CN118159532A - Compound with BTK protein degradation activity and medical application thereof - Google Patents

Compound with BTK protein degradation activity and medical application thereof Download PDF

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Publication number
CN118159532A
CN118159532A CN202280071497.9A CN202280071497A CN118159532A CN 118159532 A CN118159532 A CN 118159532A CN 202280071497 A CN202280071497 A CN 202280071497A CN 118159532 A CN118159532 A CN 118159532A
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mmol
amino
carboxamide
piperidin
piperidine
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李松熙
柳济虎
安侹玟
文熙晶
李豪玹
张美荣
尹辉翔
金艺恩
柳善美
林艺瑟
郑罗来
金韶革
崔爱烂
金瀚蔚
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Ubix Treatment Co
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Ubix Treatment Co
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Priority claimed from PCT/KR2022/017291 external-priority patent/WO2023080732A1/en
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Abstract

The present disclosure provides: a compound of a specific chemical structure having excellent activity in BTK degradation; or a pharmaceutically acceptable salt thereof. The present disclosure also provides compositions comprising the compounds or pharmaceutically acceptable salts thereof. The present disclosure also provides pharmaceutical uses of compounds, salts thereof, and compositions comprising the same according to the present disclosure for treating or preventing BTK-related diseases (e.g., autoimmune diseases or cancers). The present disclosure also provides methods for treating or preventing a BTK-related disease (e.g., an autoimmune disease or cancer), comprising administering to a subject in need thereof an effective amount of a compound according to the present disclosure, a salt thereof, or a composition comprising the same.

Description

Compound with BTK protein degradation activity and medical application thereof
Technical Field
The present disclosure relates to a group of compounds having BTK proteolytic activity. In particular, the present disclosure relates to a group of compounds having a specific structure and having very excellent BTK protein degrading activity. The present disclosure also relates to useful methods of using such compounds for treating diseases associated with BTK proteins. That is, the present disclosure relates to the medical use of compounds according to the present disclosure for the treatment or prevention of BTK protein related diseases.
Background
Bruton's tyrosine kinase (BTK, bruton's tyrosine kinase) is a member of the Tec family of tyrosine kinases. It affects early B cell development and maturation, B cell activation, and is a regulator of B cell signaling and survival. BTK is activated by B cell receptors and plays an important role in B cell signaling and development by regulating various major signaling pathways within cells and inducing signaling necessary for cell survival.
However, when BTK is overactivated or overexpressed due to abnormal signal transduction in B cells, it can cause abnormal B cells to proliferate and form pathological autoantibodies, resulting in autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, cancer, B cell malignancy, inflammatory diseases, and the like (see U.S. patent No. 9,624,224).
Furthermore, BTK is known to be overexpressed in B-lineage malignant lymphomas such as B-cell precursor acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-hodgkin's lymphoma. Inhibition of BTK in abnormal B cell proliferation may block B cell mediated diseases by blocking B cell receptor signaling. Thus, the use of BTK inhibitors may be an effective method of treating B cell mediated diseases. Significant medicinal effects have been demonstrated by inhibition of BTK in experimental animal models of autoimmune diseases or B-cell malignancies (see U.S. patent application publication No. 2021-0002285).
At present, the correlation between BTK inhibitors and a variety of diseases is well documented, and clinical trials are being conducted with various BTK inhibitors for the following diseases: leukemia (e.g., lymphoblastic leukemia, B-cell leukemia, promyelocytic leukemia, granulocytic leukemia, hairy cell leukemia), lymphoma (e.g., B-cell lymphoma), CNS (central nervous system) lymphoma, follicular lymphoma, non-hodgkin's lymphoma, lymphocytic lymphoma, mantle cell lymphoma, burkitt's lymphoma, B-cell diffuse lymphoma, marginal zone lymphoma, small cell lymphoma, lymphoplasmacytoid lymphoma, rickettsial inversion (rickettsia), fahrenheit macroglobulinemia, ependymoma, medulloblastoma, glioblastoma, primitive neuroectodermal tumors, non-small cell lung carcinoma, breast cancer, pancreatic cancer, gastroesophageal cancer, B-cell malignancy, recurrent mature B-cell tumors, multiple myeloma, metastatic pancreatic cancer, multiple sclerosis, autoimmune diseases (e.g., rheumatoid arthritis, autoimmune hemolytic anemia, warm-antibody autoimmune hemolytic anemia, chronic spontaneous hemolytic anemia (CSU), food, immune thrombocytopenia, lymphopenia, lymphomatosis, hepatitis-free conditions, ocular inflammation, inflammatory diseases of the host system, ocular system, and the like), acute lymphomatosis, systemic disease (e.g., lymphomatosis, inflammatory disease of the eye, and the like);/(www.clinicaltrials.gov /).
Disclosure of Invention
[ Technical problem ]
The deletion of BTK proteins may provide an alternative and more efficient strategy for inhibiting BTK activity. Accordingly, the problem to be solved by the present invention is to provide a compound having a Bruton's Tyrosine Kinase (BTK) degrading activity, a pharmaceutical composition comprising the compound as an active ingredient, and a medical use for treating or preventing BTK-related diseases, preferably autoimmune diseases or cancers.
Another problem to be solved by the present invention is to provide a method for the treatment or alleviation of a BTK-related disease, preferably an autoimmune disease or cancer, characterized in that it degrades BTK thereby reducing BTK activity, and which comprises administering a compound according to the present invention to a patient in need of treatment, amelioration or prophylaxis of a BTK-related disease.
Technical scheme
Compounds of the invention
In order to solve the above problems, one embodiment of the present invention provides a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof.
[ Chemical formula 1]
In the chemical formula 1, the chemical formula is shown in the drawing,
A is a carbocycle, heterocycle, aryl or heteroaryl,
R 1a and R 1b are each independently H, halogen, C 1-6 alkyl, C 1-6 alkoxy or carbocycle, wherein one or more hydrogens of the alkyl, alkoxy or carbocycle are optionally substituted with one or more selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy and C 1-6 hydroxyalkyl,
R 2a and R 2b are each independently H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxy or C 1-6 hydroxyalkyl,
R 3 is H, halogen, C 1-6 alkyl, C 1-6 haloalkyl or-NH 2,
X 1 and X 2 are each independently CH or N,
Y 1 is NH or O, and the group consisting of,
N is an integer of 0,1 or 2,
L is a compound represented by the following chemical formula 2,
[ Chemical formula 2]
In the chemical formula 2, the chemical formula is shown in the drawing,
B is aryl or heteroaryl, wherein one or more hydrogens in the aryl or heteroaryl are optionally substituted with one or more selected from the group consisting of C 1-6 alkyl, halogen, and C 1-6 haloalkyl,
C 1 and C 2 are each independently a direct bond, a carbocycle or a heterocycle, wherein one or more hydrogens in the carbocycle or heterocycle are optionally substituted with one or more selected from the group consisting of C 1-6 alkyl, halogen, C 1-6 haloalkyl and hydroxy,
D 1 and D 2 are each independently a direct bond, -O-, -N (R 4) - -, C (O) - -, -CC-, -C (O) NH-, or-NHC (O) - -, where R 4 is H, C 1-6 alkyl or C 1-6 haloalkyl,
Q 1、q2、q3 and q 4 are each independently integers from 0 to 3,
E is the following chemical formula 3 or chemical formula 4,
[ Chemical formula 3]
[ Chemical formula 4]
In the chemical formulas 3 and 4,
X 3、X4、X5 and X 6 are each independently CH or N,
Y 2 is -C(R6a)(R6b)-、-C(O)-、-C(R6a)(R6b)-C(R6a)(R6b)-、-C(R6a)＝C(R6b)-、-C(R6a)＝N-、-N＝C(R6a)- or-n=n-,
Z is a direct bond, -C (R 6a)(R6b)-、-N(R6a) -, -O-, or-C (O) NH-,
R 5a and R 5b are each independently H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy, and R 6a and R 6b are each independently H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy.
The compound according to the present invention is PROTAC (proteolytically targeted chimeric) compound of a ' BTK binding ligand-linker-E3 ligase ligand ' (moiety on the left side of L-linker (L) -moiety on the right side of L in chemical formula 1 '). The present inventors evaluated various substituents. In the case of the structure of chemical formula 1 such as the present disclosure, particularly in the case of a preferable structure described later, a compound excellent in various aspects including BTK degradation activity can be obtained. That is, the present invention provides a novel compound having excellent BTK degradation activity, (metabolic) stability, etc., and excellent physicochemical properties (cLogP value, water solubility, cell membrane permeability) as an active ingredient.
As used herein, the terms "substituent", "group", "moiety" and "fragment" are used interchangeably.
If a substituent is described as "optionally substituted," the substituent may be unsubstituted or substituted with one or more defined substituents. If the substitutable position is unsubstituted, the default substituent is hydrogen.
As used herein, the term "alkyl" refers to a saturated straight or branched acyclic hydrocarbon having from 1 to 10 carbon atoms unless the context clearly indicates otherwise. "lower alkyl" refers to an alkyl group having 1 to 4 carbon atoms. Representative saturated straight chain alkyl groups include-methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and-n-decyl, and the saturated branched alkyl group includes-isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylbutyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl 3, 3-dimethylpentyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2-diethylpentyl, 3-diethylhexyl, 2-diethylhexyl, 3-diethylhexyl, and the like. In a preferred embodiment of the invention, the alkyl group is methyl, ethyl, isopropyl or tert-butyl.
As used herein, the term "alkoxy" refers to-O- (alkyl), including -OCH3、-OCH2CH3、-O(CH2)2CH3、-OC(CH3)2H、-OC(CH3)3 and the like, wherein alkyl is as defined above.
As used herein, if the term "C 1-6", "C1-6" or "C1-C6" is used, it means a number of carbon atoms of 1 to 6. For example, C 1-6 alkyl refers to alkyl groups of any integer from 1 to 6 carbon numbers.
As used herein, the terms "halogen" and "halo" refer to fluorine, chlorine, bromine or iodine. In a preferred embodiment of the invention, the halogen is fluorine.
As used herein, the term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group in which one or more hydrogen atoms are replaced with halogen atoms. For example, haloalkyl includes -CF3、-CHF2、-CH2F、-CBr3、-CHBr2、-CH2Br、-CC13、-CHC12、-CH2CI、-CI3、-CHI2、-CH2I、-CH2-CF3、-CH2-CHF2、-CH2-CH2F、-CH2-CBr3、-CH2-CHBr2、-CH2-CH2Br、-CH2-CC13、-CH2-CHC12、-CH2-CH2CI、-CH2-CI3、-CH2-CHI2、-CH2-CH2I and the like, wherein alkyl, alkoxy, and halogen are as described above. In a preferred embodiment of the invention, the haloalkyl is-CF 3.
As used herein, the term "hydroxyalkyl" refers to a straight or branched C 1-10 alkyl group substituted with one or more hydroxyl groups. Examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxy (iso) propyl, and hydroxybutyl.
As used herein, the term "carbocycle" or "cycloalkyl" refers to a monocyclic or polycyclic saturated ring having carbon and hydrogen atoms and no carbon-carbon multiple bonds. Examples of monocyclic rings include, but are not limited to, (C 3-C7) cycloalkyl including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of polycyclic rings include, but are not limited to, fused bicyclic rings such as octahydropentylene (octahydropentalene) and decahydronaphthalene; spiro rings such as spiro [3.3] heptane, spiro [3.4] octane, spiro [3.5] nonane, spiro [4.4] nonane, spiro [4.5] decane and spiro [5.5] undecane; and bridged bicyclo rings such as bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane and bicyclo [2.2.2] octane. Cycloalkyl groups may be unsubstituted or optionally substituted. In one embodiment of the invention, cycloalkyl is a single ring.
The term "heterocycle" or "heterocycloalkyl" refers to a 5-to 7-membered monocyclic or 7-to 12-membered bicyclic saturated heterocycle containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatoms may optionally be quaternized. Heterocycles include heteroaryl groups as defined above. Representative heterocycles include oxirane, oxetane, tetrahydrofuran, tetrahydropyran, 1, 4-dioxane, aziridine, azetidine, pyrrolidine, piperidine, piperazine, pyrrolidone, hydantoin, valerolactam, thiirane, thietane, tetrahydrothiophene, tetrahydrothiopyran, morpholine, tetrahydropyridine, and tetrahydropyrimidine. Heterocycles include bicyclic rings in which a portion of the heterocycle is fused to a benzene or cyclopent-1, 3-diene ring. The heterocycle may be attached through any heteroatom or carbon atom. In addition, heterocycles include fused bicyclic, spiro, and bridged bicyclic rings in which one or more carbon atoms of the above polycyclic ring are replaced with nitrogen, oxygen, or sulfur atoms. For example, when the heteroatom is nitrogen, these include, but are not limited to, fused heterobicyclic rings such as octahydrocyclopenta [ c ] pyrrole, octahydropyrrolo [3,4-c ] pyrrole, decahydroisoquinoline and decahydro-2, 6-naphthyridine; spiro rings such as 2-azaspiro [3.3] heptane, 2, 6-diazaspiro [3.3] heptane, 2-azaspiro [3.4] octane, 2, 6-diazaspiro [3.4] octane, 2-azaspiro [3.5] nonane, 2, 7-diazaspiro [3.5] nonane, 2-azaspiro [4.4] nonane, 2, 7-diazaspiro [4.4] nonane, 8-azaspiro [4.5] decane, 2, 8-diazaspiro [4.5] decane, 3-azaspiro [5.5] undecane and 3, 9-diazaspiro [5.5] undecane; and, fumosaics heterobicyclo, such as 2-azabicyclo [2.1.1] hexane, 2-azabicyclo [2.2.1] heptane, 2, 5-diazabicyclo [2.2.1] heptane, 2-azabicyclo [2.2.2] octane, and 2, 5-diazabicyclo [2.2.2] octane.
