and tert-butyl piperidin-4-ylcarbamate (1082 mg, 5.429 mmol, 2 equiv) in DMAc (15 mL) was added K2CO3 (1125 mg, 8.143 mmol, 3.0 equiv), and the reaction solution was stirred at 120 °C for 4 h. The completion of the reaction was detected by TLC and LCMS. LCMS showed that the reaction had been completed. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL×4). The combined organic extracts were concentrated to give a crude product, which was then purified by flash (PE:EA = 3:1) to give compound 7-1-4 (570 mg, 40% yield) as a white solid. MS (m / z) 531.9 (M+H) + 。

[0561] Step 4: Synthesis of tert-butyl (1-(6-bromo-3-(3,5-difluorophenyl)quinolin-4-yl)piperidin-4-yl)carbamate (Compound 7-1-5)

[0562] Under N2, PdCl2(dppf) (78 mg, 0.107 mmol, 0.1 equiv) was added to a solution of Compound 7-1-4 (570 mg, 1.07 mmol, 1 equiv), (3,5-difluorophenyl)boronic acid (169 mg, 1.07 mmol, 1 equiv) and K2CO3 (443 mg, 3.213 mmol, 3 equiv) in a mixture of dioxane (10 mL) and H2O (1 mL). The suspension was degassed under vacuum and purged with N2 several times. Then the reaction mixture was stirred at 90 °C for 4 h. The completion of the reaction was detected by TLC and LCMS. LCMS showed that the reaction had been completed. The reaction mixture was diluted with water (30 mL) and extracted with EA (50 mL × 4). The combined organic extracts were concentrated to give the crude material, and then the crude product was purified by flash chromatography (PE:EA = 1:1) to give Compound 7-1-5 as a yellow solid (500 mg, 90% yield). MS (m / z) 518.1 (M+H) + 。

[0563] Step 5: Synthesis of tert-butyl (1-(6-(3-cyano-2-(methoxymethoxy)phenyl)-3-(3,5-difluorophenyl)quinolin-4-yl)piperidin-4-yl)carbamate (Compound 7-1-6)

[0564] Under N2, PdCl2(dppf) (71 mg, 0.096 mmol, 0.1 equiv) was added to a solution of Compound 7-1-5 (500 mg, 0.965 mmol, 1 equiv), 2-(methoxymethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (307 mg, 1.061 mmol, 1.1 equiv) and K2CO3 (399 mg, 2.894 mmol, 3 equiv) in a mixture of dioxane (10 mL) and H2O (1 mL). The suspension was degassed under vacuum and purged with N2 several times. Then the reaction mixture was stirred at 100 °C for 4 h. The completion of the reaction was detected by TLC and LCMS. LCMS showed that the reaction had been completed. The reaction mixture was diluted with water (30 mL) and extracted with EA (50 mL × 4). The combined organic extracts were concentrated to give the crude material, and then the crude product was purified by flash chromatography (PE:EA = 1:1) to give Compound 7-1-6 as a yellow oil (370 mg, 63.9% yield). MS (m / z) 601.3 (M+H) + 。

[0565] Step 6: Synthesis of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile (Compound 7-1-7)

[0566] To a solution of Compound 7-1-6 (370 mg, 0.616 mmol, 1 equiv) in DCM (5 mL) was added TFA (1 mL). The reaction mixture was then stirred at 25 °C for 1 h. Completion of the reaction was detected by TLC and LC-MS. TLC and LCMS showed completion of the reaction. The reaction mixture was concentrated to give the crude material Compound 7-1-7 (300 mg) as the TFA salt. MS (m / z) 457.2 (M+H) + 。

[0567] Step 7: Synthesis of tert-butyl (1-(6-(3-cyano-2-hydroxyphenyl)-3-(3,5-difluorophenyl)quinolin-4-yl)piperidin-4-yl)carbamate (Compound 7-1-8)

[0568] To a solution of Compound 7-1-7 (100 mg, 0.219 mmol, 1 equiv) and DIPEA (85 mg, 0.657 mmol, 3 equiv) in DCM (6 mL) was added (Boc)2O (48 mg, 0.219 mmol, 1 equiv). The reaction mixture was then stirred at 25 °C for 1 h. Completion of the reaction was detected by TLC and LC-MS. TLC and LCMS showed completion of the reaction. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL×3). The combined organic extracts were concentrated to give the crude material, which was purified by silica gel chromatography, eluting with PE:EtOAc (100:1 to 1:1), to give the product Compound 7-1-8 (70 mg, 57.4% yield) as a yellow oil. MS (m / z) 557.3 (M+H) + 。

[0569] LCMS: m / z: at 1.68 min, 557.3 (M+H + )。

[0570] Step 8: Synthesis of tert-butyl (1-(6-(2-(3-bromopropoxy)-3-cyanophenyl)-3-(3,5-difluorophenyl)quinolin-4-yl)piperidin-4-yl)carbamate (Compound 7-1-9)

[0571] To a solution of compound 7-1-8 (70 mg, 0.126 mmol, 1 equiv) and 1,3-dibromopropane (38 mg, 0.189 mmol, 1.5 equiv) in MeCN (5 mL) was added K2CO3 (52 mg, 0.377 mmol, 3 equiv). The reaction mixture was then stirred at 90 °C for 1 h. Completion of the reaction was detected by TLC and LC-MS. TLC and LCMS showed completion of the reaction. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL×3). The combined organic extracts were concentrated to give the crude material, which was purified by silica gel chromatography, eluting with PE:EtOAc (100:1 to 1:1), to give the product compound 7-1-9 as a yellow oil (40 mg, 47% yield). MS (m / z) 677.3 (M+H) + 。

[0572] Step 9: Synthesis of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-(3-bromopropoxy)benzonitrile (Compound 7-1-10)

[0573] Under N2, to a solution of compound 7-1-9 (40 mg, 0.059 mmol, 1 equiv) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was then stirred at 25 °C for 1 h. Completion of the reaction was detected by TLC and LC-MS. TLC and LCMS showed completion of the reaction. The reaction mixture was concentrated to give compound 7-1-10 as a yellow oil (50 mg crude). MS (m / z) 577.1 (M+H) + 。

[0574] The steps for the intermediates of compound 68 and compound 69 are similar to those of compound 67, but the acid is HCl / EA.

[0575] Step 10: Synthesis of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-(3-bromopropoxy)benzonitrile (Compound 67)

[0576] To a solution of compound 7-1-10 (30 mg, 0.052 mmol, 1 equiv) in DMAc (2 mL) was added NaH (6 mg, 0.156 mmol, 3 equiv). The reaction mixture was stirred at 100 °C for 1 h. Completion of the reaction was detected by LC-MS. LCMS showed completion of the reaction. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 3). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to give the crude material, which was purified by preparative HPLC to give compound 67 (5.7 mg) as a yellow solid.

[0577] The synthesis of other compounds was similar to that of compound 67, but the base was K2CO3, the additive was KI, and the solvent was DMF.

[0578] Compounds 67 - 77 were synthesized according to the 10-step procedure described in Example 7. The analytical data of compounds 67 - 77 are provided below.

[0579]

[0580]

[0581]

[0582]

[0583] Example 8

[0584]

[0585] Scheme 8

[0586] Step 1: Synthesis of 1-(6-bromo-3-(3,5-difluorophenyl)quinolin-4-yl)piperidin-4-amine (Compound 8-1-2)

[0587]

[0588] (1-(6-Bromo-3-(3,5-difluorophenyl)quinolin-4-yl)piperidin-4-yl)carbamic acid tert-butyl ester (Compound 8-1-1) (500 mg, 0.97 mmol, 1.0 equiv) was dissolved in a solution of HCl / 1,4-dioxane (4 M, 10 mL). The reaction mixture was stirred at room temperature for 2 h. The desired product was detected by LCMS. The reaction mixture was concentrated in vacuo to give the crude product 1-(6-bromo-3-(3,5-difluorophenyl)quinolin-4-yl)piperidin-4-amine (Compound 8-1-2, 404 mg, 0.97 mmol, 100%) for the next step. MS (m / z) 418.1 (M + H)+ .

[0589] Step 2: Synthesis of tert-butyl (2-((1-(6-bromo-3-(3,5-difluorophenyl)quinolin-4-yl)piperidin-4-yl)amino)ethyl)carbamate (Compound 8-1-3)

[0590]

[0591] Dissolve 1-(6-bromo-3-(3,5-difluorophenyl)quinolin-4-yl)piperidin-4-amine (4.7 g, 9.7 mmol, 1.0 equiv), methyl 6-bromopicolinate (Compound 8-1-2, 404 mg, 0.97 mmol, 1.0 equiv), K2CO3 (400 mg, 2.9 mmol, 3.0 equiv) and KI (249 mg, 1.5 mmol, 1.5 equiv) in DMF (10 mL), then add tert-butyl (2-bromoethyl)carbamate (434 mg, 1.94 mmol, 2.0 equiv) to the solution. Stir and heat the reaction mixture to 90 °C for 3 h. Detect the desired product by LCMS. Extract the reaction mixture with ethyl acetate (50 mL * 3), wash with brine, and dry over anhydrous Na2SO4. Concentrate the filtrate under vacuum and purify the residue by FCC (PE:EA = 3:1) to obtain tert-butyl (2-((1-(6-bromo-3-(3,5-difluorophenyl)quinolin-4-yl)piperidin-4-yl)amino)ethyl)carbamate (Compound 8-1-3, 170 mg, 0.30 mmol, 31%) as a yellow oil. MS (m / z) 561.2 (M+H) + .

[0592] Step 3: Synthesis of (4-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)piperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)boronic acid (Compound 8-1-4)

[0593]

[0594] (4-(4-((2-((tert-Butoxycarbonyl)amino)ethyl)amino)piperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)boronic acid (Compound 8-1-3, 170 mg, 0.3 mmol, 1.0 equiv), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (120 mg, 0.47 mmol, 1.5 equiv), and CH3COOK (61 mg, 0.62 mmol, 2.0 equiv) were dissolved in 1,4-dioxane (6 mL), and then Pd(dppf)Cl2 (46 mg, 0.062 mmol, 0.2 equiv) was added to the solution under a nitrogen atmosphere. The reaction mixture was stirred for 3 h. The desired product was heated to 90 °C for 2 h under a nitrogen atmosphere. The desired product was detected by TLC. The reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo to give the crude product (4-(4-((2-((tert-Butoxycarbonyl)amino)ethyl)amino)piperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)boronic acid (Compound 8-1-4, 157 mg, 0.3 mmol, 100%) for the next step.

[0595] Step 4: Synthesis of methyl 6-((2E,4E)-4-(4-(4-((2-((tert-Butoxycarbonyl)amino)ethyl)amino)piperidin-1-yl)-5-(3,5-difluorophenyl)pyridin-2(3H)-ylidene)but-2-en-2-yl)pyridine-2-carboxylate (Compound 8-1-5)

[0596]

[0597] Methyl 6-((2E,4E)-4-(4-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)piperidin-1-yl)-5-(3,5-difluorophenyl)pyridin-2(3H)-ylidene)but-2-en-2-yl)picolinic acid ester (Compound 8-1-4, 157 mg, 0.3 mmol, 1.0 equiv), methyl 6-bromopicolinate (102 mg, 0.47 mmol, 1.5 equiv) and K2CO3 (86 mg, 0.62 mmol, 2.0 equiv) 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 equiv) was added to the solution under a nitrogen atmosphere. The reaction mixture was stirred and heated to 90 °C for 2 h under a nitrogen atmosphere. The desired product was detected by LCMS. The reaction mixture was extracted with ethyl acetate (20 mL * 3), washed with brine and dried over anhydrous Na2SO4. The filtrate was concentrated in vacuo and the residue was purified by preparative TLC (PE:EA = 1:1) to give methyl 6-((2E,4E)-4-(4-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)piperidin-1-yl)-5-(3,5-difluorophenyl)pyridin-2(3H)-ylidene)but-2-en-2-yl)picolinate (Compound 8-1-5, 100 mg, 0.16 mmol, 53%) as a grey solid. MS (m / z) 618.5 (M+H) + 。

[0598] Step 5: Synthesis of methyl 6-(4-(4-((2-aminoethyl)amino)piperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)picolinate (Compound 8-1-6)

[0599]

[0600] Methyl 6-(4-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)piperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)picolinate (Compound 8-1-5, 100 mg, 0.16 mmol, 1.0 equiv) was dissolved in a solution of HCl / 1,4-dioxane (4 M, 4 mL). The reaction mixture was stirred at room temperature for 1 h. The desired product was detected by TLC. The reaction mixture was concentrated in vacuo to give the crude product methyl 6-(4-(4-((2-aminoethyl)amino)piperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)picolinate (Compound 8-1-6, 83 mg, 0.16 mmol, 100%) as a grey solid for the next step.

[0601] Step 6: Synthesis of Compound 78

[0602]

[0603] Dissolve methyl 6-(4-(4-((2-aminoethyl)amino)piperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)picolinate (Compound 8-1-6, 83 mg, 0.16 mmol, 1.0 equiv) in NMP (4 mL), and then add DBU (48 mg, 0.32 mmol, 2.0 equiv) to the solution. Stir and heat the reaction mixture to 120 °C for 3 h. Detect the desired product by LCMS. Extract the reaction mixture with ethyl acetate (20 mL * 3), wash with brine, and dry over anhydrous Na2SO4. Concentrate the filtrate under vacuum, and purify the residue by preparative TLC (EA:PE = 1:0, Rf = 0.16) to obtain the crude product. Purify the crude product by preparative HPLC (0.1% TFA / water) to obtain 2 3 -(3,5-difluorophenyl)-4,7-diaza-2(6,4)-quinolin-1(2,6)-pyridine-3(1,4)-piperidine-cyclooctan-8-one (Compound 78, 18.3 mg, 0.038 mmol, 24%).

[0604] Synthesis of Compound 79:

[0605] The synthesis method of Compound 8-2-5 is similar to that of Compound 8-1-5.

[0606]

[0607] Step 1': Synthesis of 3-(4-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)piperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)picolinic acid (Compound 8-2-6)

[0608] To a solution of methyl 3-(4-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)piperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)picolinate (Compound 8-2-5, 210 mg, 0.34 mmol, 1 equiv) in THF (4 ml), MeOH (1.5 ml), and H2O (1.5 ml) was added sodium hydroxide (136 mg, 3.4 mmol, 10 equiv), and the solution was stirred at 25 °C for 12 h. The reaction was monitored by TLC. After completion, HCl (2 M) was added to the reaction mixture and the mixture was filtered. The solid was concentrated under reduced pressure to afford 3-(4-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)piperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)picolinate as a white solid (Compound 8-2-6, 140 mg, 0.23 mmol, 68.21%). MS (m / z) 604 (M+H) + 。

[0609] Step 6: Synthesis of 3-(4-(4-((2-aminoethyl)amino)piperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)picolinate (Compound 8-2-7)

[0610] To a solution of 3-(4-{4-[(2-{[(tert-butoxy)carbonyl]amino}ethyl)amino]piperidin-1-yl}-3-(3,5-difluorophenyl)quinolin-6-yl)picolinate (Compound 8-2-6, 210 mg, 0.35 mmol, 1 equiv) in EA (2 ml) was added HCl / 1,4-dioxane (2 ml), and the solution was stirred at 25 °C for 12 h. The reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure to afford crude Compound 8-2-7 as a yellow oil. MS (m / z) 504 (M+H) + 。

[0611] Step 7: 2 3 - (3,5-Difluorophenyl)-4,7-diaza-2(6,4)-quinolin-1(3,2)-pyridin-3(1,4)-piperidinocyclooctan-8-one (Compound 79) Synthesis

[0612] To a solution of 3-(4-{4-[(2-aminoethyl)amino]piperidin-1-yl}-3-(3,5-difluorophenyl)quinolin-6-yl)pyridine-2-carboxylic acid (Compound 8-2-7, 135 mg, 0.27 mmol, 1 equiv) and ethyldi(propan-2-yl)amine (70 mg, 0.54 mmol, 2 equiv) in DMF (2.5 mL, 100.0%) was added [bis(dimethylamino)methylene]({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl})oxonium hexafluoro-λ 5 -phosphate (154 mg, 0.405 mmol, 1.5 equiv), and the solution was stirred at 25 °C for 2 h. The reaction was monitored by LCMS and TLC. After completion, the reaction mixture was diluted with water (100 mL) and extracted with EA (200 mL × 3). The combined organic extracts were concentrated to give the crude material, and the above mixture was purified by preparative HPLC to give 2 3 -(3,5-difluorophenyl)-4,7-diaza-2(6,4)-quinolin-1(3,2)-pyridin-3(1,4)-piperidinecyclooctan-8-one (Compound 79, 2 mg, 1.54%).

[0613] The synthetic method of Compound 80 is similar to that of Compound 79.

[0614] Compounds 78 - 80 were synthesized according to the 6-step or 7-step procedure described in Example 8. The analytical data of Compounds 78 - 80 are provided below.

[0615]

[0616] Example 9

[0617]

[0618] Scheme 9

[0619] Step 1: Synthesis of tert-butyl (1-(3-(3,5-difluorophenyl)-6-(3-((4-hydroxybutyl)(methyl)carbamoyl)phenyl)quinolin-4-yl)piperidin-4-yl)carbamate (Compound 9-1-2)

[0620] To a solution of Compound 9-1-1 (201.46 mg, 0.36 mmol, 1 equiv) in DMF (5 mL, 100.0%) was added [bis(dimethylamino)methylene]({3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl})oxonium hexafluoro-λ 5-Phosphate (509.6 mg, 1.34 mmol, 3 eq) and DIPEA (139.58 mg, 1.08 mmol, 3 eq) were added, and the solution was stirred at 20 °C for 10 min. 4-(Methylamino)butan-1-ol (92.84 mg, 0.9 mmol, 2 eq) was added to the mixture. The solution was stirred at 20 °C for 3 h. The reaction solution was diluted with EA and water. The solution was extracted with EA (3 × 25 mL). The organic layer was separated, washed with additional saturated NaCl solution, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether to afford compound 9-1-2 (270 mg, 0.42 mmol, 93.33%). MS (m / z) 645 (M+H) + .

[0621] Step 2: Synthesis of tert-butyl (1-(3-(3,5-difluorophenyl)-6-(3-(methyl(4-oxobutyl)carbamoyl)phenyl)quinolin-4-yl)piperidin-4-yl)carbamate (Compound 9-1-3)

[0622] To a solution of compound 9-1-2 (150 mg, 0.23 mmol, 1 eq) in DCM (5 mL) was added pyridinium chlorochromate (100.3 mg, 0.47 mmol, 2 eq), and the solution was stirred at 20 °C for 3 h. TLC (DCM:MeOH = 10:1) showed consumption of the material and detection of the major spot. The reaction solution was diluted with DCM and water. The solution was extracted with EA (3 × 25 mL). The organic layer was separated, washed with additional saturated NaCl solution, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether to afford compound 9-1-3 (72 mg, 0.11 mmol, 48.15%).