As used herein, the term "aryl" refers to a carbocyclic aromatic group containing 5 to 10 atoms. Representative examples include, but are not limited to, phenyl (benzene), tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracenyl, fluorenyl, indenyl, and azulenyl. The carbocyclic aromatic group may be unsubstituted or optionally substituted.
As used herein, the term "heteroaryl" refers to 5 to 10 membered aromatic heterocycles having at least one heteroatom selected from nitrogen, oxygen and sulfur and containing at least 1 carbon atom, including monocyclic and bicyclic ring systems. Representative heteroaryl groups are furan, 4H-pyran, pyrrole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, thiophene, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, benzofuran, benzothiophene, quinoline, dihydroquinoline, isoquinoline, dihydroisoquinoline, indole, benzoxazole, benzimidazole, benzothiazole, cinnoline (cinnoline), phthalazine, quinazoline, 1H-aza(1H-azepine), thiadiazole, tetrahydroisoquinoline, tetrahydropyrazolopyrazine, and the like.
In the present specification, orIndicating connection to another part.
Preferably, in various aspects such as BTK degradation activity, (metabolic) stability, physicochemical properties, and the like, a preferred embodiment of the present invention provides a compound represented by formula 1 or a pharmaceutically acceptable salt thereof, wherein
A is a carbocycle, heterocycle, aryl or heteroaryl,
R 1a and R 1b are each independently H, halogen, C 1-6 alkyl or C 1-6 alkoxy, wherein one or more hydrogens of the alkyl or alkoxy groups are optionally substituted with one or more selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 haloalkyl, hydroxy and C 1-3 hydroxyalkyl,
R 2a and R 2b are each independently H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxy or C 1-6 hydroxyalkyl,
R 3 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl or-NH 2,
X 1 and X 2 are each independently CH or N,
Y 1 is NH or O, and the group consisting of,
N is an integer of 0,1 or 2,
L is a compound represented by the following chemical formula 2,
[ Chemical formula 2]
In the chemical formula 2, the chemical formula is shown in the drawing,
B is aryl or heteroaryl, wherein one or more hydrogens in the aryl or heteroaryl are optionally substituted with one or more selected from the group consisting of C 1-3 alkyl, halogen, and C 1-3 haloalkyl,
C 1 and C 2 are each independently a direct bond, a carbocycle or a heterocycle, wherein one or more hydrogens in the carbocycle or heterocycle are optionally substituted with one or more selected from the group consisting of C 1-3 alkyl, halogen and hydroxy,
D 1 and D 2 are each independently a direct bond, -O-, -N (R 4) - -, C (O) - -, -CC-, -C (O) NH-, or-NHC (O) - -, where R 4 is H, C 1-3 alkyl or C 1-3 haloalkyl,
Q 1、q2、q3 and q 4 are each independently integers from 0 to 3,
E is the following chemical formula 3 or chemical formula 4,
[ Chemical formula 3]
[ Chemical formula 4]
In the chemical formulas 3 and 4,
X 3、X4、X5 and X 6 are each independently CH or N,
Y 2 is -C(R6a)(R6b)-、-C(O)-、-C(R6a)＝C(R6b)-、-C(R6a)＝N-、-N＝C(R6a)- or-n=n-,
Z is a direct bond, -C (R 6a)(R6b)-、-N(R6a) -, -O-, or-C (O) NH-,
R 5a and R 5b are each independently H, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl or C 1-6 haloalkoxy, and R 6a and R 6b are each independently H, halogen, C 1-3 alkyl or C 1-3 haloalkyl.
More preferably, in various aspects such as BTK degradation activity, (metabolic) stability, physicochemical properties, and the like, particularly in terms of BTK degradation activity, a more preferred embodiment of the present invention provides a compound represented by formula 1 or a pharmaceutically acceptable salt thereof, wherein
A is azetidine, pyrrolidine, piperidine, piperazine, benzene, pyridine, pyrimidine, pyrazole, triazole, oxazole, thiazole, oxadiazole or thiadiazole,
R 1a and R 1b are each independently H, halogen, C 1-6 alkyl or C 1-6 alkoxy, wherein one or more hydrogens of the alkyl or alkoxy groups are optionally substituted with one or more selected from the group consisting of halogen, C 1-3 alkyl and hydroxy,
R 2a and R 2b are each independently H, halogen, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 hydroxyalkyl,
R 3 is H or halogen, and the halogen,
X 1 is CH or N, and,
X 2 is a group of CH (CH),
Y 1 is NH or O, and the group consisting of,
N is an integer of 0,1 or 2,
L is a compound represented by the following chemical formula 2,
[ Chemical formula 2]
In the chemical formula 2, the chemical formula is shown in the drawing,
B is benzene, pyridine, pyrimidine, pyrazine, pyridazine, tetrahydroisoquinoline, pyrazole, triazole or tetrahydropyrazolopyrazine,
C 1 and C 2 are each independently a direct bond, a cyclobutane, a cyclohexane, an azetidine, a pyrrolidine, a piperidine or a piperazine, wherein one or more hydrogens of the cyclobutane, cyclohexane, azetidine, pyrrolidine, piperidine or piperazine are optionally substituted with one or more selected from the group consisting of C 1-3 alkyl, halogen and hydroxy,
D 1 and D 2 are each independently of the other a direct bond, -O-, -NH-, -C (O) NH-or-NHC (O) -,
Q 1、q2、q3 and q 4 are each independently integers from 0 to 3,
E is the following chemical formula 3 or chemical formula 4,
[ Chemical formula 3]
[ Chemical formula 4]
In the chemical formulas 3 and 4,
X 3、X4、X5 and X 6 are each independently CH or N,
Y 2 is-CH 2 -or-C (O) -,
Z is a direct bond, -NH-or-O-, and
R 5a or R 5b are each independently H, halogen, C 1-3 alkyl or C 1-3 alkoxy.
Preferably, in the BTK PROTAC compound according to the invention, the part to the left of the linker (L) (BTK ligand) is one of the following structures. When it has the following structure, BTK degradation activity is excellent and more suitable for various purposes of the present invention.
Preferably, in the BTK PROTAC compound according to the invention, the linker (L) is any one of the following linkers.
When it has the following linker, BTK degradation activity is excellent and more suitable for various purposes of the present invention.
Preferably, in the BTK PROTAC compound according to the invention, the part to the right of the linker (L) (CRBN ligand) is one of the following structures. When it has the following structure, BTK degradation activity is excellent and more suitable for various purposes of the present invention.
Non-limiting examples of compounds of formula 1 according to the present disclosure are the compounds prepared in the following examples. Each example number corresponds to each compound number. For example, the final compound prepared in example 10 is numbered compound 10.
Of these compounds, the compounds of the following table 1 are particularly preferred in terms of BTK degradation activity.
TABLE 1
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As used herein, the term "pharmaceutically acceptable salt" refers to salts prepared from the active compounds according to the present disclosure with relatively non-toxic acids or bases, depending on the particular substituents of those compounds. When the compounds have relatively acidic groups, base addition salts can be obtained by contacting the neutral compound with a sufficient amount of the desired base and a pure or inert solvent. Suitable pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, ammonium, organic amino salts, magnesium salts, and the like. When the compounds have relatively basic groups, the acid addition salts may be obtained by contacting the neutral compound with a sufficient amount of the desired acid and a pure or inert solvent. Suitable pharmaceutically acceptable acid addition salts include those derived from: non-toxic organic acids including, but not limited to, acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like, and non-toxic inorganic acids including, but not limited to, hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic, phosphorous, and the like. It also includes salts of amino acids such as arginine or analogues thereof, and also includes analogues of organic acids such as glucuronic acid or galacturonic acid. Some specific compounds of the present disclosure have both basic and acidic functionalities for converting the compounds into basic or acidic partial (addition) salts. Other examples of salts are well known from literature known in the art to which the present invention pertains.
As used herein, the phrase "compounds of the present invention" includes any compound of chemical formula 1 and isotopic variations, clathrates (clathrate), hydrates, solvates, or polymorphs thereof. Also, even though the term "compound of the present invention" does not refer to a pharmaceutically acceptable salt thereof, the term includes salts thereof. In one embodiment, compounds of the present disclosure include stereochemically pure compounds, e.g., substantially free of other stereoisomers (e.g., greater than 85% ee, greater than 90% ee, greater than 95% ee, greater than 97% ee, or greater than 99% ee). That is, if the compound of formula 1 or a salt thereof according to the present disclosure is a tautomer and/or stereoisomer (e.g., geometric isomer and conformational isomer), such isolated isomers and mixtures thereof are also included within the scope of the present disclosure. If a compound of the present disclosure or a salt thereof has asymmetric carbon in its structure, its active optical isomers and racemic mixtures thereof are also included within the scope of the present disclosure.
As used herein, the term "isotopic variant" refers to a compound comprising an abnormal proportion of an isotope at one or more atoms comprising the compound. For example, isotopic variants of the compounds can be radiolabeled. For example, the hydrogen atom may be selected from hydrogen, deuterium, and tritium, and the isotopic variant may comprise carbon 13 (13 C), nitrogen 15 (15 N), and the like.
As used herein, the term "polymorph" refers to a solid crystalline form of a compound of the present disclosure or a complex thereof. Different polymorphs of the same compound may exhibit different physical, chemical and/or spectroscopic properties. Different physical properties include, but are not limited to, stability (e.g., stability to heat or light), compressibility and density (important in formulation and product manufacturing), and dissolution rate (which may affect bioavailability). The difference in stability may be due to a change in chemical reactivity (e.g., differential oxidation such that the dosage form changes color faster when composed of one polymorph than when composed of another polymorph) or mechanical properties (e.g., the tablet disintegrates upon storage because the kinetically favored polymorph converts to a thermodynamically more stable polymorph) or both (e.g., a tablet of one polymorph is more prone to decomposition at high humidity). The different physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form solvates than another polymorph, or may be more difficult to filter or wash out impurities, e.g., due to the shape or size distribution of its particles.
As used herein, the term "solvate" refers to a compound according to the present disclosure or a salt thereof, which further comprises a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic and acceptable for administration to humans in trace amounts.
As used herein, the term "hydrate" refers to a compound according to the present disclosure or a salt thereof, which further comprises a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
As used herein, the term "clathrate" refers to a compound or salt thereof in lattice form that contains spaces (e.g., channels) within which guest molecules (e.g., solvents or water) are captured.
As used herein, the term "purified" refers to an isolate that is greater than 90% pure, in one embodiment greater than 95% pure, in another embodiment greater than 99% pure, and in another embodiment greater than 99.9% pure when isolated.
Medical use and method of treatment of compounds according to the invention
The invention also provides methods for treating a disease or disorder in a subject suffering from or susceptible to such a disease or disorder by administering to the subject a therapeutically effective amount of one or more compounds as described above. In one embodiment, the treatment is prophylactic treatment. In another embodiment, the treatment is palliative. In another embodiment, the treatment is restorative.
1. Diseases or conditions
The compounds of the invention for degrading BTK are useful for a variety of therapeutic or prophylactic uses (e.g., autoimmune diseases or cancers). These compounds are useful for degrading BTK to reduce BTK activity, and for treating BTK-related diseases or preventing exacerbations of such diseases. Accordingly, the present invention provides a method for degrading BTK in a cell. In this method, the cells are contacted with an effective amount of a compound of the invention. In one embodiment, the cell is present in a subject. The methods of the invention comprise administering to a subject in need of treatment or prevention a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound according to the invention.
In one embodiment, the invention provides a method of degrading BTK in a cell of a BTK-related disorder. For example, the present invention can be used to degrade BTK in cells of a subject suffering from a BTK-related disease (which will be described later) and thus reduce BTK activity. In another embodiment of the invention, the invention can be used to degrade BTK in cells of autoimmune diseases, cancer, and the like.
In another embodiment, the invention provides a method of treating a BTK-related disease comprising administering to a subject a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof. Such methods comprise administering to a subject in need of treatment an amount (i.e., a therapeutically effective amount) of a compound of the invention sufficient to degrade BTK. In such methods, the compounds of the invention may be administered to a subject in the form of a pharmaceutical composition as described herein.
In one embodiment of the invention, the BTK-related disease is cancer. Cancer refers to solid cancer or hematological cancer. Solid cancers include, but are not particularly limited to, brain tumors, benign astrocytomas, malignant astrocytomas, pituitary adenomas, meningiomas, brain lymphomas, oligodendrogliomas, intracranial tumors, ependymomas, brain stem tumors, head and neck tumors, laryngeal carcinoma, oropharyngeal carcinoma, nasal cavity carcinoma, nasopharyngeal carcinoma, salivary gland carcinoma, hypopharyngeal carcinoma, thyroid carcinoma, oral carcinoma, breast tumors, small cell lung carcinoma, non-small cell lung carcinoma, thymus carcinoma, mediastinal tumor, esophageal carcinoma, breast carcinoma, male breast carcinoma, abdominal tumors, stomach cancer, liver cancer, gall bladder carcinoma, biliary tract carcinoma, pancreatic carcinoma, small intestine carcinoma, colon carcinoma, anal carcinoma, bladder carcinoma, kidney carcinoma, male genital carcinoma, penis carcinoma, prostate carcinoma, female genital carcinoma, cervical carcinoma, endometrial carcinoma, ovarian carcinoma, uterine sarcoma, vaginal carcinoma, female external genitalia carcinoma, female urinary tract carcinoma, or skin carcinoma. In addition, hematological cancers may include, but are not particularly limited to, leukemia, malignant lymphoma, multiple myeloma, or aplastic anemia.
In another embodiment of the invention, the BTK-related disease is an autoimmune disease. Autoimmune diseases including but not particularly limited to rheumatoid arthritis, psoriatic arthritis, osteoarthritis, still's disease, juvenile arthritis, lupus, diabetes, myasthenia gravis, hashimoto's thyroiditis, ord ' sthyroiditis, graves ' disease, sjogren's syndromeSyndome), multiple sclerosis, guillain-barre syndrome (Guillain-barre syndrome), acute disseminated encephalomyelitis, addison's disease, ocular clonic-myoclonus syndrome, ankylosing myelitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, chronic digestive system disease, goodpasts syndrome (goodpasture syndrome), idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, takayasu' S ARTERITIS), temporal arteritis, autoimmune hemolytic anemia, wegener's granulomatosis, psoriasis, alopecia universalis (alopecia universalis), behcet's disease, chronic fatigue, autonomic nerve dysfunction, endometriosis, interstitial cystitis, neuromuscular dystonia and pain. It may be selected from the group consisting of pain, but is not particularly limited thereto.
In a preferred embodiment of the invention, the BTK-related disease is leukemia (e.g., lymphoblastic leukemia, B-cell leukemia, prolymphocytic leukemia, myelogenous leukemia, hairy cell leukemia, acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML), chronic Lymphocytic Leukemia (CLL), acute Lymphoblastic Leukemia (ALL), T-cell leukemia, T-cell acute lymphoblastic leukemia (T-ALL), myeloproliferative disease), lymphoma (e.g., B-cell lymphoma, central nervous system lymphoma, follicular lymphoma, non-hodgkin lymphoma), Hodgkin's lymphoma, lymphocytic lymphoma, mantle cell lymphoma, burkitt's lymphoma, B cell diffuse lymphoma, marginal zone lymphoma, small cell lymphoma, lymphoplasmacytoid lymphoma, rickettsia's transformation (rickettsia syndrome), small Lymphocytic Lymphoma (SLL), diffuse Large B Cell Lymphoma (DLBCL), immunoblastic large cell lymphoma, precursor B cell lymphoma (B-LBL), lymphoblastic lymphoma, primary mediastinal large B cell lymphoma (PMBCL), intravascular large B cell lymphoma (IVLBCL), primary exudative lymphoma, T cell lymphoma, Lymphomatoid granuloma (LYG), post-transplant lymphoproliferative disorder (PTLD)), solid cancers (e.g., ependymoma, medulloblastoma, glioblastoma, primitive neuroectodermal tumors, non-small cell lung cancer, breast cancer, pancreatic cancer, gastroesophageal cancer, metastatic pancreatic cancer, central nervous system cancer, brain cancer, lung cancer, head and neck cancer, esophageal and esophageal-gastric junction cancer, gastric cancer, colorectal cancer, rectal cancer, anal cancer, hepatobiliary cancer, non-melanoma skin cancer, melanoma, renal cancer, prostate cancer, bladder cancer, uterine cancer, cervical cancer, ovarian cancer, bone cancer, neuroendocrine cancer, mesothelioma, testicular cancer, Thymoma and thymus cancer, thyroid cancer), autoimmune diseases (e.g., rheumatoid arthritis, autoimmune hemolytic anemia, warm-antibody autoimmune hemolytic anemia, chronic idiopathic urticaria (CSU), food allergies, immune thrombocytopenia, sjogren's syndrome, systemic lupus erythematosus, allergic diseases, allergic reactions, systemic juvenile idiopathic arthritis (SOJIA), pemphigus vulgaris, immune thrombocytopenic purpura, myasthenia gravis, anti-neutrophil cytoplasmic antibody (ANCA) related vasculitis, cryoglobulinemia, chronic autoimmune urticaria, atopic dermatitis, Contact dermatitis, allergic rhinitis, ulcerative colitis, crohn's disease, godpas's syndrome, anti-GBM/anti-TBM nephritis, hashimoto thyroiditis, graves ' disease, cardiac achalasia, addison's disease, adult Steve's disease, alopecia areata, amyloidosis, ankylosing spondylitis, anti-phospholipid syndrome, autoimmune angioedema, autoimmune autonomic dysfunction, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune Inner Ear Disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, Axonal and neuronal neuropathy (AMAN), baluo disease (Balo disease), behcet's disease, benign mucosal pemphigoid, bullous pemphigoid, kattman's disease (CASTLEMAN DISEASE, CD), celiac disease, chronic Inflammatory Demyelinating Polyneuropathy (CIDP), chronic Recurrent Multifocal Osteomyelitis (CRMO), cheerger-Strauss Syndrome (CSS), eosinophilic Granulomatosis (EGPA), cicatricial pemphigoid, kogan's Syndrome (covan's Syndrome), Cold lectin disease, congenital heart block, coxsackie myocarditis, CREST syndrome, crohn's disease, dermatitis herpetiformis, dermatomyositis, devic's disease, neuromyelitis optica, discoid lupus, post myocardial infarction syndrome (Dressier's syndrome), endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, primary mixed cryoglobulinemia, ewens syndrome (evans syndrome), fibromyalgia, Fibroalveolitis, giant cell arteritis, temporal arteritis, giant cell myocarditis, glomerulonephritis, granulomatous polyangiitis, green-barre syndrome, allergic purpura (Henoch-Schonlein purpura, HSP), herpes gestation, pemphigoid Gestation (PG), abnormal acne, hypogammaglobulinemia, igA nephropathy, igG 4-related sclerotic diseases, inclusion Body Myositis (IBM), interstitial Cystitis (IC), juvenile arthritis, juvenile diabetes, juvenile Myositis (JM), kawasaki disease (KAWASAKI DISEASE), lanbert-Eaton syndrome (Lambert-Eaton syndrome), pregnancy, White blood cell disruption vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus, meniere's disease, microscopic polyangiitis (microscopic poly angiitis, MPA), mixed Connective Tissue Disease (MCTD), silkworm-erosive corneal ulcers (Mooren's ulcer), mu Ka-Habermann disease (Mucha-Habermann disease), multifocal Motor Neuropathy (MMN), myositis, narcolepsy, neonatal lupus erythematosus, Neutropenia, ocular scarring pemphigoid, optic neuritis, recurrent rheumatism (PR), paraneoplastic Cerebellar Degeneration (PCD), paroxysmal sleep hemoglobinuria (PNH), para-Luo Ershi syndrome (Parry Romberg syndrome), exo Zhou Putao membranitis, parkinna-Tener syndrome (Parsonnage-Tumer syndrome), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious Anemia (PA), polyarteritis nodosa, polyadendria syndrome, polymyalgia rheumatica, polymyositis, post myocardial infarction syndrome, Post-pericardial-incision syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red blood cell dysgenesis (PRCA), pyoderma gangrenosum, raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophia, recurrent polychondritis, restless Leg Syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, sarcoidosis, schmidt syndrome (Schmidt syndrome), scleritis, scleroderma, sperm and testis autoimmunity, stiff Person Syndrome (SPS), subacute Bacterial Endocarditis (SBE), susac syndrome, Sympathogenic Ophthalmia (SO), aortic inflammation (Takayasu' S ARTERITIS), thrombocytopenic purpura (TTP), tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes, undifferentiated Connective Tissue Disease (UCTD), uveitis, vasculitis, vitiligo, granulomatous Polyangiitis (GPA), systemic sclerosis), fahrenheit, B cell malignancy, recurrent mature B cell tumor, multiple myeloma, multiple sclerosis, graft-versus-host disease, agaropectinemia, hepatitis, neuromyelitis optica, myelodysplastic syndrome (MDS), plasmacytoma, asthma, chronic Obstructive Pulmonary Disease (COPD), transplant rejection, gout, atherosclerosis, inflammatory bowel disease, pancreatitis, B-cell mediated hyperacute disease, thromboembolic disease, pulmonary embolism, polycythemia vera, essential thrombocythemia, myelofibrosis with myelogenesis, or acute inflammatory disease.
That is, the present invention provides a medical use of the compound of formula 1 or a pharmaceutically acceptable salt thereof for treating or preventing the above-mentioned diseases.
2. Object(s)
Suitable subjects for treatment according to the present invention include mammalian subjects. Mammals according to the present disclosure include, but are not limited to, humans, canines, felines, bovines, caprines, equines, ovines, porcines, rodents, lagines, primates, and the like, and encompass intrauterine mammals.
In one embodiment, a suitable subject for treatment according to the present invention is a human.
3. Administration and dosage
The compounds of the present invention are generally administered in a therapeutically effective amount.
As used herein, "effective amount" refers to an amount of a compound of the invention sufficient to slow or minimize the progression of a BTK-related disease or provide a therapeutic benefit in the treatment or management of a BTK-related disease. An "effective amount" also refers to an amount sufficient to inhibit or reduce BTK activity in vitro or in vivo.
The compounds of the invention may be administered by any suitable route, in the form of a pharmaceutical composition suitable for that route, and in a dosage effective for the intended treatment. The effective dose is generally in the range of about 0.001 to about 100mg/kg body weight/day, preferably about 0.01 to about 50 mg/kg/day, and is applicable in single or divided doses. Dosage levels below the lower limit of this range may be suitable depending on the age, species and disease or condition being treated. In other cases, larger doses may be used without adverse side effects. The larger dose may also be divided into several smaller doses for administration throughout the day.
Pharmaceutical compositions of the compounds of the invention
In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In one embodiment of the invention, the pharmaceutical composition is for use in the treatment or prevention of BTK related diseases, preferably autoimmune diseases or cancers as described above.
The term "pharmaceutically acceptable" refers to those compositions which are suitable for use as pharmaceutical formulations and which are generally considered safe for such use. The term also means that it has been officially approved by a regulatory agency of the country for this use or is listed in the korean pharmacopoeia or united states pharmacopoeia.
Pharmaceutical compositions, dosage forms and routes of administration
For the treatment of the above diseases or conditions, the compounds described herein or pharmaceutically acceptable salts thereof may be administered as follows:
Oral administration
The compounds of the invention may be administered orally, including by swallowing, such that the compound enters the gastrointestinal tract, or directly from the oral cavity into the blood stream (e.g., buccal or sublingual administration).
Suitable compositions for oral administration include solid, liquid, gel or powder formulations and have dosage forms such as tablets, troches, capsules, granules or powders.
Compositions for oral administration may optionally be coated with an enteric coating and may exhibit delayed or sustained release by the enteric coating. That is, the composition for oral administration according to the present invention may be a formulation having an immediate release mode or a modified release mode.
Liquid formulations may include solutions, syrups and suspensions, which may be used in soft or hard capsules. Such formulations may comprise a pharmaceutically acceptable carrier, such as water, ethanol, polyethylene glycol, cellulose or oil. The formulation may also contain one or more emulsifying and/or suspending agents.
In a tablet dosage form, the drug, active ingredient may be present in an amount of from about 0.05% to about 95% by weight of the dosage form, more typically from about 2% to about 50% by weight. Additionally, the tablets may contain a disintegrant in an amount of about 0.5% to about 35% by weight of the dosage form, more typically about 2% to about 25% by weight. Examples of disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.
Suitable lubricants for tablets may be present in amounts of about 0.1% to about 5% by weight and include, but are not limited to, talc, silica, stearic acid, calcium stearate, zinc or magnesium stearate, sodium stearyl fumarate, and the like.
Suitable binders for tablets include, but are not limited to, gelatin, polyethylene glycol, sugar, gums, starches, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and the like. Suitable diluents for tablets include, but are not limited to, mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, microcrystalline cellulose, and starch.
Suitable solubilizing agents for tablets may be present in amounts of about 0.1% to about 3% by weight and include, but are not limited to, polysorbate, sodium lauryl sulfate, propylene carbonate, diethylene glycol monoethyl ether, dimethyl isosorbide, polyethylene glycol (natural or hydrogenated) castor oil, HCOR TM( Nikkol), oil esters, gelucire TM, caprylic/caprylic mono/diglycerides, sorbitan fatty acid esters, and Solutol HS TM.
Parenteral administration
The compounds of the present disclosure may be administered directly into the blood stream, muscle or internal organs. Modes of administration suitable for parenteral include intravenous, intramuscular, subcutaneous, intraarterial, intraperitoneal, intrathecal, intracranial and the like. Suitable devices for parenteral administration include syringes (including needle syringes and needleless syringes) and infusion methods.
Compositions for parenteral administration may be formulated for immediate release or modified release, including delayed release or sustained release.
Most parenteral formulations are liquid compositions and liquid compositions are aqueous solutions comprising an active ingredient according to the invention, salts, buffers, isotonic agents and the like.