[0623] Step 3: Synthesis of 3-(4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl)-N-methyl-N-(4-oxobutyl)benzamide (Compound 9-1-4)

[0624] To a solution of compound 9-1-3 (32.2375 mg, 0.05 mmol, 1 eq) in [1,4-dioxane (3 mL)] was added (hydrogen chloride 4 mol / L), and the solution was stirred at 20 °C for 3 h. TLC (DCM:MeOH = 10:1) showed consumption of the material and detection of the major spot. After completion, the mixture was filtered and the filtrate was concentrated under reduced pressure to afford compound 9-1-4 (10 mg, 0.02 mmol, 31.12%).

[0625] Step 4: Synthesis of 23-(3,5-difluorophenyl)-5-methyl-5,10-diaza-2(4,6)-quinolin-1(1,4)-piperidin-3(1,3)-benzospiro[4.5]decane-4-one (Compound 81)

[0626] To a solution of Compound 5 (10 mg, 0.02 mmol, 1 equiv) in DCM (5 mL) was added sodium trimethyl-λ 4 -boranetriacetate (8.44 mg, 0.04 mmol, 2 equiv), and the solution was stirred at a temperature (30 °C) for 16 h. The reaction mixture was diluted with DCM and water. The solution was extracted with DCM (2 × 5 mL). The organic layer was separated, washed with additional saturated NaCl solution, and concentrated in vacuo. The residue was purified by preparative HPLC to afford Compound 81 (2 mg, 18.99%).

[0627] The analytical data of Compound 81 are provided below.

[0628]

[0629] Example 10

[0630]

[0631] Scheme 10

[0632] Step 1: Synthesis of 6-bromo-3-chloro-1,4-dihydroquinolin-4-one (Compound 10-1-2)

[0633] At 0 °C, 1-chloropyrrolidine-2,5-dione (17.88 g, 133.9 mmol) was added to a stirred solution of 6-bromo-1,4-dihydroquinolin-4-one (Compound 10-1-1, 30 g, 133.9 mmol) in AcOH (500 mL). The reaction mixture was stirred at 60 °C for 2 h. TLC (PE:EtOAc = 1:1) indicated completion of the reaction. The reaction mixture was filtered, concentrated, and evaporated to afford 6-bromo-3-chloro-1,4-dihydroquinolin-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) + .

[0634] Step 2: Synthesis of 6-bromo-3,4-dichloroquinoline (Compound 10-1-3)

[0635] At 20 °C, N,N-dimethylformamide (702.03 mg, 9.61 mmol, 0.1 eq) was added to a stirred solution of 6-bromo-3-chloro-1,4-dihydroquinolin-4-one (Compound 10-1-2, 24.83 g, 96.05 mmol, 1 eq) in phosphoryl trichloride (250 mL, 1629.97 mmol, 16.97 eq). The reaction mixture was stirred at 97 °C for 2 h. TLC (PE:EtOAc = 5:1) indicated the completion of the reaction. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (500 mL), washed with saturated NaHCO3 (500 mL), dried over Na2SO4 and evaporated to give 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) + .

[0636] Step 3: Synthesis of 8-(6-bromo-3-chloroquinolin-4-yl)-1,4-dioxaspiro[4.5]decane (Compound 10-1-4)

[0637] At 20 °C, 1,4-dioxaspiro[4.5]decane (11.6322 g, 81.24 mmol, 1.5 eq) and potassium carbonate (14.97 g, 108.32 mmol, 2 eq) were added to a stirred solution of 6-bromo-3,4-dichloroquinoline (Compound 10-1-3, 15.00 g, 54.16 mmol, 1 eq) in DMF (150 mL). The reaction mixture was stirred at 100 °C for 16 h. TLC (PE:EtOAc = 5:1) indicated the completion of the reaction. The reaction mixture was poured into H2O (1 L), filtered and concentrated to give 8-(6-bromo-3-chloroquinolin-4-yl)-1,4-dioxaspiro[4.5]decane (Compound 10-1-4, 20 g, 52.13 mmol, 96.25%). MS (m / z) 383.1 / 385.1 (M+H) + .

[0638] Step 4: Synthesis of 1-(6-bromo-3-chloroquinolin-4-yl)piperidin-4-one (Compound 10-1-5)

[0639] At 20 °C, trifluoroacetic acid (100 ml, 877 mmol, 16.82 equiv) and 1,2-dichloroethane (100 ml, 1011 mmol, 19.39 equiv) were added to a stirred solution of 8-(6-bromo-3-chloroquinolin-4-yl)-1,4-dioxa-8-azaspiro[4.5]decane (Compound 10-1-4, 20.0006 g, 52.13 mmol, 1 equiv) in H2O (100 ml). The reaction mixture was stirred at 87 °C for 16 h. TLC (PE:EtOAc = 5:1) indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (500 mL), washed with saturated NaHCO3 (500 mL), dried over Na2SO4 and evaporated to give 1-(6-bromo-3-chloroquinolin-4-yl)piperidin-4-one (Compound 10-1-5, 15 g, 44.17 mmol, 84.73%) as a white solid. MS (m / z) 339 / 341 (M+H) + 。

[0640] Step 5: Synthesis of 1-[3-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl]piperidin-4-one (Compound 10-1-6)

[0641] At 20 °C, 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2243.22 mg, 8.83 mmol, 1.5 equiv), potassium acetate (1155.91 mg, 11.78 mmol, 2 equiv) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (449.23 mg, 0.59 mmol, 0.1 equiv) were added to a stirred solution of 1-[3-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl]piperidin-4-one (Compound 10-1-5, 2 g, 5.17 mmol, 87.83%) in 1,4-dioxane (70 ml). The reaction mixture was stirred at 100 °C for 1 h. TLC (PE:EtOAc = 5:1) indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL), washed with saturated NaHCO3 (500 mL), dried over Na2SO4 and evaporated to give 1-[3-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl]piperidin-4-one (Compound 10-1-6, 2 g, 5.17 mmol, 87.83%) as a white solid. MS (m / z) 387.2 (M+H)+ .

[0642] Step 6: Synthesis of methyl 6-[3-chloro-4-(4-oxopiperidin-1-yl)quinolin-6-yl]pyridine-2-carboxylate (Compound 10-1-7)

[0643] At 20 °C, water (15 ml), methyl 6-bromopyridine-2-carboxylate (1116.88 mg, 5.17 mmol, 1 equiv), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (394.37 mg, 0.52 mmol, 0.1 equiv), and potassium carbonate (1429.09 mg, 10.34 mmol, 2 equiv) were added to a stirred solution of 1-[3-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl]piperidin-4-one (Compound 10-1-6, 2 g, 5.17 mmol, 1 equiv) in 1,4-dioxane (60 ml). The reaction mixture was stirred at 90 °C for 1 h. TLC (PE:EtOAc = 5:1) indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL), washed with saturated NaHCO3 (50 mL), dried over Na2SO4 and evaporated to give a residue. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (9:1 - 1:1) to afford methyl 6-[3-chloro-4-(4-oxopiperidin-1-yl)quinolin-6-yl]pyridine-2-carboxylate (Compound 10-1-7, 1.9 g, 4.8 mmol, 92.84%) as a white solid. MS (m / z) 396.1 (M+H) + .

[0644] Step 7: Synthesis of methyl 6-[3-(3,5-difluorophenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl]pyridine-2-carboxylate (Compound 10-1-8)

[0645] At 20 °C, water (15 mL), (3,5-difluorophenyl)boronic acid (757.97 mg, 4.8 mmol, 1 equiv), potassium carbonate (1326.82 mg, 9.6 mmol, 2 equiv), and dichloro bis[di-tert-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (339.87 mg, 0.48 mmol, 0.1 equiv) were added to a stirred solution of methyl 6-[3-chloro-4-(4-oxopiperidin-1-yl)quinolin-6-yl]pyridine-2-carboxylate (Compound 10-1-7, 1.9 g, 4.8 mmol, 1 equiv) in 1,4-dioxane (60 mL). The reaction mixture was stirred at 100 °C for 1 h. TLC (PE:EtOAc = 1:1) indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL), washed with saturated NaHCO3 (50 mL), dried over Na2SO4 and evaporated to give a residue. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (9:1 - 1:1) to afford methyl 6-[3-(3,5-difluorophenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl]pyridine-2-carboxylate as a white solid (Compound 10-1-8, 1.6 g, 3.38 mmol, 70.42%). MS (m / z) 474.2 (M+H) + LCMS: m / z: 474.2 (M+H).

[0646] Step 8: Synthesis of 6-[3-(3,5-difluorophenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl]pyridine-2-carboxylic acid (Compound 10-1-9)

[0647] At 0 °C, sodium hydroxide (675.95 mg, 16.9 mmol, 5 equiv) and water (5 mL) were added to a stirred solution of methyl 6-[3-(3,5-difluorophenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl]pyridine-2-carboxylate (Compound 10-1-8, 1.4 g, 3.05 mmol, 90.17%) in THF (20 mL). The reaction mixture was stirred at 40 °C for 2 h. TLC (PE:EtOAc = 1:1) indicated completion of the reaction. The pH of the reaction mixture was adjusted to 3 - 4. The reaction mixture was filtered, concentrated and evaporated to afford 6-[3-(3,5-difluorophenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl]pyridine-2-carboxylic acid as a white solid (Compound 10-1-9, 1.4 g, 3.05 mmol, 90.24%). MS (m / z) 460.2 (M+H) + 。

[0648] Step 9: Synthesis of tert-Butyl N-[4-(1-{3-[3-(3,5-Difluorophenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl]phenyl}-N-methylcarbamoyl)butyl]carbamate (Compound 10-1-10)

[0649] At 20 °C, to a stirred solution of 6-[3-(3,5-difluorophenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl]pyridine-2-carboxylic acid (Compound 10-1-9, 750 mg, 1.63 mmol, 1 equiv) in DMF (10 mL) was added tert-Butyl N-[4-(methylamino)butyl]carbamate (330.22 mg, 1.63 mmol, 1 equiv), tripropyl-1,3,5,2λ 5 ,4λ 5 ,6λ 5 -trioxatriphosphane-2,4,6-trione (1038.81 mg, 3.26 mmol, 2 equiv) and ethyldi(propan-2-yl)amine (1054.87 mg, 8.16 mmol, 5 equiv). The reaction mixture was stirred at 20 °C for 1 h. TLC (PE:EtOAc = 1:1) indicated the completion of the reaction. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL), washed with saturated NaHCO3 (50 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (9:1 - 1:1) to afford tert-Butyl N-[4-(1-{3-[3-(3,5-difluorophenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl]phenyl}-N-methylcarbamoyl)butyl]carbamate (Compound 10-1-10, 520 mg, 0.81 mmol, 49.62%). MS (m / z) 644.3 (M+H) + .

[0650] Step 10: Synthesis of N-(4-Aminobutyl)-6-(3-(3,5-difluorophenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)-N-methylpyridinecarboxamide (Compound 10-1-11)

[0651] At 20 °C, trifluoroacetic acid (1 ml, 8.77 mmol, 10.84 eq) was added to a stirred solution of tert-butyl (4-(6-(3-(3,5-difluorophenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)-N-methylpyridinecarboxamido)butyl)carbamate (Compound 10-1-10, 520 mg, 0.81 mmol, 1 eq) in DCM (4 ml, 100.0%). The reaction mixture was stirred at 20 °C for 1 h. TLC (DCM:MeOH = 10:1) indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure to afford N-(4-aminobutyl)-6-(3-(3,5-difluorophenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)-N-methylpyridinecarboxamide as a white solid (Compound 10-1-11, 400 mg, 0.74 mmol, 91.11%). MS (m / z) 543.3 (M+H) + .

[0652] Step 11: Synthesis of (Compound 82)

[0653] At 20 °C, titanium(4+) tetra(propan-2-olate) (261.9 mg, 0.92 mmol, 5 eq) was added to a stirred solution of N-(4-aminobutyl)-6-(3-(3,5-difluorophenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)-N-methylpyridinecarboxamide (Compound 10-1-11, 97.6714 mg, 0.18 mmol, 1 eq) in MeOH (5 ml, 100.0%). After stirring at 20 °C for 1 h, sodium trimethyl-λ 4 -boranetriacetate (388.73 mg, 1.84 mmol, 10 eq) was added slowly to the reaction mixture. The reaction was stirred at 20 °C for an additional 1 h. TLC (DCM:MeOH = 10:1) indicated completion of the reaction. The reaction mixture was quenched with H2O (5 mL) and extracted with DCM (30 mL×2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, and concentrated. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to afford 24-(3,5-difluorophenyl)-11-methyl-2,6,11,22,27-pentaazapentacyclo[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-octadecaene-12-one (Compound 82, 26 mg, 0.05 mmol, 27.13%).

[0654] Synthesize compounds 82 - 86 according to the 11 - step procedure described in Example 10. The analytical data of compounds 82 - 86 are provided below.

[0655]

[0656]

[0657] Example 11

[0658]

[0659] Scheme 11

[0660] Step 1: Synthesis of 1 - (3 - (3 - fluoro - 5 - methylphenyl) - 6 - (2 - hydroxyphenyl)quinolin - 4 - yl)piperidin - 4 - one (Compound 11 - 1 - 2)

[0661] Dissolve 1 - (3 - (3 - fluoro - 5 - methylphenyl) - 6 - (2 - hydroxyphenyl)quinolin - 4 - yl)piperidin - 4 - one (Compound 11 - 1 - 1, 2 g, 4.84 mmol, 1.0 equivalent), 2 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl)phenol (1 g, 7.26 mmol, 1.5 equivalents) and K2CO3 (1.33 g, 9.68 mmol, 2.0 equivalents) in 1,4 - dioxane (16 mL):H2O (4 mL) = 4:1, then add Pd(dppf)Cl2 (353 mg, 0.484 mmol, 0.1 equivalent) to the solution. Stir and heat the reaction mixture under a nitrogen atmosphere to 90 °C for 2 hours. Detect the desired product by LCMS. Extract the reaction mixture with ethyl acetate (50 mL * 3), wash with brine, and dry over anhydrous Na2SO4. Concentrate the filtrate under vacuum and purify the residue by FCC (EA:PE = 1:2) to obtain 1 - (3 - (3 - fluoro - 5 - methylphenyl) - 6 - (2 - hydroxyphenyl)quinolin - 4 - yl)piperidin - 4 - one (Compound 11 - 1 - 2, 800 mg, 1.87 mmol, 38.6%) as a red solid. MS (m / z) 427.25 (M + H) + 。

[0662] Step 2: Synthesis of 2 - (3 - (3 - fluoro - 5 - methylphenyl) - 4 - (4 - oxopiperidin - 1 - yl)quinolin - 6 - yl)phenyl (4 - nitrophenyl) carbonate (Compound 11 - 1 - 3)

[0663] Dissolve 1-(3-(3-fluoro-5-methylphenyl)-6-(2-hydroxyphenyl)quinolin-4-yl)piperidin-4-one (Compound 11-1-2, 200 mg, 0.47 mmol, 1.0 eq), 4-nitrophenyl chloroformate (113 mg, 0.564 mmol, 1.2 eq) and DIPEA (151 mg, 1.175 mmol, 2.5 eq) in DCM (5 mL). Stir the reaction mixture at 25 °C for 3 h under a nitrogen atmosphere. Detect the desired product by LCMS. Extract the reaction mixture with CH2Cl2 (20 mL * 3), wash with brine, and dry over anhydrous Na2SO4. Concentrate the filtrate under vacuum and purify the residue by FCC (PE:EA = 2:1) to obtain 2-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidin-1-yl)quinolin-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) + 。

[0664] Step 3: Synthesis of tert-butyl (2-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)phenyl)ethane-1,2-diyl dicarbamate (Compound 11-1-4)

[0665] Dissolve 2-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)phenyl (4-nitrophenyl) carbonate (Compound 11-1-3, 200 mg, 0.338 mmol, 1.0 eq) in DCM (4 mL), then add tert-butyl (2-aminoethyl)carbamate (64 mg, 0.40 mmol, 1.2 eq) to the solution. Stir the reaction mixture at 25 °C for 1 h. Detect the desired product by LCMS. Extract the reaction mixture with DCM (20 mL * 3), wash with brine, and dry over anhydrous Na2SO4. Concentrate the filtrate under vacuum and purify the residue by FCC (EA:PE = 2:1) to obtain tert-butyl (2-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)phenyl)ethane-1,2-diyl dicarbamate (Compound 11-1-4, 140 mg, 0.229 mmol, 67.7%) as a yellow oil. MS (m / z) 613.5 (M+H) + 。

[0666] Step 4: Synthesis of 2-(3-(3-Fluoro-5-methylphenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)phenyl (2-aminoethyl)carbamate (Compound 11-1-5)

[0667] Dissolve tert-butyl (2-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)phenyl)ethane-1,2-diyl dicarbamate (Compound 11-1-4, 70 mg, 0.114 mmol, 1.0 equiv) in a solution of TFA (1 mL):DCM (3 mL) = 1:3. Stir the reaction mixture at 25 °C for 1 h. Detect the desired product by LCMS. Concentrate the reaction mixture under vacuum to obtain 2-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)phenyl (2-aminoethyl)carbamate (Compound 11-1-5, 58 mg, 0.114 mmol, 100%). MS (m / z) 513.35 (M+H) + 。

[0668] Step 5: Synthesis of Compound 87

[0669] Dissolve 2-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)phenyl (2-aminoethyl)carbamate (Compound 11-1-5, 58 mg, 0.114 mmol, 1.0 equiv) in MeOH (4 mL). Then add Ti(OiPr)4 (321 mg, 1.14 mmol, 10 equiv) to the solution under a nitrogen atmosphere. Stir the reaction mixture at 25 °C for 30 min. Then add NaBH(OAc)3 (241 mg, 1.14 mmol, 10 equiv) to the solution. Stir the reaction mixture at 25 °C for 12 h. Detect the desired product by LCMS. Filter the reaction mixture through diatomaceous earth and concentrate the filtrate under vacuum to obtain the crude product. Purify the crude product by preparative HPLC (0.1% TFA / water) to obtain 23-(3-fluoro-5-methylphenyl)-4-oxa-6,9-diaza-2(4,6)-quinolin-1(1,4)-piperidine-3(1,2)-benzonon-5-one (Compound 87, 5.0 mg, 0.0084 mmol, 7.4%) as a yellow solid.

[0670] The analytical data of Compound 87 are provided below.

[0671]

[0672] Example 12

[0673]

[0674] Scheme 12

[0675] Step 1: Synthesis of 5-(2-azidoethyl)-2,2-dimethyl-1,3-dioxane (Compound 12-1-2)

[0676] Sodium azide (1240.39 mg, 19.08 mmol, 2 eq) was added 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), and the solution was stirred at 60 °C for 3 h. After completion, the reaction mixture was extracted with EA (500 mL × 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 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) + 。

[0677] Step 2: Synthesis of 2-(2-azidoethyl)propane-1,3-diol (Compound 12-1-3)

[0678] 8 ml of HCl (2 M) was added to a solution of 5-(2-azidoethyl)-2,2-dimethyl-1,3-dioxane (Compound 12-1-2, 1.74 g, 9.39 mmol, 1 eq) in THF (40 ml), and the solution was stirred at 25 °C for 1 h. After completion, the reaction mixture was concentrated under reduced pressure to give the crude product in water. The crude product was lyophilized to give 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) + 。

[0679] Step 3: Synthesis of 2-(4-azido-2-(hydroxymethyl)butoxy)-3-bromobenzonitrile (Compound 12-1-4)

[0680] At -60 °C, LiHMDS (11.7 ml, 11.7 mmol, 1.1 eq) was added 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). The above 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 above mixture at 60 °C over 2 hours. After completion, the reaction mixture was extracted with EA (500 mL × 3). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (DCM:MeOH = 12:1) to give 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) + 。

[0681] Step 4: Synthesis of 2-(4-azido-2-(hydroxymethyl)butoxy)-3-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)benzonitrile (Compound 12-1-6)

[0682] 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-oxopiperidin-1-yl)quinolin-6-yl)boronic acid (Compound 12-1-5, 1.50 g, 3.97 mmol, 1 eq) in 1,4-dioxane (30 ml) and H2O (6 ml) were added potassium carbonate (1.09 g, 8 mmol, 2 eq) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (290 mg, 0.397 mmol, 0.1 eq), and the solution was stirred at 100 °C for 1 hour. The reaction was monitored by LCMS and TLC. After completion, the reaction mixture was diluted with water (50 mL) and extracted with EA (100 mL × 2). The combined organic extracts were concentrated to give a crude material, and then the crude product was purified by flash chromatography (DCM:MeOH = 10:1) to give 2-(4-azido-2-(hydroxymethyl)butoxy)-3-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)benzonitrile (Compound 12-1-6, 800 mg, 1.38 mmol) as a white solid. MS (m / z) 579 (M+H) + 。

[0683] Step 5: Synthesis of 2-(4-Amino-2-(hydroxymethyl)butoxy)-3-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)benzonitrile (Compound 12-1-7)

[0684] A solution of 2-(4-Azido-2-(hydroxymethyl)butoxy)-3-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)benzonitrile (Compound 12-1-6, 220 mg, 0.398 mmol, 1 equiv) in NH4OH (4 ml) and pyridine (4 ml) was stirred at 25 °C for 1 h. PPh3 (100 mg, 0.398 mmol, 1 equiv) was added to the above mixture and stirred at 25 °C for 12 h. The reaction was monitored by TLC. After completion, the reaction mixture was diluted with water (50 mL) and extracted with EA (100 mL×2). The combined organic extracts were concentrated to give the crude material, and then the crude product was purified by flash (DCM:MeOH = 10:1) to give 2-(4-Amino-2-(hydroxymethyl)butoxy)-3-(3-(3-fluoro-5-methylphenyl)-4-(4-oxo-piperidin-1-yl)quinolin-6-yl)benzonitrile (Compound 12-1-7, 140 mg, 0.253 mmol) as a white solid. MS (m / z) 553 (M+H) + 。

[0685] Step 6: Synthesis of (S)-2 3 -(3-Fluoro-5-methylphenyl)-6-(hydroxymethyl)-4-oxa-9-aza-2(4,6)-quinolino-1(1,4)-piperidine-3(1,2)-benzonorbornane-3 3 -carbonitrile (Compound 88) and (R)-2 3 -(3-Fluoro-5-methylphenyl)-6-(hydroxymethyl)-4-oxa-9-aza-2(4,6)-quinolino-1(1,4)-piperidine-3(1,2)-benzonorbornane-3 3 -carbonitrile (Compound 89)

[0686] A solution of 2-(4-amino-2-(hydroxymethyl)butoxy)-3-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)benzonitrile (Compound 12-1-7, 120 mg, 0.223 mmol, 1 equiv) and Ti(OiPr)4 (308 mg, 1.115 mmol, 5 equiv) in MeOH (1.8 ml) and DCE (1.8 ml) was stirred at 25 °C for 1 h. Then, NaBH(OAC)3 (460 mg, 2.23 mmol, 10 equiv) was added to the above mixture and stirred at 25 °C for 12 h. The reaction was monitored by LCMS and TLC. After completion, the reaction mixture was diluted with water (100 mL) and extracted with EA (200 mL×3). The combined organic extracts were concentrated to give the crude product, and the above mixture was purified by preparative HPLC to give 2 3 -(3-fluoro-5-methylphenyl)-6-(hydroxymethyl)-4-oxa-9-aza-2(4,6)-quinoline-1(1,4)-piperidine-3(1,2)-benzonoradamantane-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)-quinoline-1(1,4)-piperidine-3(1,2)-benzonoradamantane-33-carbonitrile (Compound 89, 4.4 mg, 0.008 mmol). The stereochemistry was arbitrarily defined.

[0687] Compounds 88 - 93 were synthesized according to the 6-step procedure described in Example 12. The analytical data of Compounds 88 - 93 are provided below.

[0688]

[0689]

[0690] *The stereochemistry was arbitrarily assigned.

[0691] Example 13

[0692]

[0693] Scheme 13

[0694] Step 1: Synthesis of 3-bromo-2-(but-3-en-1-yloxy)benzonitrile (Compound 13-1-2)

[0695] 3-bromo-2-hydroxybenzonitrile (Compound 13-1-1, 5 g, 25.51 mmol, 1.0 equiv) and K2CO3 (7 g, 51 mmol, 2.0 equiv) were dissolved in MeCN (50 mL), and then 4-bromobut-1-ene (6.8 g, 51 mmol, 2.0 equiv) was added to the solution. The reaction mixture was stirred and heated to 90 °C under a nitrogen atmosphere for 12 h. The desired product was detected by LCMS. The reaction mixture was extracted with ethyl acetate (100 mL * 3), washed with brine, and dried over anhydrous Na2SO4. The filtrate was concentrated in vacuo, and the residue was purified by FCC (EA:PE = 1:2) to afford 3-bromo-2-(but-3-en-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) - 。

[0696] Step 2: Synthesis of 2-(4-amino-3-azidobutoxy)-3-bromobenzonitrile (Compound 13-1-3)

[0697] 3-bromo-2-(but-3-en-1-yloxy)benzonitrile (Compound 13-1-2, 1 g, 4.0 mmol, 1.0 equiv) and Fe(OTf)2 (107 mg, 0.4 mmol, 0.1 equiv) were dissolved in MeOH (10 mL), and then PivONH3OTf (2.67 g, 10 mmol, 2.5 equiv) and NaN3 (312 mg, 4.8 mmol, 1.2 equiv) were added to the solution under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 h under a nitrogen atmosphere. The desired product was detected by LCMS. The reaction solution was concentrated in vacuo to afford the crude product 2-(4-amino-3-azidobutoxy)-3-bromobenzonitrile (Compound 13-1-3) for the next step. MS (m / z) 310 (M+H) + 。

[0698] Step 3: Synthesis of tert-butyl (2-azido-4-(2-bromo-6-cyanophenoxy)butyl)carbamate (Compound 13-1-4)

[0699] 2-(4-Amino-3-azidobutoxy)-3-bromobenzonitrile (Compound 13-1-3, 1 g, 4.0 mmol, 1.0 equiv) was dissolved in a solution of DCM (5 mL): NaHCO3 (aqueous solution) (5 mL) = 1:1, and then (Boc)2O (1.7 g, 8 mmol, 2.0 equiv) was added to the solution. The reaction mixture was stirred at 25 °C for 12 h. The desired product was detected by LCMS. The reaction mixture was extracted with DCM (50 mL * 3), washed with brine, and dried over anhydrous Na2SO4. The filtrate was concentrated under vacuum to obtain the crude product tert-butyl (2-azido-4-(2-bromo-6-cyanophenoxy)butyl)carbamate (Compound 13-1-4, 1.2 g, 3.0 mmol, 75%). MS (m / z) 310 / 354 / 356 (M-100 / M-56 / M-56+2) +

[0700] Step 4: Synthesis of tert-butyl (2-azido-4-(2-cyano-6-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)phenoxy)butyl)carbamate (Compound 13-1-5)

[0701] tert-Butyl (2-azido-4-(2-bromo-6-cyanophenoxy)butyl)carbamate (Compound 13-1-4, 400 mg, 1.0 mmol, 1.0 equiv), (3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)boronic acid (378 mmol, 1.0 equiv), and K2CO3 (196 mg, 1.5 mmol, 1.5 equiv) 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 equiv) was added to the solution. The reaction mixture was stirred under a nitrogen atmosphere and heated to 90 °C for 2 h. The desired product was detected by LCMS. The reaction solution was extracted with ethyl acetate (30 mL * 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 tert-butyl (2-azido-4-(2-cyano-6-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)phenoxy)butyl)carbamate (Compound 13-1-5, 230 mg, 0.347 mmol, 34.7%) as a yellow solid. MS (m / z) 664.45 (M+H) + 。

[0702] Step 5: Synthesis of 2-(4-Amino-3-azidobutoxy)-3-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)benzonitrile (Compound 13-1-6)

[0703] Dissolve tert-butyl (2-azido-4-(2-cyano-6-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)phenoxy)butyl)carbamate (Compound 13-1-5, 230 mg, 0.347 mmol, 1.0 equiv) in a solution of TFA (1 mL):DCM (3 mL) = 1:3. Stir the reaction solution at 25 °C for 1 h. Detect the desired product by LCMS. Concentrate the reaction solution in vacuo to obtain the crude product 2-(4-amino-3-azidobutoxy)-3-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)benzonitrile (Compound 13-1-6, 195 mg, 0.347 mmol, 100%). MS (m / z) 564.4 (M+H) + 。

[0704] Step 6: Synthesis of Compound 94

[0705] Dissolve 2-(4-amino-3-azidobutoxy)-3-(3-(3-fluoro-5-methylphenyl)-4-(4-oxopiperidin-1-yl)quinolin-6-yl)benzonitrile (Compound 13-1-6, 195 mg, 0.347 mmol, 1.0 equiv) in MeOH (4 mL). Then add Ti(OiPr)4 (497 mg, 1.75 mmol, 5 equiv) to the solution under a nitrogen atmosphere. Stir the reaction mixture at 25 °C for 30 min. Then add NaBH(OAc)3 (742 mg, 3.5 mmol, 10 equiv) to the solution. Stir the reaction mixture at 25 °C for 12 h. Detect the desired product by LCMS. Filter the reaction mixture through diatomaceous earth and concentrate the filtrate in vacuo to obtain the crude product. Purify the crude product by preparative HPLC (0.1% TFA / water) to obtain 7-azido-23-(3-fluoro-5-methylphenyl)-4-oxa-9-aza-2(4,6)-quinolin-1(1,4)-piperidine-3(1,2)-benzononane-33-carbonitrile (Compound 94, 2.0 mg, 0.00366 mmol, 1.0%) as a yellow solid.

[0706] Step 7: Synthesis of Compound 95

[0707] 7 - Azido - 23-(3 - fluoro - 5 - methylphenyl)-4 - oxa - 9 - azabicyclo[2.4.1]non - 2(4,6)-en - 1(1,4)-piperidin - 3(1,2)-benzonorbornane - 3 3 7 - Azido - 23-(3 - fluoro - 5 - methylphenyl)-4 - oxa - 9 - azabicyclo[2.4.1]non - 2(4,6)-en - 1(1,4)-piperidin - 3(1,2)-benzonorbornane - 3 - carbonitrile (Compound 13 - 1, 10 mg, 0.0183 mmol, 1.0 equiv) and PPh3 (7 mg, 0.022 mmol, 1.5 equiv) were dissolved in pyridine (2 mL). The reaction mixture was stirred at 25 °C for 30 min under a nitrogen atmosphere. Then NH3·H2O (2 mL) was added to the solution. The reaction mixture was stirred at 25 °C for 12 h under a nitrogen atmosphere. The desired product was detected by LCMS. The reaction solution was concentrated in vacuo, and the residue was purified by preparative HPLC (0.1% TFA / water) to give 7 - amino - 23-(3 - fluoro - 5 - methylphenyl)-4 - oxa - 9 - azabicyclo[2.4.1]non - 2(4,6)-en - 1(1,4)-piperidin - 3(1,2)-benzonorbornane - 3 - carbonitrile (Compound 95, 1.0 mg, 0.00192 mmol, 10%).

[0708] Compounds 94 - 103 were synthesized according to the 6 - step procedure described in Example 13. The analytical data of Compounds 94 - 103 are provided below.

[0709]

[0710]

[0711]

[0712] *Stereochemistry is arbitrarily assigned.

[0713] Example 14

[0714]

[0715] Scheme 14

[0716] Step 1: Synthesis of tert - butyl N - [1-(2 - chloro - 3 - formyl - 4 - pyridyl)-4 - piperidinyl]carbamate (Compound 14 - 1 - 2)

[0717] At 25 °C, DIPEA (36.65 g, 284.09 mmol) was added to a stirred mixture of Compound 14-1-1 (10 g, 56.82 mmol) and tert-butyl N-(piperidin-4-yl)carbamate (11.38 g, 56.82 mmol) in DMF (100 mL) over 2 h. The reaction was monitored by LCMS, which showed completion of the reaction. The mixture was diluted with water (60 mL), and then a large amount of solid precipitated out from the reaction solution. The cake was collected by filtration, dissolved in ethyl acetate, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford Compound 14-1-2 as a yellow solid (17.50 g, 51.50 mmol, 90.64% yield). MS (m / z) 340 (M+H) + 。

[0718] Step 2: Synthesis of tert-butyl N-[1-(5-bromo-2-chloro-3-formyl-4-pyridinyl)piperidin-4-yl]carbamate (Compound 14-1-3)

[0719] At 25 °C, NBS (9.17 g, 51.50 mmol) was added to a solution of Compound 14-1-2 (17.5 g, 51.50 mmol) in DMF (100 mL), and then the resulting mixture was stirred at 25 °C for 16 h. The reaction was monitored by LCMS, which showed completion of the reaction. The mixture was diluted with water (20 mL), washed with ethyl acetate (3 × 20 mL), the organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give Compound 14-1-3 as a yellow solid (7.00 g, crude). MS (m / z) 420 (M+H) + 。

[0720] Step 3: Synthesis of tert-butyl N-[1-[5-bromo-2-chloro-3-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-4-pyridinyl]piperidin-4-yl]carbamate (Compound 14-1-4)

[0721] 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) was added acetic acid (3.01 g, 50.15 mmol), and then the mixture was stirred at 60 °C for 2 h. Then FeCl3 (8.14 g, 50.15 mmol) was added at 25 °C, and then the resulting mixture was stirred at 60 °C for 2 h. The reaction was monitored by LCMS and TLC, which showed completion of the reaction. The reaction mixture was diluted with water (50 mL). Then it was extracted with ethyl acetate (50 mL * 2). All the organic phases were combined and dried over anhydrous Na2SO4. The organic phase was concentrated to give compound 14-1-4 (6.70 g, crude) as a brown solid. MS (m / z) 544 (M + H) + 。

[0722] Step 4: Synthesis of tert-butyl N-[1-[2-chloro-3-(5,6-difluoro-1H-benzoimidazol-2-yl)-5-(3-fluoro-5-methyl-phenyl)-4-pyridinyl]-4-piperidinyl]carbamate (Compound 14-1-5)

[0723] At 25 °C, to a solution of compound 14-1-4 (6.7 g, 12.34 mmol) and (3-fluoro-5-methyl-phenyl)boronic acid (1.71 g, 11.11 mmol) in 1,4-dioxane (40 mL) and water (10 mL) was added NaHCO3 (3.11 g, 37.03 mmol) and PdCl2(dppf) (905.65 mg, 1.23 mmol), and then the resulting mixture was stirred under N2 at 90 °C for 3 h. The reaction was monitored by LCMS, which showed completion of the reaction. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 * 50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (EA / PE = 20% - 50%) to give compound 14-1-5 (2.05 g, 3.58 mmol, 28.96% yield) as a brown solid. MS (m / z) 572.2 (M + H) + 。

[0724] Step 5: Synthesis of 1-(2-chloro-3-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl)piperidin-4-amine (Compound 104)

[0725] At 25 °C, TFA (199.33 mg, 1.75 mmol) was added to a stirred solution of Compound 14-1-5 (100 mg, 174.82 μmol) in DCM (5 mL). The mixture was stirred at room temperature for 16 h. The reaction was monitored by LCMS, which showed completion of the reaction. The mixture was concentrated in vacuo, and the residue was dissolved in methanol (3 mL), treated with NaHCO3 (solid) to adjust to pH 8, and then filtered. The filtrate was concentrated in vacuo. The contaminants were purified by preparative HPLC. Lyophilization provided the desired product, Compound 104 (11 mg, 23.31 μmol, 13.33% yield) as a white solid.

[0726] The analytical data of Compound 104 are provided below.

[0727]

[0728] Example 15

[0729]

[0730] Scheme 15

[0731] Step 1: Synthesis of tert-butyl (3-((3,5-dibromopyridin-4-yl)amino)propyl)carbamate (Compound 15-1-1)

[0732] 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 min. The progress of the reaction was monitored by LCMS. It was cooled to room temperature and poured into ice water (25 mL), and a large amount of solid was observed. The solid was collected, then washed with H2O (10 mL * 3) and dried in vacuo to give the title compound (Compound 15-1-1, 400.00 mg, 977.72 μmol, 88.21% yield) as a white solid. MS (m / z) 408.0 (M+H) + .