Parenteral formulations may also be prepared in dehydrated form (e.g., by lyophilization) or as sterile non-aqueous solutions. These formulations may be used with a suitable carrier, such as sterile water. Solubilizers may also be used to prepare parenteral solutions.
Topical application
The compounds of the present invention may be applied topically to the skin or transdermally. Formulations for such topical application may include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches and the like. Pharmaceutically acceptable carriers for topical formulations may include water, alcohols, mineral oils, glycerin, polyethylene glycols, and the like. Topical application may also be by electroporation, iontophoresis, phonophoresis, and the like.
Compositions for topical application may be formulated for immediate or modified release, including delayed or sustained release.
[ Advantageous effects ]
The present disclosure provides compounds capable of exhibiting various pharmacological activities due to very good BTK degradation activity, pharmaceutical compositions comprising the compounds as active ingredients, their medical uses (especially autoimmune diseases or cancers), and therapeutic or prophylactic methods, comprising administering the compounds to a subject in need of such treatment or prevention. The compound according to the present invention or a pharmaceutically acceptable salt thereof is excellent in various aspects such as BTK degradation activity, (metabolic) stability, physicochemical properties, and the like, and in particular, BTK degradation activity is far superior to compounds having similar structures.
Detailed Description
The present invention is described in considerable detail below by way of examples to aid those skilled in the art in understanding the present invention. However, the following examples are provided for illustration and are not intended to limit the scope of the invention. It will be apparent that various changes may be made without departing from the spirit and scope of the invention or sacrificing all of its material advantages.
Preparation of the Compounds of the invention
In the following, some synthetic methods of the compounds of the present invention will be described, and other compounds not mentioned below may be prepared in a similar manner by replacing starting materials, intermediates and/or reactants.
Intermediate 1-1: n- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Step 1: synthesis of N- (4-bromo-2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Triphosgene (0.78 g,2.63 mmol) and (4-bromo-2-methylphenyl) methylamine (1.50 g,7.50 mmol) were suspended in DCM (60 mL) and stirred at 0deg.C. After triethylamine (2.60 mL,18.75 mmol) was added to the reaction solution, 3-isopropoxyazetidine hydrochloride (1.36 g,9.0 mmol) was diluted in DCM (20 mL) and added thereto slowly. After stirring at room temperature for 1 hour, distilled water (50 mL) was added and extracted with DCM (30 ml×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (1-3% MeOH/DCM) and 1.86g (76%) of a colorless liquid was obtained.
Step 2: synthesis of 3-isopropoxy-N- (2-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) azetidine-1-carboxamide
N- (4-bromo-2-methylbenzyl) -3-isopropoxy-azetidine-1-carboxamide (1.86 g,5.45 mmol), 4', 5',5 '-octamethyl-2, 2' -bis (1, 3, 2-dioxaborolan) (1.66 g,6.54 mmol), pd (dppf) Cl 2 (0.08 g,0.11 mmol) and KOAc (1.60 g,16.35 mmol) were suspended in dioxane (20 mL) and stirred at 100℃for 16 hours. Distilled water (50 mL) was added to the reaction solution, followed by extraction with EtOAc (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (20-50% EtOAc/hexanes) to give 1.43g (68%) of a colorless liquid.
Step 3: synthesis of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
3-Isopropoxy-N- (2-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) azetidine-1-carboxamide (1.43 g,3.68 mmol), 2, 4-dichloropyrimidine (0.66 g,4.42 mmol), pd (dppf) Cl 2 (54 mg,2 mol%) and K 2CO3 (1.53 g,11.04 mmol) were suspended in dioxane (24 mL) and H 2 O (6 mL) and stirred at 90℃for 2 hours. Distilled water (50 mL) was added to the reaction solution, followed by extraction with EtOAc (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (50-90% EtOAc/hexanes) to give 1.12g (81%) of a white solid.
Intermediates 1-2 and 1-3 were synthesized using the same method as the synthesis of intermediate 1-1.
Intermediate 1-4:1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide
Step 1: synthesis of N- (4-bromo-2-methylbenzyl) -1- (tert-butyl) -1H-pyrazole-4-carboxamide
1- (Tert-butyl) -1H-pyrazole-4-carboxylic acid (0.46 g,2.75 mmol) was suspended in DMF (8 mL). Then, HATU (1.14 g,3.00 mmol), DIPEA (1.3 mL,7.50 mmol) and (4-bromo-2-methylphenyl) methylamine (0.5 g,2.50 mmol) were added and stirred at room temperature for 16 hours. Aqueous NHCl 4 (80 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (20-50% EtOAc/hexanes) to give 0.72g (82%) of a white solid.
Step 2: synthesis of 1- (tert-butyl) -N- (2-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) -1H-pyrazole-4-carboxamide
N- (4-bromo-2-methylbenzyl) -1- (tert-butyl) -1H-pyrazole-4-carboxamide (0.40 g,1.14 mmol), 4', 5',5 '-octamethyl-2, 2' -bis (1, 3, 2-dioxaborolan) (0.29 g,1.14 mmol), pd (dppf) Cl 2 (0.08 g,0.11 mmol) and KOAc (0.34 g,3.43 mmol) were suspended in dioxane (12 mL) and stirred at 100℃for 16 hours. Distilled water (50 mL) was added to the reaction solution and extracted with EtOAc (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (20-40% EtOAc/hexanes) to give 0.33g (73%) of a colorless liquid.
Step 3: synthesis of 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide
1- (Tert-butyl) -N- (2-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) -1H-pyrazole-4-carboxamide (0.33 g,0.83 mmol), 2, 4-dichloropyrimidine (0.15 g,1.00 mmol), pd (dppf) Cl 2 (12 mg,2 mol%) and K 2CO3 (0.34 g,2.49 mmol) were suspended in dioxane (8 mL) and H 2 O (2 mL) and stirred at 90℃for 2H. Distilled water (50 mL) was added to the reaction solution, extracted with EtOAc (20 mL x 3), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (50-80% EtOAc/hexanes) to give 0.15g (48%) of a bright yellow solid.
Intermediates 1-5 to 1-7 were synthesized using the same method as the synthesis of intermediate 1-4.
Intermediate 1-8: n- (3- (2-chloropyrimidin-4-yl) -5-fluoro-2-methylphenyl) -3-isopropoxy-azetidine-1-carboxamide
Step 1: synthesis of 5-fluoro-2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline
3-Bromo-5-fluoro-2-methylaniline (1.00 g,4.90 mmol), 4', 5',5 '-octamethyl-2, 2' -bis (1, 3, 2-dioxaborolan) (1.49 g,5.88 mmol), KOAc (1.44 g,14.70 mmol) and Pd (dppf) Cl 2 (36 mg,0.05 mmol) were suspended in 1, 4-dioxan (15 mL) and stirred at 100℃for 16 hours. Brine (130 mL) was added to the reaction solution and extracted with EtOAc (40 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (25% EtOAc/hexanes) to give 840mg (68%) of a white solid.
Step 2: synthesis of N- (5-fluoro-2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -3-isopropoxy azetidine-1-carboxamide
Triphosgene (351 mg,1.18 mmol) was suspended in DCM (10 mL). 5-fluoro-2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (850 mg,3.38 mmol) and TEA (0.47 mL,3.38 mmol) were dissolved in DCM (9.5 mL) and added slowly at 0deg.C. 3-Isopropoxylazetidine hydrochloride (513.26 mg,3.38 mmol) and TEA (0.47 mL,3.38 mmol) were dissolved in DCM (19.5 mL) and slowly added to the reaction solution at 0deg.C followed by stirring at room temperature for 3 hours. Distilled water (30 mL) was added to the reaction solution and extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (20% EtOAc/hexanes) to give 560mg (42%) of a white solid.
Step 3: synthesis of N- (3- (2-chloropyrimidin-4-yl) -5-fluoro-2-methylphenyl) -3-isopropoxy azetidine-1-carboxamide
N- (5-fluoro-2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -3-isopropoxyazetidine-1-carboxamide (560 mg,1.42 mmol), 2, 4-dichloropyrimidine (255 mg,1.71 mmol), pd (dppf) Cl 2 (102 mg,0.14 mmol) and K 2CO3 (292 mg,4.28 mmol) were suspended in 1, 4-dioxan-e: H 2 O=4:1 (4.4 mL) and stirred at 90℃for 3 hours. The reaction solution was filtered and concentrated under reduced pressure, and the resulting residue was MPLC (50-100% EtOAc/hexanes) to give 170mg (31%) of a white solid.
Intermediate 1-9:1- (tert-butyl) -N- (3- (2-chloropyrimidin-4-yl) -5-fluoro-2-methylphenyl) -1H-pyrazole-4-carboxamide
Step 1: synthesis of 1- (tert-butyl) -N- (5-fluoro-2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-pyrazole-4-carboxamide
5-Fluoro-2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (685.5 mg,2.73 mmol) and TEA (0.54 mL,4.0 mmol) were suspended in DCM (8.6 mL). 1- (tert-butyl) -1H-pyrazole-4-carbonyl chloride (442 mg,2.60 mmol) was then slowly added at 0℃and stirred at room temperature for 4 hours. Distilled water (20 mL) was added to the reaction solution and extracted with DCM (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (0-25% EtOAc/hexanes) to give 720mg (66%) of a white solid.
Step 2: synthesis of 1- (tert-butyl) -N- (3- (2-chloropyrimidin-4-yl) -5-fluoro-2-methylphenyl) -1H-pyrazole-4-carboxamide
1- (Tert-butyl) -N- (5-fluoro-2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-pyrazole-4-carboxamide (700 mg,1.74 mmol), 2, 4-dichloropyrimidine (300 mg,2.01 mmol), pd (dppf) Cl 2 (124.4 mg,0.17 mmol) and K 2CO3 (323 mg,5.23 mmol) were suspended in 1, 4-dioxan-e: H 2 O=4:1 (5.4 mL) and stirred at 90℃for 16H. Distilled water (40 mL) was added to the reaction solution, extracted with EtOAc (40 mL x 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (50-70% EtOAc/hexanes) to give 560mg (83%) of a white solid.
Intermediate 1-10:1- (tert-butyl) -N- (3- (2-chloropyrimidin-4-yl) -5-fluoro-2-methylphenyl) -1H-1,2, 3-triazole-4-carboxamide
Step 1: synthesis of 1- (tert-butyl) -N- (5-fluoro-2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-1,2, 3-triazole-4-carboxamide
5-Fluoro-2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) aniline (480 mg,1.90 mmol), 1- (tert-butyl) -1H-1,2, 3-triazole-4-carboxylic acid (320 mg,1.90 mmol), HATU (1.08 g,2.86 mmol) and DIPEA (1.0 mL,5.73 mmol) were suspended in DMF (9.5 mL) and stirred at room temperature for 16H. Distilled water (20 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (50% EtOAc/hexanes) to give 450mg (59%) of a white solid.
Step 2: synthesis of 1- (tert-butyl) -N- (3- (2-chloropyrimidin-4-yl) -5-fluoro-2-methylphenyl) -1H-1,2, 3-triazole-4-carboxamide
1- (Tert-butyl) -N- (5-fluoro-2-methyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-1,2, 3-triazole-4-carboxamide (450 mg,1.12 mmol), 2, 4-dichloropyrimidine (200 mg,1.34 mmol), pd (dppf) Cl 2 (80.5 mg,0.11 mmol) and K 2CO3 (464.4 mg,3.36 mmol) were suspended in 1, 4-dioxan: H 2 O=4:1 (3.5 mL) and stirred at 90℃for 2 hours. The reaction solution was filtered and concentrated under reduced pressure, and the resulting residue was MPLC (25-50% EtOAc/hexanes) to give 205mg (47%) of a yellow solid.
Intermediate 1-11:4- (2-Chloropyrimidin-4-yl) -2-methylbenzyl 3-isopropoxy azetidine-1-carboxylic acid ester
Step 1: synthesis of (2-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanol
(4-Bromo-2-methylphenyl) methanol (400 mg,2.00 mmol), 4', 5',5 '-octamethyl-2, 2' -bis (1, 3, 2-dioxaborolan) (610 mg,2.40 mmol), KOAc (586 mg,6.00 mmol) and Pd (dppf) Cl 2 (88 mg,0.12 mmol) were suspended in 1, 4-dioxan (6 mL), then heated and refluxed for 4 hours. Distilled water (30 mL) was added to the reaction solution, followed by extraction with EtOAc (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (10-15% EtOAc/hexanes) to give 365mg (74%) of a colorless oil.
Step 2: synthesis of 2-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl 3-isopropoxy azetidine-1-carboxylate
(2-Methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) methanol (365 mg,1.47 mmol) and CDI (215 mg,1.32 mmol) were suspended in THF (2 mL) and stirred at room temperature for 16 h. 3-Isopropoxylazetidine hydrochloride (178 mg,1.17 mmol) and TEA (0.20 mL,1.47 mmol) were dissolved in THF (1 mL) and added to the reaction solution, followed by stirring at room temperature for 4 hours. Distilled water (30 mL) was added to the reaction solution and extracted with DCM (40 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (35% EtOAc/hexanes) to give 330mg (58%) of a colorless oil.