[0733] Step 2: Synthesis of tert-butyl (3-((3-bromo-5-(1H-indol-2-yl)pyridin-4-yl)amino)propyl)carbamate (Compound 15-1-2)

[0734] At 25 °C, [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (94.15 mg, 128.33 μmol) and K2CO3 (181.35 mg, 1.71 mmol) were added 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). The resulting mixture was degassed completely and stirred at 110 °C under N2 for 2 h. The progress of the reaction was monitored by LCMS. The reaction solution was cooled to 25 °C and diluted with EtOAc and water. The mixture was separated, and then the aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by silica gel chromatography, eluting with DCM:MeOH = 8:1 to give the title compound as a yellow oil (Compound 15-1-2, 320.00 mg, 723.50 μmol, 84.57% yield). MS (m / z) 442.2 (M+H) + 。

[0735] Step 3: Synthesis of tert-Butyl (3-((3-(3,5-difluorophenyl)-5-(1H-indol-2-yl)pyridin-4-yl)amino)propyl)carbamate (Compound 15-1-3)

[0736] 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) was added [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (79.63 mg, 108.52 μmol) and K2CO3 (149.99 mg, 1.09 mmol), and then the resulting mixture was stirred at 110 °C under N2 for 2 h. The progress of the reaction was monitored by LCMS. The reaction solution was cooled to 25 °C and diluted with EtOAc and water. The mixture was separated, and then the aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by silica gel chromatography, eluting with PE:EtOAc = 1:1 to give the title compound as a yellow solid (Compound 15-1-3, 150.00 mg, 313.46 μmol, 57.77% yield). MS (m / z) 479.1 (M+H) + 。

[0737] Step 4: Synthesis of tert-butyl (3-(4-(3,5-difluorophenyl)-6-oxopyrido[4',3':4,5]pyrimido[1,6-a]indol-5(6H)-yl)propyl)carbamate (Compound 15-1-4)

[0738] At 0 °C, sodium hydride (17.49 mg, 437.31 μmol, 60% purity) was added to a solution of Compound 15-1-3 (75 mg, 145.77 μmol) in DMF (2 mL), and then the resulting mixture was stirred at 0 °C for 10 minutes. Methyl chloroformate (42 mg, 437.31 μmol) was added. The reaction solution was stirred overnight at 25 °C. The reaction mixture was quenched with 3 mL of saturated aqueous NH4Cl. The resulting solution was extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine (10 ml), dried over Na2SO4, then filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography, eluting with PE:EtOAc = 10:1, to afford the title compound 15-1-4 as a yellow solid (30.00 mg, 55.50 μmol, 38.08% yield). MS (m / z) 505.4 (M+H) + 。

[0739] Step 5: Synthesis of 5-(3-aminopropyl)-4-(3,5-difluorophenyl)pyrido[4',3':4,5]pyrimido[1,6-a]indol-6(5H)-one (Compound 105)

[0740] At 25 °C, TFA (1.25 g, 10.92 mmol, 0.5 mL) was added to a solution of Compound 15-1-4 (30 mg, 59.46 μmol) in DCM (1.5 mL), and then the resulting mixture was stirred at 25 °C for 10 minutes. The progress of the reaction was monitored by LCMS. The reaction proceeded well. The solvent and TFA were removed by concentration until dryness. It was diluted with MeOH and adjusted to pH = 7 using Na2CO3 (solid). The solution was purified by preparative HPLC to give the title compound 105 as a white solid (4.00 mg, 7.93 μmol, 13.33% yield).

[0741] The analytical data of Compound 105 are provided as follows.

[0742]

[0743] Example 16

[0744]

[0745] Scheme 16

[0746] Step 1: Synthesis of 2-(5-bromo-4-chloropyridin-3-yl)-5,6-difluoro-1H-benzo[d]imidazole (Compound 16-1-1)

[0747] 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) was added acetic acid (163.44 mg, 2.72 mmol), and then the mixture was stirred at 25 °C in N2 for 16 h. After adding FeCl3 (331.10 mg, 2.04 mmol) at 55 °C, the resulting mixture was stirred at 55 °C for 16 h. The reaction was monitored by LCMS, which showed completion of the reaction. The resulting mixture was extracted with ethyl acetate (100 mL × 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, eluting with PE:EtOAc = 1:1 to afford 2-(5-bromo-4-chloro-3-pyridinyl)-5,6-difluoro-1H-benzoimidazole as a yellow solid (Compound 16-1-1, 2.50 g, 5.80 mmol, 42.66% yield, 80% purity). MS (m / z) 344.0 (M+H) + 。

[0748] Step 2: Synthesis of tert-butyl (3-((3-bromo-5-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)pyridin-4-yl)amino)propyl)(methyl)carbamate (Compound 16-1-2)

[0749] At 25 °C, N,N-diisopropylethylamine (823.77 mg, 6.37 mmol) was added to a solution of compound 16-1-1 (813.37 mg, 2.12 mmol) and N-(3-aminopropyl)-N-methyl-carbamic acid tert-butyl ester (400 mg, 2.12 mmol) in N,N-dimethylformamide (3 mL). The resulting mixture was stirred in N2 at 90 °C for 4 hours. The reaction was monitored by LCMS, which showed completion of the reaction. The reaction mixture was diluted with ethyl acetate (100 mL). Then it was extracted with water (50 mL * 2). The aqueous phase was stripped and extracted with ethyl acetate (150 mL). All the organic phases were combined and dried over anhydrous Na2SO4. Concentrated to remove the organic phase to obtain the crude product, which was purified by silica gel column (100 - 200 mesh) chromatography, eluted with PE:EtOAc = 1:1 to give tert-butyl N-[3-[[3-bromo-5-(5,6-difluoro-1H-benzoimidazol-2-yl)-4-pyridinyl]amino]propyl]-N-methyl-carbamate (Compound 16-1-2, 373.00 mg, 728.95 μmol, 34.31% yield, 97% purity). MS (m / z) 496.30 (M+H) + 。

[0750] Step 3: Synthesis of tert-butyl (3-(4-bromo-9,10-difluoro-6-oxobenzo[4,5]imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-yl)propyl)(methyl)carbamate (Compound 16-1-3)

[0751] 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 then added. The mixture was stirred at 0 °C for 0.5 h, and then methyl chloroformate (57.12 mg, 604.42 μmol) was added at 0 °C. The resulting mixture was stirred at 0 °C for 2 h in 2. The reaction was monitored by LCMS, which showed completion of the reaction. The reaction mixture was diluted with ethyl acetate (150 mL). Then it was extracted with water (50 mL × 2). The aqueous phase was extracted with ethyl acetate (150 mL). All the organic phases were combined and dried over anhydrous Na2SO4. The organic phase was concentrated to obtain a residue, and the crude product was purified by silica gel column (100 - 200 mesh) chromatography, eluting with DCM:MeOH = 1:1, to give tert-butyl (3-(4-bromo-9,10-difluoro-6-oxobenzo[4,5]imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-yl)propyl)(methyl)carbamate (compound 16-1-3, 20.00 mg, 34.46 μmol, 11.40% yield, 90% purity). MS (m / z) 522.1 (M + H) + 。

[0752] Step 4: Synthesis of tert-butyl (3-(4-(3,5-difluorophenyl)-9,10-difluoro-6-oxobenzo[4,5]imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-yl)propyl)(methyl)carbamate (compound 16-1-4)

[0753] At 25 °C, 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) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.62 mg, 7.66 μmol) and K2CO3 (15.88 mg, 114.87 μmol). The resulting mixture was stirred in N2 at 120 °C for 2 h. The reaction was monitored by LCMS, which showed completion of the reaction. The reaction mixture was diluted with ethyl acetate (150 mL). Then it was extracted with water (50 mL × 2). The aqueous phase was stripped and extracted with ethyl acetate (150 mL). All the organic phases were combined and dried over anhydrous Na2SO 4干燥。The concentrated organic phase was obtained to get a residue, and the residue was purified by silica gel column (100 - 200 mesh) chromatography, eluted with PE:EtOAc = 1:3, to obtain tert-butyl (3-(4-(3,5-difluorophenyl)-9,10-difluoro-6-oxobenzo[4,5]imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-yl)propyl)(methyl)carbamate (Compound 16-1-4, 15.00 mg, 24.30 μmol, 63.47% yield, 90% purity). MS (m / z) 556.2 (M+H) + 。

[0754] 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]pyrimidin-6(5H)-one (Compound 106)

[0755] At 25 °C, trifluoroacetic acid (0.5 mL) was added to a solution of Compound 16-1-4 (15 mg, 27.00 μmol) in dichloromethane (1.5 mL), and the resulting mixture was stirred at 25 °C for 0.5 h. The reaction solution was diluted with 20 mL of dichloromethane, the organic phase was concentrated, and the above operation was repeated three times. The crude product was purified by preparative HPLC (preparative C18, 5 μMOBD, 19×250 mm column, Waters; gradient elution from 30% MeCN / water to 50% MeCN / water in a 10-minute period, where both solvents contained 10 mmol / L NH4HCO3) to obtain Compound 106 as a white solid (4.30 mg, 6.46 μmol, 23.91% yield, 98% purity).

[0756] The analytical data of Compound 106 are provided below.

[0757]

[0758] Example 17

[0759]

[0760] Scheme 17

[0761] Step 1: Synthesis of (E)-tert-butyl (1-(2-(2-ethoxyvinyl)-3-formylpyridin-4-yl)piperidin-4-yl)carbamate (Compound 17-1-1)

[0762] At 25 °C, K2CO3 (2.44 g, 17.66 mmol) and X-Phos-Pd-G2 (925.21 mg, 1.18 mmol) were added 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). The resulting mixture was stirred at 100 °C for 5 h in N2. The reaction was monitored by LCMS and TLC. LCMS and TLC showed the disappearance of the starting materials. The reaction mixture was concentrated to dryness, and the concentrated reaction mixture was diluted with H2O (100 mL). Then it was extracted with ethyl acetate (300 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, then filtered and dried under vacuum to give (1-(2-(2-ethoxyvinyl)-3-formylpyridin-4-yl)piperidin-4-yl)carbamic acid (E)-tert-butyl ester (compound 17-1-1, 3.00 g, crude, 50% purity) as a black solid. The crude product was used directly in the next step without further purification. MS (m / z) 376.2 (M+H) + 。

[0763] Step 2: Synthesis of (1-(9,10-difluorobenzo[4,5]imidazo[2,1-f][1,6]naphthyridin-1-yl)piperidin-4-yl)carbamic acid tert-butyl ester (Compound 17-1-2)

[0764] At 25 °C, FeCl3 (1.79 g, 10.79 mmol, 98% purity) was added 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). The resulting mixture was stirred at 55 °C for 12 h in N2. The reaction was monitored by LCMS. LCMS showed the disappearance of the starting materials. The reaction mixture was concentrated to dryness, and the concentrated reaction mixture was diluted with H2O (100 mL), then extracted with ethyl acetate (100 mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with DCM:MeOH (99 / 1 to 10 / 1) to give (1-(9,10-difluorobenzo[4,5]imidazo[2,1-f][1,6]naphthyridin-1-yl)piperidin-4-yl)carbamic acid tert-butyl ester (compound 17-1-2, 200.00 mg, 352.82 μmol, 50% purity) as a yellow solid. MS (m / z) 454.4 (M+H) + 。

[0765] Step 3: Synthesis of tert-butyl (1-(9,10-difluorobenzo[4,5]imidazo[2,1-f][1,6]naphthyridin-1-yl)piperidin-4-yl)carbamate (Compound 17-1-3)

[0766] Under N2, Ni (2.07 mg, 35.28 μmol) was added to a solution of Compound 17-1-2 (200 mg, 352.82 μmol) in MeOH (20 mL). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 50 °C for 1 h under a H2 balloon. The reaction was monitored by LCMS. LCMS showed the disappearance of the starting material and the clear detection of the product. The reaction mixture was filtered, and the precipitated solid was washed with ethyl acetate (10 mL * 3). The filtrate was dried under vacuum to obtain Compound 17-1-3 (141.00 mg, crude, 80% purity) as a yellow solid. The crude product was used directly in the next step. MS (m / z) 456.1 (M + H) + 。

[0767] Step 4: Synthesis of tert-butyl (1-(9,10-difluoro-2-(3-fluoro-5-methylphenyl)-5,6-dihydrobenzo[4,5]imidazo[2,1-f][1,6]naphthyridin-1-yl)piperidin-4-yl)carbamate (Compound 17-1-4)

[0768] At 25 °C, N-chlorosuccinimide (42.21 mg, 316.14 μmol) was added to a solution of Compound 17-1-3 (72 mg, 158.07 μmol) in N,N-dimethylformamide (1 mL). The resulting mixture was stirred at 40 °C for 1 h. The reaction was monitored by LCMS. LCMS showed the disappearance of the starting material. The reaction mixture was diluted with water (20 mL) and then extracted with ethyl acetate (20 mL * 2). All the organic phases were combined, dried over anhydrous Na2SO4, filtered and concentrated to obtain a residue, which was crude Compound 17-1-4 (66.00 mg, crude, 50% purity) as a yellow solid. MS (m / z) 490.2 (M + H) + 。

[0769] Step 5: Synthesis of tert-butyl (1-(9,10-difluoro-2-(3-fluoro-5-methylphenyl)-5,6-dihydrobenzo[4,5]imidazo[2,1-f][1,6]naphthyridin-1-yl)piperidin-4-yl)carbamate (Compound 17-1-5)

[0770] At 25 °C, 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) was added K2CO3 (27.93 mg, 202.06 μmol) and X-Phos-Pd-G2 (10.59 mg, 13.47 μmol). The resulting mixture was stirred in N2 at 110 °C for 1 h. The reaction was monitored by LCMS. LCMS showed the disappearance of the starting materials. The reaction solution was extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with PE:EtOAc = 5:1 to give compound 17-1-5 as a yellow solid (22.00 mg, 37.08 μmol, 55.06% yield, 95% purity). MS (m / z) 564.3 (M+H) + 。

[0771] Step 6: Synthesis of 1-(9,10-difluoro-2-(3-fluoro-5-methylphenyl)-5,6-dihydrobenzo[4,5]imidazo[2,1-f][1,6]naphthyridin-1-yl)piperidin-4-amine (Compound 107)

[0772] At 25 °C, to a solution of compound 17-1-5 (22 mg, 39.03 μmol) in dichloromethane (1 mL) was added trifluoroacetic acid (4.45 mg, 39.03 μmol). The resulting mixture was stirred at 25 °C for 2 h. The reaction was monitored by TLC. TLC showed the disappearance of the starting materials. The reaction solution was diluted with 20 mL of dichloromethane, the organic phase was concentrated, and the above operation 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 / water to 50% MeCN / water in a 9-minute period, where both solvents contained 10 mmol / L NH4HCO3) to give compound 107 as a white solid (5.00 mg, 9.71 μmol, 24.87% yield, 98.28% purity).

[0773] The analytical data of compound 107 are provided below.

[0774]

[0775] Example 18

[0776]

[0777] Scheme 18

[0778] Step 1: Synthesis of Compound 18-1-1

[0779] Under N2 at 25 °C, within 16 hours, acetic acid (163.44 mg, 2.72 mmol) was added to a solution of Compound 18-1-SM (cas: 1060802-24-5, 3 g, 13.61 mmol) and 4,5-difluorobenzene-1,2-diamine (1.96 g, 13.61 mmol) in THF (10 mL). Then, after adding iron(III) chloride (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). Then it was extracted with water (50 mL × 2). The aqueous phase was stripped 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 (100 - 200 mesh) chromatography, eluted with PE:EtOAc = 1:1, to give Compound 18-1-1 as a yellow solid (2.50 g, 5.80 mmol, 42.66% yield, 80% purity). MS (m / z) 344.0 (M + H) + 。

[0780] Step 2: Synthesis of Compound 18-1-2

[0781] At 0 °C, sodium hydride (208.97 mg, 8.71 mmol) was added 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). The resulting mixture was stirred in N2 at 0 °C for 2 hours. The reaction mixture was diluted with ethyl acetate (50 mL). Then it was extracted with water (50 mL × 2). The aqueous phase was stripped 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, and the crude product was purified by silica gel column (100 - 200 mesh) chromatography, eluted with PE:EtOAc = 3:1, to give Compound 18-1-2 as a yellow solid (800.00 mg, 1.65 mmol, 56.89% yield, 98% purity). MS (m / z) 474.20 (M + H) + 。

[0782] Step 3: Synthesis of Compound 18-1-3

[0783] At 25 °C, DIPEA (653.29 mg, 5.05 mmol) was added 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). The resulting mixture was stirred at 80 °C in N2 for 5 h. The resulting solution was 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 column chromatography (100 - 200 mesh), eluting with PE:EtOAc = 1:1 to give compound 18-1-3 as a yellow oil (780.00 mg, 1.25 mmol, 74.06% yield, 98% purity). MS (m / z) 612.40 (M+H) + 。

[0784] Step 4: Synthesis of compound 18-1-4

[0785] At 25 °C, Pd(dppf)Cl2 (71.87 mg, 97.95 μmol) and K2CO3 (203.05 mg, 1.47 mmol) were added to a solution of compound 18-1-3 (300 mg, 489.73 μmol) and (5-fluoro-2-formyl-phenyl)boronic acid (98.69 mg, 587.68 μmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL). The resulting mixture was stirred at 120 °C under N2 for 2 h. The reaction mixture was diluted with ethyl acetate (150 mL). Then it was extracted with water (50 mL * 2). The aqueous phase was stripped and extracted with ethyl acetate (150 mL). All the 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), eluting with PE:EtOAc = 1:4 to give compound 18-1-4 as a yellow solid (200.00 mg, 297.92 μmol, 60.83% yield, 95% purity). MS (m / z) 638.3 (M+H) + 。

[0786] Step 5: Synthesis of compound 18-1-5

[0787] At 25 °C, Raney nickel (9.20 mg, 156.80 μmol) was added to a solution of compound 18-1-4 (100 mg, 156.80 μmol) in methanol (6 mL), and the resulting mixture was stirred at 50 °C under H2 for 14 h. The reaction mixture was filtered to remove the solid, and this solid was washed with MeOH (25 mL * 3). The filtrates were combined, and the organic phase was dried in vacuo to afford compound 18-1-5 (65.00 mg, crude) as a yellow solid. MS (m / z) 640.2 (M + H) + 。

[0788] Step 6: Synthesis of compound 108

[0789] At 25 °C, dichloromethane (5 mL) was added to a solution of compound 18-1-5 (75 mg, 117.60 μmol) in trifluoroacetic acid (8 mL), and the resulting mixture was stirred at 25 °C for 20 h. The reaction solution was diluted with 20 mL of dichloromethane, the organic phase was concentrated, and the above operation 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 / water to 30% MeCN / water over a 10-minute period, where both solvents contained 10 mmol / L FA) to afford the target compound 108 (25.55 mg, 61.78 μmol, 52.54% yield, 99% purity) as a white solid.

[0790] The analytical data of compound 108 are provided below.