Step 3: synthesis of 4- (2-chloropyrimidin-4-yl) -2-methylbenzyl 3-isopropoxy azetidine-1-carboxylic acid ester
2-Methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl 3-isopropoxy azetidine-1-carboxylate (320 mg,0.82 mmol), 2, 4-dichloropyrimidine (146 mg,0.98 mmol), pd (dppf) Cl 2 (59 mg,0.08 mmol) and K 2CO3 (340 mg,2.46 mmol) were suspended in 1, 4-dioxan: H 2 O=4:1 (2.56 mL) and stirred at 90℃for 1.5 hours. Distilled water (30 mL) was added to the reaction solution and extracted with EtOAc (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (50-100% EtOAc/hexanes) to give 250mg (81%) of a colorless oil.
Intermediate 1-12:1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2- (hydroxymethyl) benzyl) -1H-1,2, 3-triazole-4-carboxamide
Step 1: synthesis of 4-bromo-2- (bromomethyl) benzonitrile
4-Bromo-2-methylbenzonitrile (3.0 g,15.30 mmol), N-bromosuccinimide (2.90 g,16.83 mmol) and ACHN (254 mg,1.53 mmol) were suspended in ACN (40 mL), followed by heating and refluxing for 16 hours. Distilled water (30 mL) was added to the reaction solution, followed by extraction with EtOAc (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (0-3% EtOAc/hexanes) to give 3.0g of the mixture.
Step 2: synthesis of 5-bromo-2-cyanobenzyl acetate
4-Bromo-2- (bromomethyl) benzonitrile (3.0 g,10.91 mmol) and KOAc (1.31 g,13.33 mmol) were suspended in DMF (55 mL) and stirred at 80℃for 2 h. Brine (100 mL) was added to the reaction solution and extracted with EtOAc (30 mL x 4). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (0-15% EtOAc/hexanes) to give 1.8g (65% two step yield) of a white solid.
Step 3: synthesis of (2- (aminomethyl) -5-bromophenyl) methanol
5-Bromo-2-cyanobenzyl acetate (1.20 g,4.70 mmol) was suspended in THF (23 mL). Then, a 2M solution of LAH in THF (8 mL,16.0 mmol) was slowly added thereto at 0deg.C and stirred for 6 hours. Sodium potassium L- (+) -tartrate tetrahydrate solution (40 mL) was slowly added to the reaction solution, followed by extraction with EtOAc (30 mL x 4). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 700mg of a mixture.
Step 4: synthesis of N- (4-bromo-2- (hydroxymethyl) benzyl) -1- (tert-butyl) -1H-1,2, 3-triazole-4-carboxamide
(2- (Aminomethyl) -5-bromophenyl) methanol (800 mg,3.70 mmol), 1- (tert-butyl) -1H-1,2, 3-triazole-4-carboxylic acid (751 mg,4.44 mmol), HOBT (750 mg,5.55 mmol), TBTU (1.70 g,5.55 mmol) and DIPEA (1.9 mL,11.10 mmol) were suspended in DCM (20.0 mL) and stirred at room temperature for 4 hours. Distilled water (30 mL) was added to the reaction solution, followed by extraction with EtOAc (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (0-40% EtOAc/hexanes) to give 650mg of the mixture.
Step 5: synthesis of 1- (tert-butyl) -N- (2- (hydroxymethyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) -1H-1,2, 3-triazole-4-carboxamide
N- (4-bromo-2- (hydroxymethyl) benzyl) -1- (tert-butyl) -1H-1,2, 3-triazole-4-carboxamide (300 mg,0.81 mmol), 4', 5',5 '-octamethyl-2, 2' -bis (1, 3, 2-dioxaborolan) (249 mg,0.98 mmol), pd (dppf) Cl 2 (40 mg,5.55 mmol) and KOAc (238 mg,2.43 mmol) were suspended in 1, 4-dioxan (4 mL) and stirred at 100℃for 16 hours. The reaction solution was filtered through celite and concentrated under reduced pressure. The resulting residue was MPLC (0-100% EtOAc/hexanes) to give 340mg of the mixture.
Step 6: synthesis of 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2- (hydroxymethyl) benzyl) -1H-1,2, 3-triazole-4-carboxamide
1- (Tert-butyl) -N- (2- (hydroxymethyl) -4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) -1H-1,2, 3-triazole-4-carboxamide (280 mg,0.67 mmol), 2, 4-dichloropyrimidine (110 mg,0.74 mmol), pd (dppf) Cl 2 (24 mg,0.03 mmol) and K 2CO3 (185 mg,1.34 mmol) were suspended in 1, 4-dioxan-i.e. H 2 O=5:1 (3.35 mL) and stirred at 90℃for 1 hour. The reaction solution was filtered through celite and concentrated under reduced pressure. The resulting residue was MPLC (0-60% EtOAc/hexanes) to give 100mg (6.0%, 4 steps yield) of a bright yellow solid.
Intermediate 2-1:4- (4-Aminophenyl) piperazine-1-carboxylic acid tert-butyl ester
Step 1: synthesis of tert-butyl 4- (4-nitrophenyl) piperazine-1-carboxylate
1-Fluoro-4-nitrobenzene (3.00 g,21.26 mmol) was suspended in ACN (100 mL). Then, 1-Boc-piperazine (4.36 g,23.39 mmol) and DIPEA (11.10 mL,63.78 mmol) were added and stirred at 85℃for 16 hours. The reaction solution was concentrated under reduced pressure, distilled water (100 mL) was added, and extracted with EtOAc (30 ml×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (2% MeOH/DCM) to give 4.53g (77%) of a yellow solid.
Step 2: synthesis of tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate
Tert-butyl 4- (4-nitrophenyl) piperazine-1-carboxylate (2.52 g,8.20 mmol) was suspended in MeOH (40 mL). Then 10% Pd/C (0.44 g,0.41 mmol) was added and stirred under a stream of hydrogen for 2 hours. The reaction solution was filtered and concentrated under reduced pressure and the resulting residue was MPLC (1-3% MeOH/DCM) to give 2.22g (98%) of a gray solid.
Intermediates 2-2 to 2-4 were synthesized using the same method as the synthesis of intermediate 2-1.
Intermediate 2-5:4- (4-Aminophenyl) piperidine-1-carboxylic acid tert-butyl ester
Tert-butyl 4- (4-nitrophenyl) piperidine-1-carboxylate (0.15 g,0.49 mmol) was suspended in MeOH. Then, 10% Pd/C (26 mg) was added and stirred at room temperature under a hydrogen stream for 2 hours. The reaction solution was filtered and concentrated under reduced pressure to give 0.13g (97%) of a gray solid.
Intermediate 2-6:4- (5-Aminopyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester
Step 1: synthesis of 5-nitro-3 ',6' -dihydro- [2,4' -bipyridine ] -1' (2 ' H) -carboxylic acid tert-butyl ester
2-Bromo-5-nitropyridine (500 mg,2.46 mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (761 mg,2.46 mmol), pdCl 2(PPh3)2 (86 mg,0.12 mmol) and 3M Na 2CO3 (2.4 mL,7.4 mmol) were suspended in 1, 4-dioxan (16 mL) and stirred at 100deg.C for 16H. Distilled water (40 mL) was added to the reaction solution, followed by extraction with EtOAc (40 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (15% EtOAc/hexanes) to give 295mg (40%) of a yellow solid.
Step 2: synthesis of tert-butyl 4- (5-aminopyridin-2-yl) piperidine-1-carboxylate
5-Nitro-3 ',6' -dihydro- [2,4' -bipyridine ] -1' (2 ' H) -carboxylic acid tert-butyl ester (290 mg,0.95 mmol) was dissolved in MeOH (160 mL) and DCM (1 mL). Then, 10% Pd/C (140 mg) was added and stirred at room temperature under a hydrogen stream for 15 hours. The reaction solution was filtered and concentrated under reduced pressure to give 262mg (99%) of a white solid.
Intermediate 2-7:4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester
Step 1: synthesis of tert-butyl 4- (4-nitro-1H-pyrazol-1-yl) piperidine-1-carboxylate
4-Nitro-1H-pyrazole (500 mg,4.40 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (560 mg,3.00 mmol), diethyl azodicarboxylate (0.76 mL,4.4 mmol) and triphenylphosphine (1.15 g,4.4 mmol) were suspended in THF (8.8 mL) at 0deg.C and stirred for 10 min. Then, the mixture was stirred at room temperature for 3 days. Distilled water (30 mL) was added to the reaction solution, followed by extraction with EtOAc (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (10% EtOAc/hexanes) to give 474mg (54%) of a colorless oil.
Step 2: synthesis of tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate
Tert-butyl 4- (4-nitro-1H-pyrazol-1-yl) piperidine-1-carboxylate (470 mg,1.59 mmol) was dissolved in MeOH (16 mL). Then, 10% Pd/C (250 mg) was added and stirred at room temperature under a hydrogen stream for 16 hours. The reaction solution was filtered and concentrated under reduced pressure to give 418mg (99%) of a purple oil.
Intermediate 2-8:4- ((1- (4-aminophenyl) piperidin-4-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester
Step 1: synthesis of tert-butyl 4- ((1-benzyl-piperidin-4-yl) methyl) piperazine-1-carboxylate
1-Benzyl-4-piperidinecarbaldehyde (2.0 g,9.84 mmol) and 1-Boc piperazine (2.20 g,1.18 mmol) were suspended in ACN (20 mL) and stirred at room temperature for 30 min. NaBH (OAc) 3 (4.17 g,19.70 mmol) was added and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, aqueous NaHCO 3 was added, and extracted with EtOAc (40 ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (50% EtOAc/hexanes) to give 3.06g (83%) of a white solid.
Step 2: synthesis of tert-butyl 4- (piperidin-4-ylmethyl) piperazine-1-carboxylate
Tert-butyl 4- ((1-benzylpiperidin-4-yl) methyl) piperazine-1-carboxylate (2.52 g,6.74 mmol) was dissolved in MeOH (30 mL). Then, 10% Pd/C (504 mg) was added and stirred under a hydrogen stream at room temperature for 6 hours. The reaction solution was filtered and concentrated under reduced pressure to give 1.89g (99%) of a white solid.
Step 3: synthesis of tert-butyl 4- ((1- (4-nitrophenyl) piperidin-4-yl) methyl) piperazine-1-carboxylate
Tert-butyl 4- (piperidin-4-ylmethyl) piperazine-1-carboxylate (300 mg,1.05 mmol) and 1-fluoro-4-nitrobenzene (124 mg,0.88 mmol) were suspended in ACN (2 mL). Then, DIPEA (0.45 mL,2.64 mmol) was added and stirred at 100deg.C for 16 hours. The reaction solution was concentrated under reduced pressure, distilled water (30 mL) was added, and extracted with EtOAc (30 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was triturated (EtOAc/hexanes) to give 295mg (69%) of a yellow solid.
Step 4: synthesis of tert-butyl 4- ((1- (4-aminophenyl) piperidin-4-yl) methyl) piperazine-1-carboxylate
Tert-butyl 4- ((1- (4-nitrophenyl) piperidin-4-yl) methyl) piperazine-1-carboxylate (290 mg,0.71 mmol) was dissolved in MeOH (3.6 mL). Then, 10% Pd/C (30 mg) was added and stirred under a hydrogen stream at room temperature for 3 hours. The reaction solution was filtered and concentrated under reduced pressure to give 224mg (83.4%) of a gray solid.
Intermediate 2-9:4- ((1- (4-aminophenyl) azetidin-3-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester
Step 1: synthesis of (1- (4-nitrophenyl) azetidin-3-yl) methanol
1-Fluoro-4-nitrobenzene (350 mg,1.68 mmol), azetidin-3-ylmethanol hydrochloride (480 mg,3.90 mmol) and DIPEA (1.85 mL,10.63 mmol) were suspended in DMSO (5 mL) and stirred at 100deg.C for 16 h. Distilled water (50 mL) was added to the reaction solution and extracted with EtOAc (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (2-4% MeOH/DCM) to give 730mg (90%) of an orange solid.
Step 2: synthesis of 1- (4-nitrophenyl) azetidine-3-carbaldehyde
(1- (4-Nitrophenyl) azetidin-3-yl) methanol (350 mg,1.68 mmol) was suspended in DCM (20 mL). Then, DMP (1.40 g,3.36 mmol) was added and stirred at room temperature for 2 hours. An aqueous Na 2S2O3 solution (15 mL) was added to the reaction solution, followed by extraction with DCM (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (1-6% MeOH/DCM) to give 475mg (crude) of a yellow solid.
Step 3: synthesis of tert-butyl 4- ((1- (4-nitrophenyl) azetidin-3-yl) methyl) piperazine-1-carboxylate
1- (4-Nitrophenyl) azetidine-3-carbaldehyde (200 mg,0.97 mmol) and piperazine-1-carboxylic acid tert-butyl ester (298 mg,1.60 mmol) were suspended in DCM (8 mL). Then, naBH (OAc) 3 (564 mg,2.66 mmol) was added and stirred at room temperature for 2 hours. Aqueous NaHCO 3 (20 mL) was added to the reaction solution and extracted with DCM (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (1-3% MeOH/DCM) to give 193mg (53%) of a yellow solid.