[0791]

[0792] Example 19

[0793]

[0794] Scheme 19

[0795] Step 1: Synthesis of tert-butyl N-[(Z)-3-[4-[(3,4-difluorophenyl)carbamoyl]-9-fluoro-6H-benzo[c][1,6]naphthyridin-5-yl]-1-methylallyl]carbamate (Compound 19-1-1)

[0796] At 25 °C, HATU (2.95 g, 7.75 mmol) and DIPEA (3.00 g, 23.24 mmol) were added 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). The resulting mixture was then stirred at 25 °C for 2 h. The reaction was monitored by LCMS. LCMS showed the disappearance of the major starting materials. Water was added until a large amount of solid was observed. The precipitated solid was collected and washed with H2O (20 mL * 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, 70.36% yield, 80% purity) as a yellow solid. The crude product was used directly in the next step. MS (m / z) 269.1 (M + H) + 。

[0797] Step 2: Synthesis of tert-butyl N-[3-[[3-[(3,4-difluorophenyl)carbamoyl]-4-pyridinyl]amino]-1-methylpropyl]carbamate (Compound 19-1-2)

[0798] At 25 °C, DIPEA (411.88 mg, 3.19 mmol) was added to a solution of compound 19-1-1 (356.74 mg, 1.06 mmol) and tert-butyl N-(3-amino-1-methylpropyl)carbamate (200 mg, 1.06 mmol) in dimethyl sulfoxide (1 mL), and then the resulting mixture was stirred at 120 °C for 2.5 h. The completion of the reaction was detected by LC-MS, and LCMS showed that the reaction proceeded completely. The reaction mixture was diluted with H2O (15 mL) and EtOAc (15 mL). The mixture was extracted with ethyl acetate (25 mL * 2). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with PE:EtOAc (100 / 0 to 60 / 40) to obtain tert-butyl N-[3-[[3-[(3,4-difluorophenyl)carbamoyl]-4-pyridinyl]amino]-1-methylpropyl]carbamate (compound 19-1-2, 187.00 mg, 435.86 μmol, 41.03% yield, 98% purity) as a yellow solid. MS (m / z) 421.2 (M + H) + 。

[0799] Step 3: Synthesis of tert-butyl N-[3-[[3-chloro-5-[(3,4-difluorophenyl)carbamoyl]-4-pyridinyl]amino]-1-methylpropyl]carbamate (Compound 19-1-3)

[0800] At 25 °C, NCS (112.04 mg, 839.10 μmol) was added to a solution of compound 19-1-2 (120 mg, 279.70 μmol) in N,N-dimethylformamide (0.5 mL). The resulting mixture was stirred at 30 °C for 8 hours. The reaction was monitored by LC-MS. LCMS showed the disappearance of the starting material and the clear detection of the product. The reaction mixture was diluted with H2O (15 mL). Then it was extracted with ethyl acetate (15 mL * 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, eluting with PE:EtOAc (100 / 0 to 64 / 36) to give tert-butyl N-[3-[[3-chloro-5-[(3,4-difluorophenyl)carbamoyl]-4-pyridinyl]amino]-1-methyl-propyl]carbamate (compound 19-1-3, 115.00 mg, 247.75 μmol, 88.58% yield, 98% purity) as a yellow solid. MS (m / z) 454.9 (M+H) + 。

[0801] Step 4: Synthesis of tert-butyl N-[(Z)-3-[4-[(3,4-difluorophenyl)carbamoyl]-9-fluoro-6H-benzo[c][1,6]naphthyridin-5-yl]-1-methyl-allyl]carbamate (compound 19-1-4)

[0802] At 25 °C, XPhosPdG2 (17.27 mg, 21.98 μmol) and K2CO3 (91.01 mg, 659.49 μmol) were added to a mixture of compound 19-1-3 (100 mg, 219.83 μmol) and (5-fluoro-2-formyl-phenyl)boronic acid (44.30 mg, 263.80 μmol) in 1,4-dioxane (2 mL) and water (0.1 mL). The resulting mixture was degassed and then stirred at 110 °C under N2 for 3 hours. The reaction mixture was concentrated to dryness. The crude product was purified by silica gel chromatography, eluting with PE:EtOAc (100 / 0 to 1 / 1) to give tert-butyl N-[(Z)-3-[4-[(3,4-difluorophenyl)carbamoyl]-9-fluoro-6H-benzo[c][1,6]naphthyridin-5-yl]-1-methyl-allyl]carbamate (compound 19-1-4, 67.00 mg, 122.62 μmol, 55.78% yield, 96% purity) as a yellow solid. MS (m / z) 525.2 (M+H) + 。

[0803] Step 5: Synthesis of tert-butyl-[3-[4-[(3,4-difluorophenyl)carbamoyl]-N9-fluoro-6H-benzo[c][1,6]naphthyridin-5-yl]-1-methyl-propyl]carbamate (Compound 19-1-5)

[0804] Under N2, Raney nickel (100 mg) was added to a solution of Compound 19-1-4 (50 mg, 95.32 μmol) in MeOH (10 mL), and then the suspension was completely degassed under H2. The mixture was stirred at 50 °C for 5 h under a H2 balloon. The reaction was monitored by LC-MS. LCMS showed the disappearance of the starting material. The operation was completed. The reaction mixture was filtered, and the precipitated solid was washed with MeOH (20 mL * 3), and the filtrate was dried in vacuo to obtain tert-butyl-[3-[4-[(3,4-difluorophenyl)carbamoyl]-N9-fluoro-6H-benzo[c][1,6]naphthyridin-5-yl]-1-methyl-propyl]carbamate (Compound 19-1-5, 33.00 mg, crude product) as a white solid. The crude product was directly used in the next step. MS (m / z) 527.3 (M + H) + 。

[0805] Step 6: Synthesis of 5-(3-aminobutyl)-N-(3,4-difluorophenyl)-9-fluoro-6H-benzo[c][1,6]naphthyridine-4-carboxamide (Compound 109)

[0806] 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 h. The reaction was monitored by LC-MS. LCMS showed the disappearance of the starting material. Excess dichloromethane was added and evaporated in vacuo by rotary evaporation. The crude product was purified by preparative HPLC (preparative C18, 5 μM OBD, 19 × 250 mm column, Waters; gradient elution from 40% MeCN / water to 50% MeCN / water in a 9 min period, where both solvents contained 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, 63.31% yield, 97% purity) as a white solid.

[0807] The analytical data of Compound 109 are provided below.

[0808]

[0809]

[0810] Example 20

[0811]

[0812] Scheme 20

[0813] Step 1: Synthesis of Compound 20-1-2

[0814] At 25 °C, tert-butyl piperidin-4-ylcarbamate (2.92 g, 14.56 mmol) was added to a solution of compound 20-1-1 (2 g, 9.71 mmol) in dimethyl sulfoxide (8 mL), and the resulting mixture was stirred in N2 at 120 °C for 2 h. The progress of the reaction was monitored by LCMS. 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 give a residue, which was purified by silica gel chromatography with PE / EtOAc from 20 / 1 to 4 / 1 to give compound 20-1-2 as a white solid (2.50 g, 6.08 mmol, 62.67% yield, 90% purity). MS (m / z) 369.9 (M+H) + 。

[0815] Step 2: Synthesis of Compound 20-1-3

[0816] At 25 °C, potassium carbonate (934.25 mg, 6.76 mmol) and Xantphos Pd G2 (224.08 mg, 270.39 μmol) were added 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). The resulting mixture was stirred in N2 at 110 °C for 2 h. The progress of the reaction was monitored by LCMS. After cooling to room temperature, the reaction mixture was quenched with H2O (20 mL). Then it was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with PE / EtOAc from 10 / 1 to 1 / 1 to give compound 20-1-3 as a yellow solid (500.00 mg, 1.38 mmol, 51.16% yield, 100% purity). MS (m / z) 362.0 (M+H) + 。

[0817] Step 3: Synthesis of Compound 20-1-4

[0818] At 25 °C, to a solution of compound 20-1-3 (300 mg, 830.03 μmol) and 3,4-difluoroaniline (535.81 mg, 4.15 mmol) in toluene (3 mL) and acetic acid (1 mL), the resulting mixture was stirred at 110 °C for 4 h under N2. The progress of the reaction was monitored by LCMS. LCMS showed the disappearance of the starting materials. The reaction mixture was cooled to 25 °C and quenched with H2O (20 mL). Then the mixture was separated, and the aqueous phase was washed twice with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by silica gel chromatography with PE / EtOAc from 10 / 1 to 1 / 1 to give compound 20-1-4 as a yellow oil (45.00 mg, 78.52 μmol, 9.46% yield, 80% purity). MS (m / z) 458.9 (M+H) + 。

[0819] Step 4: Synthesis of compound 20-1-5

[0820] At 25 °C, NCS (21.84 mg, 163.58 μmol) was added to a solution of compound 20-1-4 (45 mg, 109.05 μmol) in DMF (1.5 mL), and the resulting mixture was stirred at 30 °C for 2 h. The progress of the reaction was monitored by LCMS. LCMS showed the disappearance of the starting materials. The reaction mixture was cooled to room temperature and quenched with H2O (20 mL). Then the mixture was 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 give a residue, which was purified by silica gel chromatography with PE / EtOAc from 30 / 1 to 8 / 1 to give compound 20-1-5 as a yellow solid (40.00 mg, 81.14 μmol, 74.41% yield). MS (m / z) 469.2 (M+H) + 。

[0821] Step 5: Synthesis of compound 20-1-6

[0822] At 25 °C, 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) was added K2CO3 (28.04 mg, 202.86 μmol) and G2-Xphos-Pd (10.09 mg, 12.17 μmol). The resulting mixture was stirred in N2 at 110 °C for 2 h. The progress of the reaction was monitored by LCMS. LCMS showed the disappearance of the starting materials. The reaction mixture was cooled to 25 °C and quenched with H2O (20 mL). Then the mixture was 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 give a residue, which was purified by silica gel chromatography with PE / EtOAc of 5 / 1 to 3 / 1 to give compound 20-1-6 as a yellow oil (20.00 mg, 35.05 μmol, 43.20% yield). MS (m / z) 571.2 (M+H) + 。

[0823] Step 6: Synthesis of target compound 110

[0824] At 25 °C, to a solution of compound 20-1-6 (20 mg, 35.05 μmol) in DCM (2.53 mL) was added TFA (707.63 mg, 6.21 mmol, 474.92 μL). The resulting mixture was stirred at 25 °C for 2 h. The reaction solution was diluted with 20 mL of dichloromethane, the organic phase was concentrated, and the above operation was repeated three times. The crude product was purified by preparative HPLC (preparative C18, 5 μMOBD, 19×250 mm column, Waters; gradient elution from 40% MeCN / water to 50% MeCN / water in a 9-minute period, where both solvents contained 10 mmol / L NH4HCO3) to give compound 110 as a colorless oil (7.50 mg, 15.94 μmol, 45.48% yield, 100% purity).

[0825] Compound 110-116 was synthesized according to the 6-step procedure described in Example 20. The analytical data of compounds 110-116 are provided below.

[0826]

[0827]

[0828] Example 21

[0829]

[0830] Scheme 21

[0831] Step 1: Synthesis of Compound 21-1-1

[0832] At 25 °C, HATU (2.43 g, 6.35 mmol) and DIPEA (2.46 g, 19.04 mmol) were added 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), and the resulting mixture was stirred in N2 at 25 °C for 2 h. The reaction was monitored by LCMS, which showed completion of the reaction. 20 mL of water was added to the reaction solution, and then the solid was collected by filtration, which was Compound 21-1-1 as a white solid (1.46 g, 4.88 mmol, 76.93% yield, 89.84% purity). MS (m / z) 269.0 (M+H) + 。

[0833] Step 2: Synthesis of Compound 21-1-2

[0834] At 25 °C, DIPEA (1.92 g, 14.89 mmol) was added to a solution of Compound 21-1-1 (800 mg, 2.98 mmol) and N-(3-aminopropyl)-N-methylcarbamic acid tert-butyl ester (2.80 g, 14.89 mmol) in DMSO (2 mL), and the resulting mixture was stirred at 120 °C for 2 h. The reaction was monitored by LCMS, which showed completion of the reaction. 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 the organic phases were combined and dried over anhydrous Na2SO4. The organic phase was concentrated to obtain the crude product, and the crude product was purified by silica gel column (100-200 mesh) chromatography, eluting with PE / EtOAc = 4 / 1 for purification, to obtain Compound 21-1-2 as a yellow solid (1.03 g, 2.34 mmol, 78.49% yield, 95.14% purity). MS (m / z) 421.2 (M+H) + 。

[0835] Step 3: Synthesis of Compound 21-1-3

[0836] At 25 °C, a solution of compound 21-1-2 (600 mg, 1.43 mmol) and NCS (571.67 mg, 4.28 mmol) in DMF (5 mL) was taken, and the resulting mixture was stirred at 30 °C for 12 h. The reaction was monitored by LCMS, which showed completion of the reaction. The reaction mixture was diluted with ethyl acetate (100 mL) and water (50 mL). The aqueous phase was extracted twice with ethyl acetate (60 mL). All the organic phases were combined, dried over anhydrous Na2SO4, and the organic phase was concentrated to obtain the crude product, which was purified by silica gel column chromatography eluting with DCM / MeOH = 1 / 1 to give the title compound as a brown oil (compound 21-1-3, 400 mg, 854.35 μmol, 59.87% yield, 97.16% purity). MS (m / z) 454.9 (M+H) + 。

[0837] Step 4: Synthesis of compound 21-1-4

[0838] At 25 °C, K2CO3 (182.29 mg, 1.32 mmol) and X-Phox-Pd-G2 (34.59 mg, 43.97 μmol) were added 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), and the resulting mixture was stirred at 110 °C for 1 h under N2. The reaction was monitored by LCMS, which showed completion of the reaction. The reaction mixture was diluted with ethyl acetate (60 mL). Then it was extracted with water (20 mL * 2). The aqueous phase was stripped and extracted with ethyl acetate (50 mL). All the 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 eluting with DCM:MeOH = 10:1 to give the title compound as a yellow oil (compound 21-1-4, 186.00 mg, 337.30 μmol, 76.72% yield, 96.57% purity). MS (m / z) 533.2 (M+H) + 。

[0839] Step 5: Synthesis of compound 117

[0840] At 25 °C, compound 21-1-4 (50 mg, 93.89 μmol) was added to a solution in hydrochloric acid methanol solution (1 mL) and DCM (5 mL). The resulting mixture was stirred at 40 °C for 1 hour. The reaction was monitored by LCMS, which showed completion of the reaction. The organic phase was concentrated to obtain the crude product. The crude product was washed with 5 mL of dichloromethane, and the above operation was repeated three times. After concentration, compound 117 as a gray solid was obtained (22.77 mg, 49.85 μmol, 53.09% yield, 94.67% purity).

[0841] Step 6: Synthesis of compound 21-1-5

[0842] At 25 °C, sodium hydride (36.05 mg, 901.36 μmol) was added to a solution of compound 21-1-4 (100 mg, 187.78 μmol) and bis(2,5-dioxopyrrolidin-1-yl) carbonate (230.90 mg, 901.36 μmol) in DMF (2 mL). The resulting mixture was stirred at 60 °C in N2 for 6 hours. The reaction was monitored by LCMS, which showed completion of the reaction. The reaction mixture was diluted with ethyl acetate (30 mL). Then it was extracted with water (10 mL * 2). The aqueous phase was stripped and extracted with ethyl acetate (300 mL). All the organic phases were combined, dried over anhydrous Na2SO4, filtered, and the organic phase was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography, eluting with DCM:MeOH = 10:1 to obtain the title compound as a white solid (compound 21-1-5, 12.00 mg, 20.85 μmol, 11.51% yield, 97.04% purity). MS (m / z) 559.2 (M+H) + 。

[0843] Step 7: Synthesis of compound 118

[0844] At 25 °C, compound 21-1-5 (12 mg, 21.49 μmol) was added to a solution in hydrochloric acid methanol solution (1 mL) and DCM (5 mL). The resulting mixture was stirred at 40 °C for 2 hours. The reaction was monitored by LCMS, which showed completion of the reaction. The reaction solution was directly concentrated to obtain the crude product. The crude product was washed with 5 mL of dichloromethane, and the above operation was repeated three times. After concentration, compound 118 as a gray solid was obtained (9.00 mg, 19.63 μmol, 91.38% yield, 100% purity).

[0845] The analytical data of compounds 117 and 118 are provided below.

[0846]

[0847] Example 22

[0848]

[0849] Scheme 22

[0850] Step 1: Synthesis of Compound 22-1-1

[0851] At 25 °C, TEA (1.28 g, 12.63 mmol) was added to a solution of Compound 22-1-SM-1 (1 g, 4.21 mmol) and Compound 22-1-SM-2 (1.01 g, 5.05 mmol) in THF (10 mL), and the resulting mixture was stirred at 0 °C for 1 h. Water (50 mL) and saturated salt solution (15 mL) were added to the reaction mixture, and then it was extracted with EA (50 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated to obtain crude product Compound 22-1-1 (1.82 g). MS (m / z) 403.0 (M+H) + 。

[0852] Step 2: Synthesis of Compound 22-1-2

[0853] At 25 °C, Pd(dppf)Cl2 (91.43 mg, 124.61 μmol) and K2CO3 (516.65 mg, 3.74 mmol) were added to a solution of Compound 22-1-1 (500 mg, 1.25 mmol) and (3-Fluoro-5-methylphenyl)boronic acid (6 - 5230.20 mg, 1.50 mmol) in 1,4-dioxane (2 mL), and the resulting mixture was stirred under N2 at 120 °C for 2 h. The crude product was purified by silica gel chromatography (100 - 200 mesh) with PE:EtOAc (100:1 to 72:28) to obtain Compound 22-1-2 as a yellow solid (576.00 mg, 1.20 mmol, 96.64% yield, 90% purity). MS (m / z) 431.3 (M+H) + 。

[0854] Step 3: Synthesis of Compound 22-1-3

[0855] At 25 °C, Fe (721.36 mg, 12.92 mmol) was added 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), and the resulting mixture was stirred at 80 °C for 2 h. Water (50 mL) and saturated salt solution (15 mL) were added to the reaction mixture, and then it was extracted with EA (50 mL * 3). The combined organic layers were dried over Na2SO4 and then concentrated to obtain the crude product compound 22-1-3 (409 mg). MS (m / z) 401.3 (M+H) + 。

[0856] Step 4: Synthesis of compound 22-1-4

[0857] At 25 °C, 3-chloroperoxybenzoic acid (51.71 mg, 299.63 μmol) was added to a solution of compound 22-1-3 (80 mg, 199.76 μmol) in DCM (5 mL), and the resulting mixture was stirred at 0 °C for 10 h. The reaction mixture was diluted with ethyl acetate (150 mL). Then it was extracted with water (50 mL * 2). The aqueous phase was stripped and extracted with ethyl acetate (150 mL). All the 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 (100 - 200 mesh) chromatography, eluting with DCM:MeOH (15:1) to obtain compound 22-1-4 as a yellow solid (41.00 mg, 96.67 μmol, 48.39% yield, 98.20% purity). MS (m / z) 417.3 (M+H) + 。

[0858] Step 5: Synthesis of compound 22-1-5

[0859] At 25 °C, NaH (7.09 mg, 295.33 μmol) was added 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), and the resulting mixture was stirred at 40 °C for 16 h. The reaction mixture was diluted with ethyl acetate (30 mL). Then it was extracted with water (10 mL * 2). The aqueous phase was stripped and extracted with ethyl acetate (30 mL). All the 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 (100 - 200 mesh) chromatography, eluting with DCM:MeOH (30:1) to give compound 22-1-5 as a yellow solid (10.00 mg, 18.36 μmol, 18.65% yield, 92.28% purity). MS (m / z) 503.3 (M + H) + 。

[0860] Step 6: Synthesis of Compound 119

[0861] At 25 °C, hydrochloric acid methanol solution (1 mL) was added to a solution of compound 22-1-5 (10 mg, 19.90 μmol) in DCM (5 mL), and the resulting mixture was stirred at 40 °C for 3 h. The reaction solution was diluted with dichloromethane (20 mL), the organic phase was concentrated, and the above operation was repeated three times. The crude product was purified by tert-butyl methyl ether to give compound 119 as a brown solid (3.02 mg, 7.17 μmol, 36.06% yield, 95.62% purity).