Step 4: synthesis of tert-butyl 4- ((1- (4-aminophenyl) azetidin-3-yl) methyl) piperazine-1-carboxylate
Tert-butyl 4- ((1- (4-nitrophenyl) azetidin-3-yl) methyl) piperazine-1-carboxylate (193 mg,0.51 mmol) was suspended in MeOH (3 mL). Then, 10% Pd/C (27 mg) was added and stirred at room temperature under a hydrogen stream for 2 hours. The reaction solution was filtered through celite and concentrated under reduced pressure to give 169mg (95%) of a yellow solid.
Intermediate 2-10:1- (4-aminophenyl) piperidine-4-carboxylic acid tert-butyl ester
Step 1: synthesis of tert-butyl 1- (4-nitrophenyl) piperidine-4-carboxylate
1-Fluoro-4-nitrobenzene (3.0 g,21.26 mmol), piperidine-4-carboxylic acid tert-butyl ester (4.72 g,25.51 mmol) and DIPEA (11 mL,63.78 mmol) were suspended in ACN (38 mL) and stirred at 100deg.C for 16 hours. Distilled water (40 mL) was added to the reaction solution and extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was triturated (EtOAc/hexanes) to give 5.64g (87%) of a yellow solid.
Step 2: synthesis of tert-butyl 1- (4-aminophenyl) piperidine-4-carboxylate
Tert-butyl 1- (4-nitrophenyl) piperidine-4-carboxylate (1.0 g,3.26 mmol) was dissolved in MeOH (16 mL). Then, 10% Pd/C (100 mg) was added and stirred at room temperature under a hydrogen stream for 2 hours. The reaction solution was filtered through celite and concentrated to give 800mg (89%) of a bright pink solid.
Intermediate 2-11:4- (4- (1, 3-dioxolan-2-yl) piperidin-1-yl) aniline
Step 1: synthesis of 1- (4-nitrophenyl) piperidine-4-carbaldehyde
(1- (4-Nitrophenyl) piperidin-4-yl) methanol (0.5 g,2.12 mmol) was suspended in DCM (80 mL). Then, DMP (1.79 g,4.23 mmol) was added and stirred at room temperature for 16 hours. An aqueous Na 2S2O3 solution (100 mL) was added to the reaction solution, followed by extraction with DCM (20 ml×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (20-50% EtOAc/hexanes) to give 0.41g (83%) of a yellow solid.
Step 2: synthesis of 4- (1, 3-dioxolan-2-yl) -1- (4-nitrophenyl) piperidine
1- (4-Nitrophenyl) piperidine-4-carbaldehyde (413 mg,1.76 mmol) was suspended in toluene (20 mL). Then, ethylene glycol (219 mg,3.53 mmol) and PPTS (44 mg,0.18 mmol) were added and stirred at 115℃for 3 hours. Distilled water (50 mL) was added to the reaction solution and extracted with EtOAc (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (1-4% MeOH/DCM) to give 303mg (62%) of a yellow solid.
Step 3: synthesis of 4- (4- (1, 3-dioxolan-2-yl) piperidin-1-yl) aniline
4- (1, 3-Dioxolan-2-yl) -1- (4-nitrophenyl) piperidine (303 mg,1.09 mmol) was suspended in MeOH (10 mL). Then, 10% Pd/C (58 mg) was added and stirred at room temperature under a hydrogen stream for 2 hours. The reaction solution was filtered through celite and concentrated to give 190mg (70%) of a yellow solid.
Intermediate 2-12 was synthesized using the same method as intermediate 2-11.
Intermediate 2-13:4- (4-aminobenzyl) piperazine-1-carboxylic acid tert-butyl ester
Step 1: synthesis of tert-butyl 4- (4-nitrobenzyl) piperazine-1-carboxylate
1- (Chloromethyl) -4-nitrobenzene (887 mg,5.17 mmol), piperazine-1-carboxylic acid tert-butyl ester (1.07 g,5.74 mmol) and TEA (0.78 mL,5.58 mmol) were suspended in ACN (26 mL) and stirred at room temperature for 16 h. Distilled water (30 mL) was added to the reaction solution, followed by extraction with EtOAc (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (0-40% EtOAc/hexanes) to give 1.3g (78%) of a white solid.
Step 2: synthesis of tert-butyl 4- (4-aminobenzyl) piperazine-1-carboxylate
Tert-butyl 4- (4-nitrobenzyl) piperazine-1-carboxylate (1.34 g,4.16 mmol) was dissolved in MeOH (20 mL). Then, 10% Pd/C (134 mg) was added and stirred under a hydrogen stream at room temperature for 16 hours. The reaction solution was filtered through celite and concentrated to give 190mg (16%) of a pale yellow solid.
Intermediate 2-14:4- ((4- (1, 3-dioxolan-2-yl) piperidin-1-yl) methyl) aniline
Step 1: synthesis of (1- (4-nitrobenzyl) piperidin-4-yl) methanol
1- (Chloromethyl) -4-nitrobenzene (3.0 g,17.48 mmol), piperidin-4-ylmethanol (2.0 g,17.48 mmol) and TEA (4.90 mL,35.0 mmol) were suspended in ACN (87 mL) and stirred at room temperature for 16 h. Distilled water (60 mL) was added to the reaction solution, followed by extraction with EtOAc (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (0-4% MeOH/DCM) and gave 2.45g (56%) of a bright yellow solid.
Step 2: synthesis of 1- (4-nitrobenzyl) piperidine-4-carbaldehyde
Oxalyl chloride (0.87 mL,10.18 mmol) was dissolved in DCM (20.0 mL). Then, DMSO (0.75 mL,10.66 mmol) was diluted in DCM (4 mL) and added slowly at-78deg.C. (1- (4-nitrobenzyl) piperidin-4-yl) methanol (1.70 g,6.79 mmol) was diluted in DCM (4 mL) and added slowly and the reaction solution stirred at-78℃for 1 hour. TEA (2.83 mL,20.37 mmol) was diluted in DCM (4 mL) and slowly added at-78deg.C, and the reaction solution was stirred at room temperature for 0.5 h. 1N NaOH (50 mL) was added to the reaction solution and extracted with DCM (30 mL. Times.3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1.56g (92.5%) of a yellow liquid.
Step 3: synthesis of 4- (1, 3-dioxolan-2-yl) -1- (4-nitrobenzyl) piperidine
1- (4-Nitrobenzyl) piperidine-4-carbaldehyde (1.56 g,6.28 mmol), PPTS (158 mg,0.63 mmol) and ethylene glycol (780 mg,12.56 mmol) were suspended in toluene (26 mL) and heated and refluxed for 16 hours. The residue obtained by concentrating the reaction solution was MPLC (0-50% EtOAc/hexane) to give 635mg (35%) of a yellow solid.
Step 4: synthesis of 4- ((4- (1, 3-dioxolan-2-yl) piperidin-1-yl) methyl) aniline
4- (1, 3-Dioxolan-2-yl) -1- (4-nitrobenzyl) piperidine (635 mg,2.17 mmol) was suspended in EtOH (10 mL). SnCl 2 (2.06 g,10.86 mmol) was then added and stirred at 80℃for 3 hours. Aqueous NaHCO 3 (40 mL) was added to the reaction solution, followed by extraction with EtOAc (30 mL x 4). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 530mg (93%) of a yellow solid.
Intermediate 3-1:1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde
Step 1: synthesis of 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione
5-Fluoroisobenzofuran-1, 3-dione (5.00 g,30.10 mmol), 3-aminopiperidine-2, 6-dione hydrochloride (4.95 g,30.10 mmol) and sodium acetate (4.94 mg,60.20 mmol) were suspended in AcOH (50 mL) and stirred at 120℃for 24 hours. The reaction solution was concentrated under reduced pressure, distilled water (30 mL) was added, and the resulting solid was filtered and dried to give 7.55g (90%) of a purple solid.
Step 2: synthesis of 2- (2, 6-dioxopiperidin-3-yl) -5- (4- (hydroxymethyl) piperidin-1-yl) isoindoline-1, 3-dione
2- (2, 6-Dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (300 mg,1.09 mmol), piperidin-4-ylmethanol (149 mg,1.30 mmol) and DIPEA (0.29 mL,1.64 mmol) were suspended in DMSO (5.0 mL) and stirred at 100℃for 16 hours. Distilled water (30 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (50% EtOAc/hexanes) to give 332mg (82%) of a yellow solid.
Step 3: synthesis of 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde
2- (2, 6-Dioxopiperidin-3-yl) -5- (4- (hydroxymethyl) piperidin-1-yl) isoindoline-1, 3-dione (336 mg,0.89 mmol) was suspended in DCM (5.0 mL). Then, DMP (569 mg,1.34 mmol) was added and stirred at room temperature for 2 hours. An aqueous Na 2S2O3 solution (10 mL) was added to the reaction solution, followed by extraction with DCM (25 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (50% EtOAc/DCM) to give 303mg (92%) of a yellow solid.
Intermediates 3-2 to 3-5 were synthesized using the same method as the synthesis of intermediate 3-1.
Intermediate 3-6:1- (6- (2, 6-dioxopiperidin-3-yl) -5-oxo-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) piperidine-4-carbaldehyde
Step 1: synthesis of methyl 2- (bromomethyl) -6-chloronicotinate
Methyl 6-chloro-2-methylnicotinate (1.00 g,5.38 mmol), N-bromosuccinimide (1.44 g,8.08 mmol) and AHCN (130 mg,0.05 mmol) were suspended in ACN (10 mL) and stirred in a microwave at 110℃for 4 hours. Distilled water (10 mL) was added to the reaction solution and extracted with EtOAc (10 mL x 2). The organic layer was washed with brine (10 ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (10% EtOAc/hexanes) to give 980mg of a white solid. m/z 263.99[ M+H ] +.
Step 2: synthesis of 3- (2-chloro-5-oxo-5, 7-dihydro-6H-pyrrolo [3,4-b ] pyridin-6-yl) piperidine-2, 6-dione
Methyl 2- (bromomethyl) -6-chloronicotinate (980 mg), 3-aminopiperidine-2, 6-dione hydrochloride (686 mg,4.17 mmol) and DIPEA (1.05 mL,10.40 mmol) were suspended in ACN (10 mL) and stirred at 110 ℃ for 2 hours. Distilled water (30 mL) was added to the reaction solution, followed by extraction with EtOAc (25 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized (MeOH) to give 244mg (16% yield in two steps) of an off-white solid. m/z 280.09[ M+H ] +.
Step 3: synthesis of 3- (2- (4- (hydroxymethyl) piperidin-1-yl) -5-oxo-5, 7-dihydro-6H-pyrrolo [3,4-b ] pyridin-6-yl) piperidine-2, 6-dione
3- (2-Chloro-5-oxo-5, 7-dihydro-6H-pyrrolo [3,4-b ] pyridin-6-yl) piperidine-2, 6-dione (0.77 g,2.75 mmol), piperidin-4-ylmethanol (0.38 g,3.30 mmol) and DIPEA (0.96 mL,5.51 mmol) were suspended in DMSO (10 mL) and stirred at 100deg.C for 16 hours. Distilled water (50 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL x 3) and DCM (10 mL x 12). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was suspended in DCM (10 mL), filtered and dried to give 0.43g (44%) of a bright yellow solid.
Step 4: synthesis of 1- (6- (2, 6-dioxopiperidin-3-yl) -5-oxo-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) piperidine-4-carbaldehyde
3- (2- (4- (Hydroxymethyl) piperidin-1-yl) -5-oxo-5, 7-dihydro-6H-pyrrolo [3,4-b ] pyridin-6-yl) piperidine-2, 6-dione (0.43 g,1.21 mmol) was suspended in DCM (40 mL). Then, DMP (1.02 g,2.41 mmol) was added and stirred at room temperature for 2 hours. An aqueous Na 2S2O3 solution (20 mL) was added to the reaction solution, followed by extraction with DCM (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (3-8% MeOH/DCM) to give 0.36mg (83%) of a yellow solid.
Intermediate 3-7:3- ((3-aminophenyl) amino) piperidine-2, 6-dione
Step 1: synthesis of tert-butyl (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) carbamate
Tert-butyl (3-aminophenyl) carbamate (300 mg,1.44 mmol) and 3-bromopiperidine-2, 6-dione (331 mg,1.73 mmol) were suspended in DMF (5.0 mL). NaHCO 3 (241 mg,2.88 mmol) was then added and stirred at 50℃for 16 hours. Distilled water (30 mL) was added to the reaction solution, and the resulting solid was filtered and dried to give 323mg (70%) of a green solid. m/z 342.20[ M+Na ] +.
Step 2: synthesis of 3- ((3-aminophenyl) amino) piperidine-2, 6-dione
Tert-butyl (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) carbamate (100 mg,0.31 mmol) was suspended in DCM (1 mL). Then, 4M HCl (0.39 mL,1.57 mmol) in dioxane was added and stirred at room temperature for 1 hour. The reaction solution was concentrated, aqueous NaHCO 3 (15 mL) was added, and extracted with DCM (20 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 34mg (51%) of a brown solid. m/z 220.20[ M+H ] +.
Intermediate 3-8:3- ((2, 6-dioxopiperidin-3-yl) amino) benzoic acid
Step 1: synthesis of tert-butyl 3- ((2, 6-dioxopiperidin-3-yl) amino) benzoate
Tert-butyl 3-aminobenzoate (0.50 g,2.59 mmol) and 3-bromopiperidine-2, 6-dione (0.60 g,3.10 mmol) were suspended in DMF (10 mL). Then NaHCO 3 (0.44 g,5.17 mmol) was added and stirred at 80℃for 16 hours. Aqueous NH 4 Cl (50 mL) was added to the reaction solution, followed by extraction with EtOAc (30 mL x 4). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (20-50% EtOAc/hexanes) to give 0.22g (28%) of a green oil.
Step 2: synthesis of 3- ((2, 6-dioxopiperidin-3-yl) amino) benzoic acid
Tert-butyl 3- ((2, 6-dioxopiperidin-3-yl) amino) benzoate (0.22 g,0.73 mmol) was suspended in DCM (2.0 mL). Then, 4M HCl (2 mL,8.03 mmol) in dioxane was added and stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure and dried to give 0.18g (73%) of a gray solid.
Intermediate 3-9:3- ((4- (piperidin-4-yl) phenyl) amino) piperidine-2, 6-dione hydrochloride
Step 1: synthesis of 4- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester
Tert-butyl 4- (4-nitrophenyl) piperidine-1-carboxylate (3.08 g,12.4 mmol) was suspended in MeOH (80 mL). Then, 10% Pd/C (0.66 g) was added and stirred under a hydrogen stream at room temperature for 4 hours. The reaction solution was filtered through celite and concentrated under reduced pressure to give 3.70g (108%) of a light gray solid.
Step 2: synthesis of tert-butyl 4- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidine-1-carboxylate
Tert-butyl 4- (4-aminophenyl) piperidine-1-carboxylate (3.7 g,13.39 mmol) was suspended in DMF (30 mL). Then, 3-bromopiperidine-2, 6-dione (3.08 g,16.06 mmol) and DIPEA (4.77 mL,26.77 mmol) were added and stirred at 100℃for 16 hours. Distilled water (150 mL) was added to the reaction solution, followed by extraction with EtOAc (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (20-50% EtOAc/hexanes) to give 1.22g (25% two step yield) of a green solid.
Step 3: synthesis of 3- ((4- (piperidin-4-yl) phenyl) amino) piperidine-2, 6-dione hydrochloride
Tert-butyl 4- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidine-1-carboxylate (1.22 g,3.15 mmol) was suspended in DCM (30 mL). Then, 4M HCl in dioxane (5 mL) was added and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure and then triturated (DCM/diethyl ether) to give 1.06g (104%) of a green solid.
Intermediate 3-10 was synthesized using the same method as intermediate 3-9.
Intermediate 3-11:3- (2, 4-Dioxotetrahydropyrimidin-1 (2H) -yl) benzoic acid
Step 1: synthesis of 3- ((2-carboxyethyl) amino) benzoic acid
3-Aminobenzoic acid (400 mg,2.92 mmol) was suspended in toluene (8 mL). Then, acrylic acid (0.26 mL,3.79 mmol) was added and stirred at 120℃for 19 hours. After the reaction solution was cooled to room temperature, the precipitated solid was filtered, washed with toluene and dried to obtain 501mg (82%) of a white solid.
Step 2: synthesis of 3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) benzoic acid
3- ((2-Carboxyethyl) amino) benzoic acid (405 mg,1.94 mmol) and urea (349 mg,5.81 mmol) were suspended in AcOH (6.5 mL) and stirred at 120℃for 18 h. The reaction solution was concentrated under reduced pressure, excess water was added, and the resulting solid was filtered, washed with water and dried to give 254mg (56%) of a light brown solid.
Intermediate 3-12 was synthesized using the same method as intermediate 3-11.
Intermediate 3-13:3- ((3- (bromomethyl) phenyl) amino) piperidine-2, 6-dione
Step 1: synthesis of 3- ((3- (hydroxymethyl) phenyl) amino) piperidine-2, 6-dione
(3-Aminophenyl) methanol (300 mg,2.44 mmol) and 3-bromopiperidine-2, 6-dione (515 mg,2.68 mmol) were suspended in DMF (5.0 mL). Then NaHCO 3 (169 mg,4.87 mmol) was added and stirred at 80℃for 16 hours. Distilled water (50 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL x 6). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (2-8% MeOH/DCM) and 258mg (45%) of a yellow solid was obtained.
Step 2: synthesis of 3- ((3- (bromomethyl) phenyl) amino) piperidine-2, 6-dione
3- ((3- (Hydroxymethyl) phenyl) amino) piperidine-2, 6-dione (14 mg,0.06 mmol) was suspended in 30% HBr in acetic acid (0.5 mL) and stirred at 90℃for 10 min. Distilled water (10 mL) was added to the reaction solution and extracted with EtOAc (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (2-4% MeOH/DCM) to give 14mg (crude) of a yellow solid.
Intermediate 3-14:3- ((2, 6-dioxopiperidin-3-yl) oxy) benzoic acid
Step 1: synthesis of tert-butyl 3- ((2, 6-dioxopiperidin-3-yl) oxy) benzoate
Tert-butyl 3-hydroxybenzoate (300 mg,1.54 mmol) was suspended in THF (10 mL). Then sodium hydride (60%, dispersed in paraffin solution, 185mg,4.63 mmol) was slowly added and stirred at 60℃for 30 minutes. 3-bromopiperidine-2, 6-dione (445 mg,2.3 mmol) was added to the reaction solution and stirred at 60℃for 50 minutes. Distilled water (50 mL) was added to the reaction solution, followed by extraction with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (30% EtOAc/hexanes) to give 214mg (46%) of a white solid.
Step 2: synthesis of 3- ((2, 6-dioxopiperidin-3-yl) oxy) benzoic acid
Tert-butyl 3- ((2, 6-dioxopiperidin-3-yl) oxy) benzoate (212 mg,0.7 mmol) was suspended in DCM (5 mL). 4M HC in dioxane l (3.5 mL) was then added and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to give 186mg (93%) of a white solid.
Intermediate 3-15:1- (4- ((2, 6-dioxopiperidin-3-yl) oxy) phenyl) piperidine-4-carbaldehyde
Step 1: synthesis of 1- (benzyloxy) -4-iodobenzene
4-Iodophenol (1.0 g,4.54 mmol), benzyl bromide (778 mg,4.54 mmol) and K 2CO3 (1.25 g,9.08 mmol) were suspended in acetonitrile (10 mL) and stirred at 60℃for 15 hours. Distilled water (40 mL) was added to the reaction solution, followed by extraction with EtOAc (40 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (1% EtOAc/hexanes) to give 1.38g (98%) of a white solid.
Step 2: synthesis of (1- (4- (benzyloxy) phenyl) piperidin-4-yl) methanol
1- (Benzyloxy) -4-iodobenzene (1.38 g,4.47 mmol), piperidin-4-ylmethanol (1.0 g,8.94 mmol), cuI (170 mg,0.89 mmol), 2-acetylcyclohexanone (131 mg,0.89 mmol) and Cs 2CO3 (2.9 g,8.94 mmol) were suspended in DMF (15 mL) and stirred at 50℃for 24 hours. Distilled water (100 mL) was added to the reaction solution, followed by extraction with EtOAc (100 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (40% EtOAc/hexanes) to give 567mg (43%) of a white solid.
Step 3: synthesis of 1- (4- (benzyloxy) phenyl) -4- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) piperidine
(1- (4- (Benzyloxy) phenyl) piperidin-4-yl) methanol (567 mg,1.91 mmol), 3, 4-dihydro-2H-pyran (481 mg,5.7 mmol) and pTSA (33 mg,0.19 mmol) were suspended in 1, 4-dioxane (18 mL) and stirred at 100℃for 2 hours. Distilled water (40 mL) was added to the reaction solution, followed by extraction with EtOAc (40 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (10% EtOAc/hexanes) to give 602mg (83%) of a pink solid.
Step 4: synthesis of 4- (4- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) piperidin-1-yl) phenol
1- (4- (Benzyloxy) phenyl) -4- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) piperidine (602 mg,1.58 mmol) was suspended in MeOH (2 mL) and DCM (2 mL). Then, palladium (10 wt% on activated carbon, 300 mg) was added and stirred under a hydrogen stream at room temperature for 14 hours. The reaction solution was filtered through celite and concentrated under reduced pressure. The resulting residue was MPLC (30% EtOAc/hexanes) to give 448mg (97%) of a clear oil.
Step 5: synthesis of 3- (4- (4- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) piperidin-1-yl) phenoxy) piperidine-2, 6-dione
4- (4- (((Tetrahydro-2H-pyran-2-yl) oxy) methyl) piperidin-1-yl) phenol (447 mg,1.54 mmol) was suspended in THF (10 mL). Then sodium hydride (60%, dispersed in paraffin solution, 185mg,4.63 mmol) was slowly added and stirred at 60℃for 30 minutes. 3-bromopiperidine-2, 6-dione (447 mg,2.3 mmol) was added to the reaction solution and stirred at 60℃for 30 minutes. Distilled water (50 mL) was added to the reaction solution, followed by extraction with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (40% EtOAc/hexanes) to give 268mg (43%) of a white solid.
Step 6: synthesis of 3- (4- (4- (hydroxymethyl) piperidin-1-yl) phenoxy) piperidine-2, 6-dione
3- (4- (4- (((Tetrahydro-2H-pyran-2-yl) oxy) methyl) piperidin-1-yl) phenoxy) piperidine-2, 6-dione (266 mg,0.66 mmol) was suspended in DCM (5 mL). Then, 4M HCl in dioxane (1.6 mL) was added and stirred at room temperature for 20 min. Aqueous NaHCO 3 (20 mL) was added to the reaction solution, followed by extraction with EtOAc (20 mL x 2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 208mg (99%) of a gray solid.
Step 7: synthesis of 1- (4- ((2, 6-dioxopiperidin-3-yl) oxy) phenyl) piperidine-4-carbaldehyde
3- (4- (4- (Hydroxymethyl) piperidin-1-yl) phenoxy) piperidine-2, 6-dione (30 mg,0.094 mmol) was suspended in DCM (1 mL). Then, DMP (48 mg,0.11 mmol) was added and stirred at room temperature for 20 minutes. Aqueous NaHCO 3 (10 mL) was added to the reaction solution and extracted with DCM (10 mL x 2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (3% MeOH/DCM) to give 17mg (58%) of a purple solid.
Intermediate 3-16 was synthesized using the same method as intermediate 3-15.
Intermediate 3-17:3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride
Step 1: synthesis of tert-butyl 4- (4- ((2, 6-dioxopiperidin-3-yl) oxy) phenyl) piperidine-1-carboxylate
Tert-butyl 4- (4-hydroxyphenyl) piperidine-1-carboxylate (400 mg,1.44 mmol) was suspended in DMF (5 mL). Then, naH (173 mg,4.33 mmol) was added and stirred for 10 minutes. 3-bromopiperidine-2, 6-dione (554 mg,2.88 mmol) was added and stirred at 90℃for 16 hours. Distilled water (50 mL) was added to the reaction solution and extracted with EtOAc (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (NH silica, 1-2% MeOH/DCM) to give 239mg (43%) of a pink solid.
Step 2: synthesis of 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride
Tert-butyl 4- (4- ((2, 6-dioxopiperidin-3-yl) oxy) phenyl) piperidine-1-carboxylate (239 mg,0.62 mmol) was suspended in DCM (2 mL). Then, 4M HCl in dioxane (0.5 mL) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give 198mg (99%) of a pink solid.
Intermediate 3-18:1- (5- ((2, 6-dioxopiperidin-3-yl) oxy) pyridin-2-yl) piperidine-4-carbaldehyde
Step 1: synthesis of 5- (benzyloxy) -2-bromopyridine
6-Bromopyridin-3-ol (2 g,11.49 mmol), benzyl bromide (1.5 mL,12.64 mmol) and K 2CO3 (3.18 g,22.98 mmol) were suspended in MeCN (50 mL) and stirred at 60℃for 16 h. The reaction solution was concentrated under reduced pressure, distilled water (80 mL) was added, and extracted with EtOAc (20 ml×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (10-20% EtOAc/hexanes) to give 2.48g (82%) of a bright yellow solid.
Step 2: synthesis of (1- (5- (benzyloxy) pyridin-2-yl) piperidin-4-yl) methanol
5- (Benzyloxy) -2-bromopyridine (1 g,3.79 mmol), piperidin-4-ylmethanol (0.52 g,4.54 mmol), pd 2(dba)3 (0.69 g,0.76 mmol), BINAP (0.47 g,0.76 mmol) and sodium tert-butoxide (0.73 g,7.57 mmol) were suspended in dioxane (30 mL) and stirred at 105℃for 16 h. Distilled water (80 mL) was added to the reaction solution and extracted with EtOAc (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (50-100% EtOAc/hexanes) to give 0.51g (45%) of an orange solid.
Step 3: synthesis of 1- (5- (benzyloxy) pyridin-2-yl) piperidine-4-carbaldehyde
DMSO (0.22 mL,3.11 mmol) was diluted in DCM (20 mL) and oxalyl chloride (0.2 mL,2.33 mmol) was added thereto at 0deg.C. (1- (5- (benzyloxy) pyridin-2-yl) piperidin-4-yl) methanol (460 mg,1.56 mmol) was added to the reaction solution, and triethylamine (0.65 mL,4.67 mmol) diluted in DCM (10 mL) was slowly added and stirred at room temperature for 1 hour. Distilled water (50 mL) was added to the reaction solution and extracted with EtOAc (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (20-50% EtOAc/hexanes) to give 341mg (74%) of an orange liquid.