[0862] The analytical data of compound 119 are provided below.

[0863]

[0864] Example 23

[0865]

[0866] Scheme 23

[0867] Step 1: Synthesis of Compound 23-1-3

[0868] 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 under N2 for 2 h. Then FeCl3 (7.78 g, 48.00 mmol) was added at 25 °C. The mixture was stirred at 60 °C under N2 for 2 h. Water (10 mL) was added, and then the reaction mixture was extracted with EA (50 mL * 2). The combined organic phases were dried over Na2SO4, filtered, concentrated and purified by silica gel column (100 - 200 mesh) chromatography, eluting with PE:EA (100:0 to 3:1) to give Compound 23-1-3 as a yellow solid (2.3 g, 7.69 mmol, 64.10% yield). MS (m / z) 300.1 (M + H) + 。

[0869] Step 2: Synthesis of Compound 23-1-5

[0870] 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 h. Water was added, and then the mixture was filtered and washed with PE to give crude Compound 23-1-5 as a yellow solid (2.8 g, 78.65% yield). MS (m / z) 464.1 (M + H) + 。

[0871] Step 3: Synthesis of Compound 23-1-7

[0872] A mixture of compound 23-1-5 (2.8 g, 6.05 mmol), compound 23-1-6 (1.24 g, 9.07 mmol), Pd2(dba)3 (1.11 g, 1.21 mmol), ruphos (1.13 g, 2.42 mmol) and sodium 2-methylpropane-2-olate (1.45 g, 15.13 mmol) in DMSO (20 mL) was stirred at 100 °C for 2 h under N2. The mixture was cooled to 25 °C, then (Boc)2O (2.64 g, 12.1 mmol) was added, and the mixture was stirred at 25 °C for 1 h. Water (50 mL) was added, and then the reaction mixture was extracted with EA (80 mL × 2). The combined organic phases were dried over Na2SO4, filtered, concentrated and purified by silica gel column (100 - 200 mesh) chromatography, eluting with PE:EA (100:0 to 1:1) to give compound 23-1-7 (800 mg, 1.21 mmol, 20.00% yield) as a yellow solid. MS (m / z) 664.9 (M + H) + 。

[0873] Step 4: Synthesis of compound 23-1-8

[0874] A mixture of compound 23-1-7 (800 mg, 1.21 mmol) and NBS (248.46 mg, 1.45 mmol) in DCM (12 mL) was stirred at 0 °C for 1 h. Water (15 mL) was added, and then the reaction mixture was extracted with EA (20 mL × 2). The combined organic phases were dried over Na2SO4, filtered, concentrated and purified by silica gel column (100 - 200 mesh) chromatography, eluting with PE:EA (100:0 to 2:1) to give compound 23-1-8 (350 mg, 0.47 mmol, 38.84% yield) as a yellow oil. MS (m / z) 743.3 (M + H) + 。

[0875] Step 5: Synthesis of compound 23-1-9

[0876] A mixture of compound 23-1-8 (350 mg, 0.47 mmol) and DDQ (106.69 mg, 0.47 mmol) in DCM (12 mL) was stirred at 25 °C for 1 h. The reaction mixture was filtered and purified by silica gel column (100 - 200 mesh) chromatography, eluting with PE:EA (100:0 to 2:1) to afford compound 23-1-9 (150 mg, 0.24 mmol, 51.31% yield) as a yellow oil. MS (m / z) 623.1 (M + H) + 。

[0877] Step 6: Synthesis of Compound 23-1-11

[0878] A mixture of Compound 23-1-9 (150 mg, 0.24 mmol), Compound 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 stirred under N2 at 95 °C for 0.5 h. The reaction mixture was concentrated and purified by preparative TLC (DCM / MeOH = 20 / 1) to afford Compound 23-1-11 as a yellow solid (15 mg, 0.027 mmol, 11.41% yield). MS (m / z) 549.2 (M+H) + 。

[0879] Step 7: Synthesis of Compound 120

[0880] A mixture of Compound 23-1-11 (15 mg, 0.027 mmol) in DCM (2 mL) and TFA (2 mL) was stirred at 15 °C for 1 h. The reaction mixture was concentrated and purified by retention phase column (MeOH / H2O = 3 / 7) and preparative TLC (DCM / MeOH = 5 / 1) to afford Compound 120 as a white solid (4.06 mg, 0.009 mmol, 33.33% yield).

[0881] The analytical data of Compound 120 are provided below.

[0882]

[0883] Example 24

[0884]

[0885] Scheme 24

[0886] Step 1: Synthesis of tert-Butyl ((1-(2-chloro-5-formylpyridin-4-yl)piperidin-4-yl)carbamate (Compound 24-1-2))

[0887] At 20 °C, tert-butyl (1-(2-chloro-5-formylpyridin-4-yl)piperidin-4-yl)carbamate (Compound 24-1-2, 8 g, 23.53 mmol, 42%) as a white solid was obtained by adding tert-butyl piperidin-4-ylcarbamate (11.36 g, 56.8 mmol, 1 equiv), DIPEA (36.64 g, 284 mmol, 5 equiv) to a stirred solution of 4,6-dichloronicotinaldehyde (Compound 24-1-1, 10 g, 56.8 mmol, 1 equiv) in MeCN (150 mL), stirring the reaction mixture at 20 °C for 16 h. TLC (PE:EtOAc = 1:1) indicated the completion of the reaction. The reaction mixture was diluted with EtOAc (700 mL), washed with H2O (500 mL×3), dried over Na2SO4 and evaporated to give a residue. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (100:1 - 1:1). MS (m / z) 340.3 (M+H) + 。

[0888] Step 2: tert-butyl (1-(5-formyl-2-methoxypyridin-4-yl)piperidin-4-yl)carbamate (Compound 24-1-3)

[0889] At 0 °C, MeONa (5.08 g, 94.12 mmol, 4 equiv) was added to a stirred solution of tert-butyl (1-(2-chloro-5-formylpyridin-4-yl)piperidin-4-yl)carbamate (Compound 24-1-2, 8 g, 23.53 mmol, 1 equiv) in MeOH (150 mL, 100.0%). The reaction mixture was stirred at 60 °C for 3 h. TLC (PE:EtOAc = 1:1) indicated the completion of the reaction. The reaction mixture was diluted with EtOAc (700 mL), washed with H2O (500 mL×3), dried over Na2SO4 and evaporated to give tert-butyl (1-(5-formyl-2-methoxypyridin-4-yl)piperidin-4-yl)carbamate (7 g, 20.9 mmol, 88%) as a white solid. MS (m / z) 336.3 (M+H) + 。

[0890] Step 3: Synthesis of tert-butyl (1-(3-bromo-5-formyl-2-methoxypyridin-4-yl)piperidin-4-yl)carbamate (Compound 24-1-4)

[0891] At 20 °C, NBS (3.72 g, 20.9 mmol, 1 equiv) was added to a stirred solution of tert-butyl (1-(5-formyl-2-methoxypyridin-4-yl)piperidin-4-yl)carbamate (Compound 24-1-3, 7 g, 20.9 mmol, 1 equiv) in MeCN (150 ml, 100.0%). The reaction mixture was stirred at 20 °C for 1 h. TLC (PE:EtOAc = 3:1) indicated completion of the reaction. The reaction mixture was diluted with EtOAc (700 mL), washed with H2O (500 mL × 3), dried over Na2SO4 and evaporated to give a residue. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (100:1 - 1:1) to give tert-butyl (1-(3-bromo-5-formyl-2-methoxypyridin-4-yl)piperidin-4-yl)carbamate (Compound 24-1-4, 6 g, 14.5 mmol, 69%) as a white solid. MS (m / z) 414.1 / 416.1 (M+H) + 。

[0892] Step 4: Synthesis of tert-butyl (1-(3-bromo-5-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-methoxypyridin-4-yl)piperidin-4-yl)carbamate (Compound 24-1-6)

[0893] At 20 °C, 4,5-difluorobenzene-1,2-diamine (2.09 g, 14.5 mmol, 1 equiv) and NaHSO3 (6.03 g, 58 mmol, 4 equiv) were added to a stirred solution of tert-butyl (1-(3-bromo-5-formyl-2-methoxypyridin-4-yl)piperidin-4-yl)carbamate (Compound 24-1-4, 6 g, 14.5 mmol, 1 equiv) in DMA (150 ml, 100.0%). The reaction mixture was stirred at 120 °C for 5 h. TLC (PE:EtOAc = 1:1) indicated completion of the reaction. The reaction mixture was diluted with EtOAc (700 mL), washed with H2O (500 mL × 3), dried over Na2SO4 and evaporated to give a residue. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (100:1 - 1:1) to give tert-butyl (1-(3-bromo-5-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-methoxypyridin-4-yl)piperidin-4-yl)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) + 。

[0894] Step 5: tert-Butyl (1-(5-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-3-(5-fluoro-2-formylphenyl)-2-methoxypyridin-4-yl)piperidin-4-yl)carbamate (Compound 24-1-8)

[0895] At 20 °C, (5-fluoro-2-formylphenyl)boronic acid (2.03 g, 12.1 mmol, 1 equiv) and K2CO3 (3.34 g, 24.2 mmol, 2 equiv) were added to a stirred solution of tert-butyl (1-(3-bromo-5-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-2-methoxypyridin-4-yl)piperidin-4-yl)carbamate (Compound 24-1-6, 6.5 g, 12.1 mmol, 1 equiv) in toluene (60 mL), EtOH (40 mL), and H2O (20 mL). The reaction mixture was stirred at 90 °C for 5 h. TLC (PE:EtOAc = 1:1) indicated completion of the reaction. The reaction mixture was diluted with EtOAc (700 mL), washed with H2O (500 mL × 3), dried over Na2SO4 and evaporated to give a residue. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (100:1 - 1:1) to give tert-butyl (1-(5-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-3-(5-fluoro-2-formylphenyl)-2-methoxypyridin-4-yl)piperidin-4-yl)carbamate (Compound 24-1-8, 4 g, 6.87 mmol, 57%) as a white solid. MS (m / z) 582.3 (M+H) + 。

[0896] Step 6: tert-Butyl (1-(5-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-3-(5-fluoro-2-(hydroxymethyl)phenyl)-2-methoxypyridin-4-yl)piperidin-4-yl)carbamate (Compound 24-1-9)

[0897] At 25 °C, NaBH4 (522 mg, 13.74 mmol, 2 equiv) was added portionwise to a solution of tert-butyl (1-(5-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-3-(5-fluoro-2-formylphenyl)-2-methoxypyridin-4-yl)piperidin-4-yl)carbamate (Compound 24-1-8, 4 g, 6.87 mmol) in MeOH (20 mL). The solution was stirred at 25 °C for 2 h. The reaction mixture was quenched with 1N HCl solution and extracted with EA (20 mL * 3). The combined layers were combined and concentrated under reduced pressure to give tert-butyl (1-(5-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-3-(5-fluoro-2-(hydroxymethyl)phenyl)-2-methoxypyridin-4-yl)piperidin-4-yl)carbamate (Compound 24-1-9, 3.5 g, crude) as a colorless oil.

[0898] Step 7: tert-butyl (1-(5-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-3-(5-fluoro-2-(hydroxymethyl)phenyl)-2-hydroxypyridin-4-yl)piperidin-4-yl)carbamate (Compound 24-1-10)

[0899] A solution of tert-butyl (1-(5-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-3-(5-fluoro-2-(hydroxymethyl)phenyl)-2-methoxypyridin-4-yl)piperidin-4-yl)carbamate (Compound 24-1-9, 3.5 g, crude) was dissolved in DCE (20 mL), then BBr3 (10 mL) was added, and the solution was heated at 80 °C for 4 h. The reaction solution was quenched with saturated NaHCO3 solution until the pH was about 8 - 9. The mixture was extracted with DCM (10 mL * 3), and the combined layers were concentrated under reduced pressure to give tert-butyl (1-(5-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-3-(5-fluoro-2-(hydroxymethyl)phenyl)-2-hydroxypyridin-4-yl)piperidin-4-yl)carbamate (Compound 24-1-10, 250 mg, 0.44 mmol, 10% yield) as a white solid.

[0900] Step 8: tert-butyl (1-(2-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-9-fluoro-6H-isobenz[3,4-b]pyridin-1-yl)piperidin-4-yl)carbamate (Compound 24-1-11)

[0901] At 0 °C, DIAD (111 mg, 0.55 mmol, 1.1 eq) and PPh3 (144 mg, 0.55 mmol, 1.1 eq) were added separately to a solution of tert-butyl (1-(5-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-3-(5-fluoro-2-(hydroxymethyl)phenyl)-2-hydroxypyridin-4-yl)piperidin-4-yl)carbamate (Compound 24-1-10, 250 mg, 0.44 mmol) in THF (10 mL). The solution was then stirred overnight at 25 °C. The reaction mixture was extracted with EA (10 mL * 3), and the combined layers were concentrated under reduced pressure to obtain tert-butyl (1-(2-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-9-fluoro-6H-isobenz[3,4-b]pyridin-1-yl)piperidin-4-yl)carbamate (Compound 24-1-11, 100 mg, white solid).

[0902] Step 9: 1-(2-(5,6-Difluoro-1H-benzo[d]imidazol-2-yl)-9-fluoro-6H-isobenz[3,4-b]pyridin-1-yl)piperidin-4-amine (Compound 121)

[0903] TFA (5 mL) was added to a solution of tert-butyl (1-(2-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-9-fluoro-6H-isobenz[3,4-b]pyridin-1-yl)piperidin-4-yl)carbamate (Compound 24-1-11, 100 mg, 0.18 mmol) in DCM (5 mL). The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (0.5% FA as an additive) to obtain 1-(2-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)-9-fluoro-6H-isobenz[3,4-b]pyridin-1-yl)piperidin-4-amine (Compound 121, 13.8 mg, white solid) as a white solid.

[0904] The analytical data of Compound 121 are provided below.

[0905]

[0906] Example 25

[0907]

[0908] Scheme 25

[0909] Step 1: Synthesis of 6-bromo-3-iodoquinolin-4-ol (Compound 25-1-2)

[0910] To a mixture of Compound 25-1-1 (3000 mg, 13.389 mmol, 1 equiv) dissolved in AcOH (50 mL) was added NIS (3012 mg, 13.389 mmol, 1 equiv). The mixture was stirred at 60 °C for 3 h. The mixture was cooled to zero degree, and a large amount of solid was observed. LCMS showed that the solid was the title compound with good purity. After filtration, 6-bromo-3-iodoquinolin-4-ol (Compound 25-1-2, 4.4 g, yield 94%) as a white solid was obtained. MS (m / z) 349.9 (M+H) + .

[0911] Step 2: Synthesis of 6-bromo-4-chloro-3-iodoquinoline (Compound 25-1-3)

[0912] A solution of Compound 25-1-2 (4.4 g, crude) in POCl3 (45 mL) was stirred at 100 °C for 16 h. The mixture was cooled to zero degree, then poured into ice-NaHCO3 (aqueous solution), and solid NaHCO3 was continuously added until pH = 7. The solution was extracted with EA (50 mL x 4). The combined organic extracts were concentrated to give a crude material, which was purified by silica gel chromatography using PE:EtOAc (100:1 to 5:1) to give 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) + .

[0913] Step 3: Synthesis of 6-bromo-4-chloro-3-(3,5-difluorophenyl)quinoline (Compound 25-1-4)

[0914] Under N2, to a solution of Compound 25-1-3 (4.4 g, crude), (3,5-difluorophenyl)boronic acid (1.16 g, 7.36 mmol, 1.1 equiv) and K2CO3 (3.05 g, 22.08 mmol, 3 equiv) in dioxane (40 mL) was added PdCl2(dppf) (600 mg, 0.74 mmol, 0.1 equiv). The suspension was degassed under vacuum and purged with N2 several times. Then the reaction mixture was stirred at 90 °C for 4 h. The reaction mixture was filtered and washed with EA (200 mL×3). The combined organic extracts were concentrated to give a crude material, which was purified by silica gel chromatography using PE:EtOAc (100:1 to 5:1) to give 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) + .

[0915] Step 4: Synthesis of 3-(4-chloro-3-(3,5-difluorophenyl)quinolin-6-yl)-2-(methoxymethoxy)benzonitrile (Compound 25-1-5)

[0916] To a mixture of Compound 25-1-4 (300 mg, 0.85 mmol, 1 equiv) and 2-(methoxymethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzonitrile (400 mg, 0.85 mmol, 1 equiv) dissolved in dioxane (10 mL) was added PdCl2(dppf) (73 mg, 0.056 mmol, 0.1 equiv) and K2CO3 (352 mg, 2.25 mmol, 3 equiv). The mixture was stirred at 90 °C for 2 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, and filtered. The organic layer was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (PE:EA from 10 / 1 to 1 / 1) to afford Compound 25-1-5 as a yellow solid (200 mg, 53.95% yield). MS (m / z) 437.1 (M+H) + 。

[0917] Step 5: Synthesis of tert-butyl (4-(6-(3-cyano-2-(methoxymethoxy)phenyl)-3-(3,5-difluorophenyl)quinolin-4-yl)phenyl)carbamate (Compound 25-1-6)

[0918] To a mixture of Compound 25-1-5 (100 mg, 0.23 mmol, 1 equiv) and (4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (112 mg, 0.47 mmol, 2 equiv) dissolved in THF (6 mL) and H2O (0.5 mL) was added Pd(PPh3)4 (58 mg, 0.05 mmol, 0.2 equiv) and K2CO3 (96 mg, 0.69 mmol, 3 equiv). The mixture was stirred at 70 °C for 4 h. The reaction was monitored by LCMS, which showed a good reaction. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, and filtered. The organic layer was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (PE:EA from 10 / 1 to 1 / 1) to afford Compound 25-1-6 as a yellow solid (70 mg, 51.31% yield). MS (m / z) 594.2 (M+H) + 。

[0919] Step 6: Synthesis of 3-(4-(4-aminophenyl)-3-(3,5-difluorophenyl)quinolin-6-yl)-2-hydroxybenzonitrile (Compound 122)

[0920] To a mixture of Compound 25-1-6 (70 mg, 0.12 mmol, 1 equiv) dissolved in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated and purified by preparative HPLC to afford Compound 122 as a yellow solid (11.4 mg, 21.15% yield).

[0921] Compounds 122 - 125 were synthesized according to the 6-step procedure described in Example 25. The analytical data for Compounds 122 - 125 are provided below.

[0922]

[0923] Example 26

[0924]

[0925] Scheme 26

[0926] Step 1: Synthesis of 5-chloro-2-iodopyridin-3-ol (Compound 26-1-2)

[0927] At 25 °C, to a solution of sodium carbonate (4.8 g, 46.41 mmol) in water (45 mL) was added 5-chloropyridin-3-ol (Compound 26-1-1, 3.0 g, 23.16 mmol) and I2 (6.0 g, 23.16 mmol). The resulting mixture was stirred at 25 °C for 5 h. It was treated with hydrochloric acid solution (90 mL, 2 M), the formed precipitate was collected by filtration and redissolved in ethyl acetate (200 mL). The mixture was washed with brine (100 mL × 2) and the organic phase was dried over sodium sulfate. The solvent was removed under reduced pressure to afford 5-chloro-2-iodopyridin-3-ol as a yellow solid (Compound 26-1-2, 5.7 g, 96%). LCMS: m / z: at 1.49 min, 255.9 (M+H + )

[0928] Step 2: Synthesis of 6-chloro-2-(trimethylsilyl)furo[3,2-b]pyridine (Compound 26-1-3)

[0929] At 25 °C, 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 to a solution of compound 26-1-2 (5.7 g, 22.3 mmol) in dioxane (91.2 mL, 1.076 mol). The resulting mixture was stirred at 120 °C for 6 h. The mixture was cooled to 25 °C and treated with water (350 mL). The resulting mixture was extracted with ethyl acetate (350 mL × 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, eluting with a hexane solution of ethyl acetate (0% to 5% gradient) to afford 6-chloro-2-(trimethylsilyl)furo[3,2-b]pyridine as a brown solid (compound 26-1-3, 1.5 g, 70%). MS (m / z) 226.0 (M+H) + 。

[0930] Step 3: Synthesis of 6-chloro-2-(trimethylsilyl)furo[3,2-b]pyridine-4-oxide (Compound 26-1-4)

[0931] m-CPBA (1.71 g, 9.96 mmol) was added portionwise to a solution of compound 26-1-3 (1.5 g, 6.64 mmol, 1.00 equiv) in dichloromethane (50 mL) at 0 °C. The resulting solution was stirred at 0 °C for 30 min, then warmed to room temperature and stirred for an additional 16 h at 25 °C. The reaction mixture was treated with water (100 mL) and the pH was adjusted to 8 using saturated sodium bicarbonate solution. The resulting mixture was then extracted with dichloromethane (100 mL × 2) and the organic phases were combined, washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford compound 26-1-4 (1.9 g, crude). MS (m / z) 242.1 (M+H) + 。

[0932] Step 4: Synthesis of 6,7-dichloro-2-(trimethylsilyl)furo[3,2-b]pyridine (Compound 26-1-5)

[0933] At 25 °C, POCl3 (2 g, 13.07 mmol) was added to a solution of compound 26-1-4 (1.9 g, crude) in toluene (50 mL). 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 saturated sodium carbonate solution. The resulting mixture was then extracted with dichloromethane (70 mL × 3). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with a hexane solution of ethyl acetate (0% to 2% gradient) to give compound 26-1-5 (800 mg, 47% over 2 steps). MS (m / z) 260.0 (M+H) + 。

[0934] Step 5: Synthesis of tert-butyl (1-(6-chloro-2-(trimethylsilyl)furo[3,2-b]pyridin-7-yl)piperidin-4-yl)carbamate (Compound 26-1-6)

[0935] To a solution of compound 26-1-5 (300 mg, 1.2 mmol, 1 equiv) in DMSO (0.05 mL) was added tert-butyl piperidin-4-ylcarbamate (2317 mg, 11.6 mmol, 10 equiv). 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 × 3). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with a hexane solution of ethyl acetate (0% to 2% gradient) to give compound 26-1-6 as a yellow solid (400 mg, 81.7%). MS (m / z) 424.4 (M+H) + 。

[0936] Step 6: Synthesis of tert-butyl (1-(6-(3,5-difluorophenyl)-2-(trimethylsilyl)furo[3,2-b]pyridin-7-yl)piperidin-4-yl)carbamate (Compound 26-1-7)

[0937] To a solution of Compound 26-1-6 (400 mg, 0.243 mmol, 1 equiv) and (3,5-difluorophenyl)boronic acid (46 mg, 0.84 mmol, 1.2 equiv) in a 10:1 mixture of dioxane:H2O (6 mL) was added K2CO3 (67 mg, 0.487 mmol, 2 equiv) and Pd-G2 (19 mg, 0.024 mmol, 0.1 equiv). The reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was cooled and diluted with water (30 mL) and extracted with EA (50 mL×3). The combined organic extracts were concentrated to give the crude material which was purified by chromatography through a Redi-Sep prepacked silica gel column (12 g) eluting with a gradient of 0% to 10% MeOH in DCM to give Compound 26-1-7 (300 mg) as a grey solid. MS (m / z) 502.1 (M+H) + 。

[0938] Step 7: Synthesis of tert-butyl (1-(6-(3,5-difluorophenyl)-2-iodofuro[3,2-b]pyridin-7-yl)piperidin-4-yl)carbamate (Compound 26-1-8)

[0939] At 25 °C, potassium fluoride (161 mg, 2.7 mmol) and NIS (621 mg, 3 equiv) were added to a solution of Compound 26-1-7 (300 mg, 0.92 mmol, 1 equiv) in CH3CN (10 mL). The resulting solution was stirred at 55 °C for 3 h. The reaction mixture was cooled to 25 °C and treated with a NaHSO3 solution (100 mL, 4 M). The resulting mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give Compound 26-1-8 (190 mg) as a yellow solid. MS (m / z) 556.0 (M+H) + 。

[0940] Step 8: Synthesis of tert-butyl (1-(2-(3-cyano-2-hydroxyphenyl)-6-(3,5-difluorophenyl)furo[3,2-b]pyridin-7-yl)piperidin-4-yl)carbamate (Compound 26-1-9)

[0941] To a solution of compound 26-1-8 (190 mg, 0.342 mmol, 1 equiv), 2-(3-bromopropoxy)-3-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)benzonitrile (81 mg, 0.513 mmol, 1.5 equiv) and K2CO3 (142 mg, 1.027 mmol, 3 equiv) in a mixed solvent of dioxane (8 mL) and H2O (0.8 mL) was added Pd(dppf)Cl2 (25 mg, 0.034 mmol, 0.1 equiv). The reaction mixture was stirred at 110 °C under N2 for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with EA (50 mL×3). The combined organic extracts were concentrated to give a crude material, which was purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g) eluting with a gradient of 0% to 30% EA / PE to give compound 26-1-9 (45 mg) as a yellow oil. MS (m / z) 547.1 (M+H) + 。

[0942] Step 9: Synthesis of 3-(7-(4-aminopiperidin-1-yl)-6-(3,5-difluorophenyl)furo[3,2-b]pyridin-2-yl)-2-hydroxybenzonitrile (Compound 127)

[0943] To a solution of compound 26-1-9 (45 mg, 0.076 mmol, 1 equiv) in DCM (2 mL) was added TFA (1 mL). The reaction mixture was stirred at 25 °C for 2 h. Completion of the reaction was detected by LC-MS. Then it was concentrated to give a crude material, and the crude product was purified by preparative HPLC to give compound 127 (13.3 mg).

[0944] Compounds 127 - 131 were synthesized according to the 9-step procedure described in Example 26. The analytical data of compounds 127 - 131 are provided below.

[0945]

[0946] Example 27

[0947]

[0948] Scheme 27

[0949] Step 1: Synthesis of Compound 27-1-1

[0950] To a solution of compound 27-1-SM (5 g, 33.07 mmol) in acetonitrile (100 mL) was added NBS (7.65 g, 42.99 mmol), and the resulting mixture was stirred at 100 °C for 3 h. The reaction mixture was concentrated to dryness and used in the next step without additional compound 27-1-1 as a yellow solid (12.30 g, crude). MS (m / z) 229.9 (M+H) + 。

[0951] Step 2: Synthesis of compound 27-1-2

[0952] A solution of compound 27-1-1 (12.3 g, 53.46 mmol) in POCl3 (164.50 g, 1.07 mol, 100 mL) was stirred at 110 °C for 2 h. The reaction mixture was cooled to 25 °C, then concentrated to remove POCl3, and then diluted with DCM. The process was repeated to concentrate again. The residue was diluted with DCM (100 mL) and then slowly poured into ice water. The resulting mixture was extracted with CH2Cl2 (200 mL×2). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography, eluting with PE:EtOAc = 10:1 to give compound 27-1-2 as a light red solid (7.28 g, 24.90 mmol, 46.58% yield, 85% purity). MS (m / z) 248.9 (M+H) + 。

[0953] Step 3: Synthesis of compound 27-1-3

[0954] At 25 °C, to a solution of compound 27-1-2 (1.00 g, 3.82 mmol) in acetic acid (10 mL) was added NCS (1.53 g, 11.47 mmol), and the resulting mixture was stirred at 120 °C under N2 for 12 h. The reaction mixture was diluted with ethyl acetate (20 mL). Then it was extracted with water (20 mL*2). The aqueous phase was stripped and extracted with ethyl acetate (20 mL). All the 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, eluting with PE:EtOAc from 98:2 to 95:5 to obtain compound 27-1-3 as a white solid (470.00 mg, 1.25 mmol, 32.75% yield, 75.38% purity). MS (m / z) 282.00 (M+H) + 。

[0955] Step 4: Synthesis of compound 27-1-

[0956] At 25 °C, a solution of compound 27-1-3 (350 mg, 932.35 μmol) and tert-butyl piperidin-4-ylcarbamate (186.73 mg, 932.35 μmol) in dimethyl sulfoxide (4 mL) was added with DIPEA (361.50 mg, 2.80 mmol), and the resulting mixture was stirred at 150 °C for 4 h. The reaction mixture was diluted with ethyl acetate (20 mL). Then it was extracted with water (20 mL × 2). The aqueous phase was stripped and extracted with ethyl acetate (20 mL). All the 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, eluting with PE:EtOAc (V / V: 90 / 10 to 75 / 25) to give compound 27-1-4 as a yellow solid (200.00 mg, 348.62 μmol, 37.39% yield, 77.88% purity). MS (m / z) 446.0 (M+H) + 。

[0957] Step 5: Synthesis of compound 27-1-5

[0958] At 25 °C, 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) was added K2CO3 (49.49 mg, 358.11 μmol) and Pd(dppf)Cl2 (26.28 mg, 35.81 μmol), and the resulting mixture was stirred in N2 at 100 °C for 16 h. Then the resulting mixture was extracted with dichloromethane (100 mL × 2), and the organic phases were combined, washed with brine, and dried over sodium sulfate. The crude product was purified by silica chromatography, eluting with PE / EtOAc from 15 / 1 to 5 / 1 to give compound 27-1-5 as a yellow oil (65.00 mg, 135.43 μmol, 75.63% yield). MS (m / z) 480.2 (M+H) + 。

[0959] Step 6: Synthesis of compound 27-1-6

[0960] At 25 °C, 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) was added K2CO3 (37.43 mg, 270.85 μmol) and G2-XPhos-Pd (15.96 mg, 20.31 μmol), and the resulting mixture was stirred in N2 at 100 °C for 16 h. The reaction solution was concentrated directly to give a residue, which was purified by silica gel chromatography eluting with PE / EtOAc from 15 / 1 to 1 / 1 to afford compound 27-1-6 as a yellow solid (50.00 mg, 89.67 μmol, 66.21% yield). MS (m / z) 558.2 (M+H) + 。

[0961] Step 7: Synthesis of compound 132

[0962] At 25 °C, to a solution of compound 27-1-6 (50 mg, 73.81 μmol) in dichloromethane (2 mL) was added TFA (1.49 g, 13.07 mmol, 1 mL), and the resulting mixture was stirred at 25 °C for 2 h. The reaction solution was concentrated to dryness, then diluted with dichloromethane (20 mL). The concentration was repeated three times. The crude product was dissolved in MeOH, then solid NaHCO3 was added until pH = 6. The methanol solution was purified directly by preparative HPLC (preparative C18, 5 μM OBD, 19×250 mm column, Waters; gradient elution from 40% MeCN / water to 50% MeCN / water over a 9 min period, where both solvents contained 10 mmol / L NH4HCO3) to give compound 132 as a white solid (5.00 mg, 10.93 μmol, 14.81% yield, 100% purity).

[0963] Compounds 132 - 134 were synthesized according to the 7-step procedure described in Example 27. The analytical data for compounds 132 - 134 are provided below.

[0964]

[0965] Example 28

[0966]

[0967] Scheme 28

[0968] Step 1: Synthesis of tert-butyl 4-(6-bromo-3-chloroquinolin-4-yl)piperazine-1-carboxylate (compound 28-1-2)

[0969] At 20 °C, to a stirred solution of 6-bromo-3,4-dichloroquinoline (Compound 28-1-1, 2 g, 7.22 mmol, 1 equiv) in DMF (20 mL, 100.0%) was added tert-butyl piperazine-1-carboxylate (1345.06 mg, 7.22 mmol, 1 equiv) and potassium carbonate (2 g, 14.44 mmol, 2 equiv). The reaction mixture was stirred at 100 °C for 16 h. TLC (PE:EtOAc = 5:1) indicated completion of the reaction. The reaction mixture was poured into H2O (100 mL), filtered and concentrated to give tert-butyl 4-(6-bromo-3-chloroquinolin-4-yl)piperazine-1-carboxylate (Compound 28-1-2, 2.3 g, 5.39 mmol, 74.63%). MS (m / z) 426.1 / 428.1 (M+H) + 。

[0970] Step 2: tert-butyl 4-[3-chloro-6-(3-cyano-2-hydroxyphenyl)quinolin-4-yl]piperazine-1-carboxylate (Compound 28-1-3)

[0971] At 20 °C, to a stirred solution of tert-butyl 4-(6-bromo-3-chloroquinolin-4-yl)piperazine-1-carboxylate (Compound 28-1-2, 900 mg, 2.11 mmol, 1 equiv) in 1,4-dioxane (12 mL, 100.0%) was added water (3 mL, 166.53 mmol, 78.96 equiv), 2-hydroxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (516.88 mg, 2.11 mmol, 1 equiv), potassium carbonate (582.97 mg, 4.22 mmol, 2 equiv) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (160.88 mg, 0.21 mmol, 0.1 equiv). The reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (300 mL), washed with saturated NaHCO3 (50 mL), dried over Na2SO4 and evaporated to give a residue. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (9:1 - 1:1) to give tert-butyl 4-[3-chloro-6-(3-cyano-2-hydroxyphenyl)quinolin-4-yl]piperazine-1-carboxylate (Compound 28-1-3, 500 mg, 1.08 mmol, 50.99%) as a white solid. MS (m / z) 465.2 (M+H) + 。

[0972] Step 3: Synthesis of tert-butyl 4-[6-(3-cyano-2-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)quinolin-4-yl]piperazine-1-carboxylate (Compound 28-1-4)

[0973] At 20 °C, water (2.5 ml, 138.78 mmol, 129.04 eq), (3-fluoro-5-methylphenyl)boronic acid (165.56 mg, 1.08 mmol, 1 eq), potassium carbonate (297.26 mg, 2.15 mmol, 2 eq) and dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (76.15 mg, 0.11 mmol, 0.1 eq) were added to a stirred solution of tert-butyl 4-[3-chloro-6-(3-cyano-2-hydroxyphenyl)quinolin-4-yl]piperazine-1-carboxylate (Compound 28-1-3, 500 mg, 1.08 mmol, 1 eq) in 1,4-dioxane (10 ml, 100.0%). The reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (300 mL), washed with saturated NaHCO3 (50 mL), dried over Na2SO4 and evaporated to give a residue. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (9:1 - 1:1) to afford tert-butyl 4-[6-(3-cyano-2-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)quinolin-4-yl]piperazine-1-carboxylate (Compound 28-1-4, 400 mg, 0.74 mmol, 69.06%) as a white solid. MS (m / z) 539.3 (M+H) + 。

[0974] Step 4: Synthesis of 3-[3-(3-fluoro-5-methylphenyl)-4-(piperazin-1-yl)quinolin-6-yl]-2-hydroxybenzonitrile (Compound 28-1-5)

[0975] At 20 °C, trifluoroacetic acid (1 ml, 8.77 mmol, 47.24 eq) was added to a stirred solution of tert-butyl 4-[6-(3-cyano-2-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)quinolin-4-yl]piperazine-1-carboxylate (Compound 28-1-4, 100 mg, 0.19 mmol, 1 eq) in DCM (3 ml). The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated and evaporated to afford 3-[3-(3-fluoro-5-methylphenyl)-4-(piperazin-1-yl)quinolin-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) + 。

[0976] Step 5: Synthesis of Compound 135

[0977] At 20 °C, to a stirred solution of 3-[3-(3-fluoro-5-methylphenyl)-4-(piperazin-1-yl)quinolin-6-yl]-2-hydroxybenzonitrile (Compound 28-1-5, 80 mg, 0.18 mmol, 1 equiv) in DMF (2 ml, 0%) was added pyrazole-1-carboxamide (40.18 mg, 0.36 mmol, 2 equiv) and ethyldi(propan-2-yl)amine (235.79 mg, 1.82 mmol, 10 equiv). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL), washed with saturated H2O (50 mL×3), dried over Na2SO4 and evaporated to give a residue. The residue was purified by HPLC to give 4-[6-(3-cyano-2-hydroxyphenyl)-3-(3-fluoro-5-methylphenyl)quinolin-4-yl]piperazine-1-carboxamide (Compound 135, 3.8 mg, 0.01 mmol, 4.33%) as a white solid.

[0978] Compound 135 and 136 were synthesized according to the 5-step procedure described in Example 28. The analytical data of Compound 135 and 136 are provided below.

[0979]

[0980] II. Biological Examples

[0981] Example 29

[0982] Biochemical Assay for Somatostatin Receptor 2 (SSTR2) Activation

[0983] Agonist activation of SSTR results in an increase in intracellular cAMP levels. Cisbio's homogeneous time-resolved fluorescence (HTRF) cAMP assay was used to measure cAMP concentration in a high-throughput manner. The increase in intracellular cAMP concentration was measured using a stably transfected cell line expressing SSTR2. The test compound was dissolved in DMSO. The cells were incubated with the compound for 1 - 2 h and then the competitive binding of cAMP due to activation of SSTR2 by the test compound was measured using the Cisbio cAMP Gs Dynamic Assay System (Perkin Elmer, Bedford, MA).

[0984] Determine the mean pEC of the test compound 50 . The data are provided in Table 2 below.

[0985] Table 2

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997]

[0998]

[0999]

[1000]

[1001] *Indicates that the stereochemistry is arbitrarily assigned.

[1002] Efforts have been made to ensure the accuracy of the numbers used (e.g., amounts, temperatures, etc.), but some experimental errors and deviations should still be considered.

[1003] Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which can be used to practice the subject matter described herein. This disclosure is in no way limited to the methods and materials described.

[1004] Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject matter pertains and are consistent with the following documents: Singleton et al. (1994), Dictionary of Microbiology and Molecular Biology, 2nd Edition, John Wiley & Sons, New York, NY; and Janeway, C., Travers, P., Walport, M., Shlomchik (2001), Immunobiology, 5th Edition, Garland Publishing, New York.

[1005] Throughout this specification and the claims, unless the context requires otherwise, the words "comprise", "comprises" and "comprising" are used in a non-exclusive sense. It should be understood that the embodiments described herein include embodiments of "consisting of" and / or "consisting essentially of".

[1006] Where a range of values is provided, it is to be understood that each intervening value, to the tenth of the unit of the lower limit (unless the context clearly dictates otherwise), between the upper and lower limits of that range and any other stated value or intervening value within the stated range is encompassed within the invention. Also encompassed are the upper and lower limits of these smaller ranges which may independently be included within the smaller ranges, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included.

[1007] Benefiting from the teachings presented in the foregoing description and the associated drawings, many modifications and other embodiments will occur to those skilled in the art to which this subject matter pertains. Accordingly, it is to 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. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof; wherein g is 1 or 0; Z is absent, is -N(H)-C(=O)- or -C(=O)-NH-; R 1 is hydrogen or a halogen; or R 1 R and Z together with the rings to which they are attached form a fused bicyclic ring, optionally substituted by one or two R 8 substituents; or R 1 and R C1 together with the rings to which they are attached form a fused tricyclic ring; Ring C is selected from the group consisting of 4- to 10-membered monocyclic or bicyclic fused heterocyclic groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups, each of which is substituted by R C1 , R C2 , and R C3 . wherein said 4- to 10-membered monocyclic or bicyclic fused heterocyclic group or 5- to 10-membered heteroaryl each independently contains 1, 2, 3 or 4 ring heteroatoms selected from N, O and S; and wherein R C1 is hydrogen, or can combine with R 1 , R 3 or R 6 to combine; R C2 and R C3 each independently is selected from the group consisting of: hydrogen, halogen, cyano, C1-C6 alkyl, hydroxy, -C(=O)NH2, -O-C2-C6 alkenyl, -C1-C6 alkoxy, -NH-(CH2) 1-5 -NH2, -O-piperidinyl, -O-(CH2) qC -O-(CH2) rC -CH3, where qC and rC are each independently an integer from 1 to 4, R 2 is hydrogen or a halogen; or R 2 and R B1 together with the rings to which they are attached form a fused tricyclic ring; R 3 , if present, is a group covalently bonded to R C1 ; Ring B is phenyl or pyridyl, each of which is monosubstituted by R B1 or disubstituted by R B1 and R B2 ; wherein R B1 and R B2 each independently selected from the group consisting of: 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 -CH3, -C(O)-NR Na R Nb , where q2 and r2 are each independently integers from 1 to 4, where each R Na and R Nb each independently selected from the group consisting of: hydrogen and C1-C6 alkyl; and A is selected from the group consisting of: i.-NR 4 R 5 , wherein R 4 is an optionally substituted C1-C6 alkyl group, -NH-C1-C6 alkyl -NHR 4a or -C1-C6 alkyl -NHR 4a , where R 4a is hydrogen or methyl; and R 5 is hydrogen or an optionally substituted C1-C6 alkyl group; wherein the optional substituents are selected from the group consisting of: halogen and hydroxyl; or R 5 and R B1 with R 5 The N and R linked B1 together with the linked ring B form a fused heterocyclic group; or R 5 and R C1 with R 5 The N and R linked C1 together with the linked ring C form a fused heterocyclic group; or R 5 and R 8 with R 5 The N and R connected 8 together with the connected ring form a fused heterocyclic group; ii. substituted by -NH-R 6 or R S substituted spiro ring, where R S is hydrogen or -C(=O)-C1-C6 alkyl; and iii. -O-(C3-C8 cycloalkyl), 5- to 11-membered heterocyclic group or 5- to 6-membered heteroaryl, each of which is substituted by -NH-R 6 or is substituted by R F and R G wherein R F selected from the group consisting of: 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 , where x is 0 or 1; and R F1 and R F2 each independently is H, -(C=O)-O-C1-C6 alkyl, and C1-C6 alkyl; R G is hydrogen or -C1-C6 alkoxy; or R G Together with R C1 forms -O-(CH2) k -O-, where k is an integer from 1 to 5; or R F and R G together form a carboxyl group; and R 6 Together with R C1 forms: wherein Denote R 6 The connection point with A; p is an integer from 1 to 4; R 7a and R 7b is independently selected, in each case, from the group consisting of: hydroxy, optionally substituted -C1-C6 alkyl, -N3, -NR a R b , where R a and R b are each independently H or C1-C6 alkyl; E does not exist and is -O- or -N(R b )-, where R b is H or an optionally substituted C1-C6 alkyl group; J is -C(O)- or -C(R 7a R 7b )-; and L is absent, is -O- or -N(H)-, wherein the optional substituents are selected from the group consisting of: halogen, -NH2 and hydroxyl; provided that the compound is not one of the following:

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

3. The compound according to claim 2, which has the structure of formula Ia or Ib, wherein Z and R 1 together with the rings to which they are respectively attached form a fused: wherein X 1 and X 2 are each independently selected from the group consisting of: O, N, N-R 8 , S and C-R 8 ; wherein R 8 is selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, and -C(=O)OR 8a , wherein R 8a is hydrogen or C1-C6 alkyl, and wherein the optional substituent is selected from the group consisting of halogen, -NH2, and hydroxy.

4. The compound according to claim 3, which has the structure of formula Ia-1:

5. The compound according to claim 4, which has the structure of formula Ia-2:

6. The compound according to claim 5, which has the structure of formula Ia-3:

7. The compound according to claim 3, which has the structure of formula Ib-1:

8. The compound according to claim 7, which has the structures of formulae Ib-1a to Ib-1e: and 9. The compound according to claim 8, wherein R B1 and R B2 in each of Ib-1a to Ib-1e is located at:

10. The compound according to any one of claims 1 to 9, wherein R B1 and R B2 are each independently selected from the group consisting of C1-C6 alkyl, halogen, and C1-C6 alkoxy.

11. The compound according to claim 10, wherein the C1-C6 alkyl is methyl, the halogen is fluorine, and the C1-C6 alkoxy is methoxy.

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

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

14. A compound according to any one of claims 5 to 13, wherein R C1 is hydrogen and the positions of R C2 and R C3 are as follows:

15. The compound according to claim 14, wherein R C2 selected from the group consisting of: hydroxy, C1-C6 alkoxy, -O-piperidinyl, -N-(CH2)3-NH2, -O-C2-C6 alkenyl, -O-(CH2) q1 -O-(CH2) r1 -CH3, where q1 and r1 are each independently an integer from 1 to 4; and R C3 selected from the group consisting of: cyano and halogen.

16. The compound according to claim 15, wherein R C2 is selected from the group consisting of a hydroxyl group, a methoxy group, -O-CH2-CH=CH2 and -O-CH2-O-CH3, and R C3 is selected from the group consisting of: cyano and bromo.

17. A compound according to any one of claims 5 to 13, wherein R C1 is hydrogen, and the positions of R C2 and R C3 are:

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

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

20. A compound according to any one of claims 5 to 13, wherein R C1 is hydrogen and the positions of R C2 and R C3 are:

21. The compound according to claim 20, wherein R C2 and R C3 each independently selected from the group consisting of: hydroxy, C1-C6 alkoxy, halogen, -(C=O)-NH2, -O-C2-C6 alkenyl, and C1-C6 alkyl.

22. The compound according to claim 21, wherein R C2 and R C3 each independently selected from the group consisting of: -(C=O)-NH2, methoxy, fluorine, and methyl.

23. The compound according to claim 3, wherein Ring B is phenyl disubstituted by R B1 and R B2 ; and ring C is a 4- to 10-membered monocyclic or bicyclic heterocyclic group.

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

25. The compound according to claim 24, wherein ring C is selected from the group consisting of:

26. The compound according to claim 2, which has the structure of formula Ic, wherein Z is absent, and R 1 and R C1 together with the ring to which R 1 is attached and the ring to which R C1 is attached form a fused ring substituted by R 8 :

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

28. A compound according to claim 26 or 27, wherein ring C is an 8- to 10-membered heteroaryl ring substituted by R C2 and R C3 ​ 29. The compound according to claim 28, wherein ring C is:

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

31. A compound according to any one of claims 26 to 30, wherein ring B is a phenyl group disubstituted by R B1 and R B2 .

32. The compound according to claim 31, wherein R B1 is halogen, and R B2 is halogen or C1-C6 alkyl.

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

34. A compound according to any one of claims 31 to 33, wherein R B1 and R B2 are in the following positions in the benzene ring:

35. The compound according to claim 2, which has the structure of formula Id, wherein Z and R 1 together with the rings to which they are respectively attached form a fused ring:

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

37. The compound according to claim 36, wherein ring C is a phenyl group substituted by R C1 , R C2 and R C3 .

38. The compound according to claim 37, wherein R C1 is hydrogen, and the positions of R C2 and R C3 are:

39. The compound according to claim 38, wherein R C2 and R C3 are each independently selected from the group consisting of C1-C6 alkyl and halogen.

40. The compound according to claim 39, wherein the C1-C6 alkyl is methyl and the halogen is fluorine.

41. A compound according to any one of claims 36 to 40, wherein ring B is a phenyl group disubstituted by R B1 and R B2 .

42. The compound according to claim 41, wherein R B1 is a halogen, and R B2 is a halogen or a C1-C6 alkyl group.

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

44. The compound according to claim 43, wherein R B1 and R B2 are located in the phenyl group as follows:

45. The compound according to claim 2, which has the structure of formula Ie, wherein R 2 and R B1 and the ring to which R 2 is attached and the ring to which R B1 is attached together form a fused ring: wherein Q is O or CH2, and is a single bond; or Q is N, and is a double bond; R 1 is hydrogen or a halogen; and Ring B is phenyl substituted by R B2 substituent.

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

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

48. The compound according to claim 47, wherein R C1 is hydrogen and ring C is:

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

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

51. A compound according to any one of claims 45 to 50, wherein Q is N, and is a double bond.

52. A compound according to any one of claims 45 to 50, wherein Q is O and is a single bond.

53. A compound according to any one of claims 1 to 52, wherein A is a 5- to 11-membered heterocyclic group or a 5- to 6-membered heteroaryl group, each of which is substituted by -NH-R 6 ; or is substituted by R F and R G .

54. The compound according to claim 53, wherein A has the following structure: wherein ring A1 is a 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclic group.

55. The compound according to claim 54, wherein A has the following structure: wherein G is N; D is CH2; y is 0 or 1; and each is a single bond; G is C; D is CH2; y is 1; and is a double bond, and the others are each single bonds; G is N, D is CH2; y is 0; and and each is a double bond, and the others each is a single bond; G is C; D is N or C-H; y is 1; and each is a double bond.

56. The compound according to claim 55, wherein A is selected from the group consisting of:

57. The compound according to any one of claims 1 to 52, wherein A is a spiro ring having the following structure: 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:

59. A compound according to any one of claims 1 to 52, wherein A is -NH-R 6 substituted or is R F and R G substituted -O-(C3-C8 cycloalkyl).

60. The compound according to claim 59, wherein A has the following structure: wherein Ring A2 is C4-C6 cycloalkyl.

61. The compound according to claim 60, wherein A is selected from the group consisting of:

62. A compound according to any one of claims 53 to 61, wherein R 6 together with R C1 forms: wherein Denote R 6 The connection point with A; p is an integer from 1 to 4; R 7a and R 7b is independently selected in each case from the group consisting of: hydroxy, optionally substituted -C1-C6 alkyl, -N3, -NR a R b , where R a and R b are each independently H or C1-C6 alkyl; E does not exist and is -O- or -N(R b )-, where R b is H or an optionally substituted C1-C6 alkyl group; J is -C(O)- or -C(R 7a R 7b )-; and L is absent, is -O- or -N(H)-.

63. The compound according to claim 62, wherein R 6 together with R C1 forms:

64. The compound according to claim 62 or 63, which has the structure of formula Ia-4:

65. The compound according to claim 64, which has the structure of formula Ia-4A:

66. The compound according to claim 65, wherein the ring C to which R C1 is attached has the following structure:

67. The compound according to claim 66, wherein R C1 The attached ring C has the following structure:

68. The compound according to claim 67, wherein R C2 is cyano or –(C=O)-NH2.

69. The compound according to any one of claims 53 to 61, which has the structures of formula Ia-6, Ia-7, Ib-2 and Ib-3:

70. The compound according to claim 69, wherein R B1 and R B2 are each in positions Ia-6, Ia-7, Ib-2 and Ib-3 as follows:

71. A compound according to claim 69 or 70, wherein R B1 and R B2 are each independently selected from the group consisting of C1-C6 alkyl, halogen, and C1-C6 alkoxy.

72. The compound according to 71, wherein the C1-C6 alkyl is methyl, the halogen is fluorine, and the C1-C6 alkoxy is methoxy.

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

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

75. A compound according to any one of claims 69 to 74, wherein the positions of R C2 and R C3 are:

76. The compound according to claim 75, wherein R C2 selected from the group consisting of: hydroxy, C1-C6 alkoxy, -O-piperidinyl, -N-(CH2)3-NH2, -O-C2-C6 alkenyl, -O-(CH2) q1 -O-(CH2) r1 -CH3, where q1 and r1 are each independently an integer from 1 to 4; and R C3 selected from the group consisting of: cyano and halogen.

77. The compound according to claim 76, wherein R C2 is selected from the group consisting of hydroxy, methoxy, -O-CH2-CH=CH2 and -O-CH2-O-CH3, and R C3 Selected from the group consisting of: cyano and bromo.

78. A compound according to any one of claims 69 to 74, wherein R C1 is hydrogen and the positions of R C2 and R C3 are as follows:

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

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

81. A compound according to any one of claims 69 to 74, wherein R C1 is hydrogen, and the positions of R C2 and R C3 are:

82. The compound according to claim 81, wherein R C2 and R C3 each independently selected from the group consisting of: hydroxy, C1-C6 alkoxy, halogen, -(C=O)-NH2, -O-C2-C6 alkenyl, and C1-C6 alkyl.

83. The compound according to claim 82, wherein R C2 and R C3 each independently selected from the group consisting of: -(C═O)-NH2, methoxy, fluoro and methyl.

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

85. The compound according to claim 84, wherein R 4 is an optionally substituted C1-C6 alkyl group, -C1-C6 alkyl-NH-CH3, C1-C6 alkyl-NH2, -NH-C1-C6 alkyl-NH-CH3, -NH-C1-C6 alkyl-NH2, and R 5 is hydrogen or an optionally substituted C1-C6 alkyl group.

86. The compound according to claim 85, wherein R 4 is -(CH2)3-NH-CH3; and R 5 is hydrogen.

87. The compound according to claim 84, which has the structure of formula If, wherein R 5 and R B1 and the N to which R 5 is attached and ring B to which R B1 is attached together form a fused ring: wherein M is a carbonyl group or C-R M1 R M2 , wherein R M1 and R M2 are each independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, and C1-C6 alkyl-NH2, wherein the optional substituents are selected from the group consisting of halogen and hydroxyl.

88. The compound according to 87, wherein M is CH2; R 1 and R 2 each is hydrogen, and R 4 is C1-C6 alkyl-NHR 4a .

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

90. The compound according to any one of claims 87 to 89, wherein Ring B is mono-substituted by R B1 or disubstituted by R B1 and R B2 to form a disubstituted phenyl group.

91. The compound according to claim 90, wherein R B1 and R B2 are each fluorine.

92. The compound according to claim 90 or 91, wherein ring C is a 4- to 10-membered monocyclic or bicyclic fused heterocyclic group or a 5- to 10-membered heteroaryl group each substituted by R C1 , R C2 and R C3 .

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

94. The compound according to claim 84, which has the structure of formula Ig, wherein Z is absent, and R 5 and R C1 connected to R 5 and the N to which R C1 is attached, together with ring C, form a fused ring: wherein M is a carbonyl group or C-R M1 R M2 , wherein R M1 and R M2 are each independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, and C1-C6 alkyl-NH2, wherein the optional substituent is halogen or hydroxy.

95. The compound according to 94, wherein M is a carbonyl group; R 1 and R 2 are each hydrogen, and R 4 is a C1-C6 alkyl-NHR 4a .

96. The compound according to claim 94 or 95, wherein Ring B is mono-substituted by R B1 or is di-substituted by R B1 and R B2 to form a phenyl group.

97. The compound according to claim 96, wherein R B1 and R B2 are each fluorine.

98. A compound according to claim 90 or 91, wherein ring C is a 4- to 10-membered monocyclic or bicyclic fused heterocyclic group or a 5- to 10-membered heteroaryl group each substituted by R C1 , R C2 and R C3 .

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

100. The compound according to claim 99, wherein R C1 together with R 3 forms: wherein Represents R 6 Connection point with A; p is an integer from 1 to 4; R 7a and R 7b are each independently selected from the group consisting of: hydroxy, optionally substituted -C1-C6 alkyl, -N3, -NR a R b , where R a and R b are each independently H or C1-C6 alkyl; E does not exist and is -O- or -N(R b )-, where R b is H or an optionally substituted C1-C6 alkyl group; J is -C(O)- or -C(R 7a R 7b )-; and L is absent, is -O- or -N(H)-.

101. The compound according to claim 99 or 100, which has the structure of formula I-2:

102. The compound according to claim 100 or 101, wherein -L-J-E-(CR 7a R 7b ) p - forms:

103. A compound according to any one of claims 99 to 102, wherein ring B is a phenyl group disubstituted by R B1 and R B2 .

104. The compound according to claim 103, wherein R B1 is halogen, and R B2 is halogen or C1-C6 alkyl.

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

106. A compound according to any one of claims 103 to 105, wherein R B1 and R B2 are located in the benzene ring as follows:

107. A compound according to any one of claims 99 to 106, wherein the ring C to which R C1 is attached has the following structure:

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

109. The compound according to any one of claims 99 to 108, wherein A has the following structure: wherein G is N; D is CH2; y is 0 or 1; and each is a single bond; G is C; D is CH2; y is 1; and is a double bond, and the others are each single bonds; G is N, D is CH2; y is 0; and and each is a double bond, and the others each is a single bond; G is C; D is N or C-H; y is 1; and each is a double bond.

110. The compound according to claim 109, wherein A is selected from the group consisting of:

111. The compound according to any one of claims 99 to 108, wherein A has the following structure: wherein ring A2 is C4-C6 cycloalkyl.

112. The compound according to claim 111, wherein A is selected from the group consisting of:

113. A compound as shown in Table 1 or a pharmaceutically acceptable salt thereof.

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

115. A method for treating a subject suffering from a somatostatin-related disease, the method 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, diarrhea, inflammatory bowel disease, irritable bowel syndrome, cancer, acromegaly, depression, chronic atrophic gastritis, Crohn's disease, ulcerative colitis, retinopathy, arthritis, restenosis, neuroendocrine tumor (NET), and pain.

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

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