Step 4: synthesis of 2- (4- (1, 3-dioxolan-2-yl) piperidin-1-yl) -5- (benzyloxy) pyridine
1- (5- (Benzyloxy) pyridin-2-yl) piperidine-4-carbaldehyde (3411 mg,1.15 mmol) was suspended in toluene (15 mL). Then, ethylene glycol (143 mg,2.30 mmol) and PPTS (29 mg,0.12 mmol) were added and stirred at 115℃for 1 hour. Distilled water (50 mL) was added to the reaction solution and extracted with EtOAc (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (1-2% MeOH/DCM) and 382mg (98%) of a yellow solid was obtained.
Step 5: synthesis of 6- (4- (1, 3-dioxolan-2-yl) piperidin-1-yl) pyridin-3-ol
2- (4- (1, 3-Dioxolan-2-yl) piperidin-1-yl) -5- (benzyloxy) pyridine (382 mg,1.12 mmol) was suspended in MeOH (10 mL). Then, 10% Pd/C (60 mg) was added and stirred under a hydrogen stream at room temperature for 6 hours. The reaction solution was filtered through celite and concentrated under reduced pressure. The resulting residue was MPLC (1-3% MeOH/DCM) and 155mg (55%) of a bright yellow solid was obtained.
Step 6: synthesis of (3- ((6- (4- (1, 3-dioxolan-2-yl) piperidin-1-yl) pyridin-3-yl) oxy) piperidine-2, 6-dione
6- (4- (1, 3-Dioxolan-2-yl) piperidin-1-yl) pyridin-3-ol (155 mg,0.62 mmol) was suspended in THF (10 mL). Then, naH (74 mg,1.86 mmol) was added and stirred for 5 minutes. 3-bromopiperidine-2, 6-dione (178 mg,0.93 mmol) was added and stirred at 65℃for 2 hours. Distilled water (50 mL) was added to the reaction solution and extracted with EtOAc (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (60-80% EtOAc/hexanes) to give 48mg (21%) of a bright yellow solid.
Step 7: synthesis of (1- (5- ((2, 6-dioxopiperidin-3-yl) oxy) pyridin-2-yl) piperidine-4-carbaldehyde
(3- ((6- (4- (1, 3-Dioxolan-2-yl) piperidin-1-yl) pyridin-3-yl) oxy) piperidine-2, 6-dione (48 mg,0.13 mmol) was suspended in DCM (2 mL) and then TFA (0.5 mL) was added and stirred at 50℃for 16 h. Aqueous NaHCO 3 (30 mL) was added to the reaction solution and extracted with DCM (10 mL x 3.) the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 29mg (69%) of a bright yellow solid.
Intermediate 3-19:3- ((6- (piperidin-4-yl) pyridin-3-yl) amino) piperidine-2, 6-dione hydrochloride
Step 1: synthesis of 5-nitro-3 ',6' -dihydro- [2,4' -bipyridine ] -1' (2 ' H) -carboxylic acid tert-butyl ester
2-Chloro-5-nitropyridine (1.20 g,7.56 mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (2.52 g,8.28 mmol), pd (dppf) Cl 2 (302 mg,0.37 mmol) and K 2CO3 (2.09 g,15.12 mmol) were suspended in 1, 4-dioxan-e.g. H 2 O=5:1 (24 mL) and stirred at 100℃for 16H. The reaction solution was filtered through celite and concentrated under reduced pressure. The resulting residue was MPLC (0-60% EtOAc/hexanes) to give 1.53g (66%) of a white solid.
Step 2: synthesis of tert-butyl 4- (5-aminopyridin-2-yl) piperidine-1-carboxylate
5-Nitro-3 ',6' -dihydro- [2,4' -bipyridine ] -1' (2 ' H) -carboxylic acid tert-butyl ester (1.53 g,5.01 mmol) was dissolved in MeOH (25 mL). Then, 10% Pd/C (153 mg) was added and stirred under a hydrogen stream at room temperature for 4 hours. The reaction solution was filtered through celite and concentrated under reduced pressure to give 1.39g (100%) of a bright white solid.
Step 3: synthesis of tert-butyl 4- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperidine-1-carboxylate
Tert-butyl 4- (5-aminopyridin-2-yl) piperidine-1-carboxylate (1.39 g,5.01 mmol), 3-bromopiperidine-2, 6-dione (1.15 g,6.01 mmol) and NaHCO 3 (840 mg,10.0 mmol) were suspended in DMF (25 mL) and stirred at 60℃for 16 h. Distilled water (30 mL) was added to the reaction solution, followed by extraction with EtOAc (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (0-100% EtOAc/hexanes) to give 373mg (20.0%) of a green solid.
Step 4: synthesis of 3- ((6- (piperidin-4-yl) pyridin-3-yl) amino) piperidine-2, 6-dione hydrochloride
Tert-butyl 4- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperidine-1-carboxylate (373 mg,0.96 mmol) and 4N HCl in dioxane (1.5 mL) were suspended in DCM (3 mL) and stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure to give 350mg (112.0%) of a gray solid.
3-20 Of intermediate: 3- ((6- (piperazin-1-yl) pyridin-3-yl) amino) piperidine-2, 6-dione hydrochloride
Step 1: synthesis of tert-butyl 4- (5-nitropyridin-2-yl) piperazine-1-carboxylate
2-Chloro-5-nitropyridine (1.0 g,6.30 mmol), piperazine-1-carboxylic acid tert-butyl ester (2.90 g,9.40 mmol) and DIPEA (3.3 mL,19.0 mmol) were suspended in DMF (30 mL) and stirred at 100deg.C for 16 hours. Brine (50 mL) was added to the reaction solution and extracted with EtOAc (30 mL x 4). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was triturated (EtOAc/hexanes) to give 1.86g (96%) of a bright yellow solid.
Step 2: synthesis of tert-butyl 4- (5-aminopyridin-2-yl) piperazine-1-carboxylate
Tert-butyl 4- (5-nitropyridin-2-yl) piperazine-1-carboxylate (1.86 g,6.03 mmol) was dissolved in MeOH (30 mL). Then, 10% Pd/C (186 mg) was added and stirred under a hydrogen stream at room temperature for 4 hours. The reaction solution was filtered through celite and concentrated under reduced pressure to give 1.58g (94%) of a brown solid.
Step 3: synthesis of tert-butyl 4- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperazine-1-carboxylate
Tert-butyl 4- (5-aminopyridin-2-yl) piperazine-1-carboxylate (1.58 g,5.67 mmol), 3-bromopiperidine-2, 6-dione (1.30 g,6.80 mmol) and NaHCO 3 (954 mg,11.35 mmol) were suspended in DMF (28 mL) and stirred at 60℃for 16 h. Distilled water (30 mL) was added to the reaction solution, followed by extraction with EtOAc (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (0-100% EtOAc/hexanes) to give 723mg (33%) of a brown solid.
Step 4: synthesis of 3- ((6- (piperazin-1-yl) pyridin-3-yl) amino) piperidine-2, 6-dione hydrochloride
Tert-butyl 4- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperazine-1-carboxylate (723 mg,1.85 mmol) and 4N HCl in dioxane (3 mL) were suspended in DCM (6 mL) and stirred at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure to give 667mg (110%) of a gray solid.
Intermediates 3-21 to 3-22 were synthesized using the same method as the synthesis of intermediate 3-20.
Intermediate 3-23:1- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperidine-4-carbaldehyde
Step 1: synthesis of (1- (5-nitropyridin-2-yl) piperidin-4-yl) methanol
2-Chloro-5-nitropyridine (500 mg,3.15 mmol) and piperidin-4-ylmethanol (803 mg,3.15 mmol) were suspended in EtOH (15 mL) and stirred at 80℃for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was MPLC (50% EtOAc/hexane) to give 335mg (45%) of a yellow solid.
Step 2: synthesis of 1- (5-nitropyridin-2-yl) piperidine-4-carbaldehyde
(1- (5-Nitropyridin-2-yl) piperidin-4-yl) methanol (332 mg,1.4 mmol) was suspended in DCM (10 mL). Then, DMP (710 mg,1.7 mmol) was added and stirred at room temperature for 50 minutes. Aqueous NaHCO 3 (30 mL) was added to the reaction solution, followed by extraction with DCM (30 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (30% EtOAc/hexanes) to give 318mg (97%) of a yellow solid.
Step 3: synthesis of 2- (4- (1, 3-dioxolan-2-yl) piperidin-1-yl) -5-nitropyridine
1- (5-Nitropyridin-2-yl) piperidine-4-carbaldehyde (318 mg,1.35 mmol), ethylene glycol (67 mg,2.7 mmol) and pyridinium p-toluenesulfonate (35 mg,0.14 mmol) were suspended in toluene (10 mL) and stirred at 115℃for 1 hour. Distilled water (40 mL) was added to the reaction solution, followed by extraction with EtOAc (40 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (25% EtOAc/hexanes) to give 199mg (53%) of a yellow solid.
Step 4: synthesis of 6- (4- (1, 3-dioxolan-2-yl) piperidin-1-yl) pyridin-3-amine
2- (4- (1, 3-Dioxolan-2-yl) piperidin-1-yl) -5-nitropyridine (192 mg,0.69 mmol), fe (192 mg,3.45 mmol) and NH 4 Cl (37 mg,0.69 mmol) were suspended in EtOH (7 mL) and H 2 O (2 mL) and stirred at 70℃for 1.5H. The reaction solution was concentrated under reduced pressure, aqueous NaHCO 3 (30 mL) was added, and extracted with EtOAc (30 mL). The organic layer was filtered through celite and concentrated under reduced pressure. The resulting residue was MPLC (3% MeOH/DCM) to give 126mg (73%) of a dark red solid.
Step 5: synthesis of 3- ((6- (4- (1, 3-dioxolan-2-yl) piperidin-1-yl) pyridin-3-yl) amino) piperidine-2, 6-dione
6- (4- (1, 3-Dioxolan-2-yl) piperidin-1-yl) pyridin-3-amine (124 mg,0.5 mmol), 3-bromopiperidine-2, 6-dione (115 mg,0.6 mmol), naHCO 3 (84 mg,1 mmol) were suspended in DMF (2.5 mL) and stirred at 60℃for 18 hours. Distilled water (40 mL) was added to the reaction solution, followed by extraction with EtOAc (40 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (5% MeOH/DCM) to give 81mg (45%) of a purple solid.
Step 6: synthesis of 1- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperidine-4-carbaldehyde
3- ((6- (4- (1, 3-Dioxolan-2-yl) piperidin-1-yl) pyridin-3-yl) amino) piperidine-2, 6-dione (79 mg,0.22 mmol) was suspended in DCM (2 mL). TFA (1 mL) was then added and stirred at 50 ℃ for 15 hours. The reaction solution was concentrated under reduced pressure and the resulting residue was MPLC (10% MeOH/DCM) to give 56mg (81%) of a purple solid.
Intermediates 3-24 to 3-26 were synthesized using the same method as the synthesis of intermediate 3-23.
Intermediate 3-27:3- ((6- (piperidin-4-yl) pyridin-3-yl) oxy) piperidine-2, 6-dione hydrochloride
Step 1: synthesis of tert-butyl 5- (benzyloxy) -3',6' -dihydro- [2,4' -bipyridine ] -1' (2 ' H) -carboxylate
5- (Benzyloxy) -2-bromopyridine (500 mg,1.89 mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (702 mg,2.27 mmol), pd (dppf) Cl 2( mg,2 mol%) and K 2CO3 (75 mg,5.68 mmol) were suspended in dioxane (20 mL) and H 2 O (5 mL) and stirred at 90℃for 2H. Distilled water (80 mL) was added to the reaction solution and extracted with EtOAc (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (20-50% EtOAc/hexanes) to give 728mg (105%) of a white solid.
Step 2: synthesis of tert-butyl 4- (5-hydroxypyridin-2-yl) piperidine-1-carboxylate
5- (Benzyloxy) -3',6' -dihydro- [2,4' -bipyridine ] -1' (2 ' H) -carboxylic acid tert-butyl ester (328 mg,1.99 mmol) was suspended in MeOH (30 mL). Then, 10% Pd/C (106 mg) was added and stirred at room temperature under a hydrogen stream for 16 hours. The reaction solution was filtered through celite and concentrated under reduced pressure to give 550mg (99%) of a gray solid.
Step 3: synthesis of tert-butyl 4- (5- ((2, 6-dioxopiperidin-3-yl) oxy) pyridin-2-yl) piperidine-1-carboxylate
Tert-butyl 4- (5-hydroxypyridin-2-yl) piperidine-1-carboxylate (450 mg,1.62 mmol) was suspended in THF (30 mL). Then, naH (129 mg,3.23 mmol) was added and stirred for 10 minutes. Next, 3-bromopiperidine-2, 6-dione (372 mg,1.94 mmol) was added and stirred at 60℃for 6 hours. 3-bromopiperidine-2, 6-dione (94 mg,0.49 mmol) was additionally added and stirred at 45℃for 16 hours. Distilled water (80 mL) was added to the reaction solution and extracted with EtOAc (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (1-4% MeOH/DCM) to give 233mg (37%) of a white solid.
Step 4: synthesis of 3- ((6- (piperidin-4-yl) pyridin-3-yl) oxy) piperidine-2, 6-dione hydrochloride
Tert-butyl 4- (5- ((2, 6-dioxopiperidin-3-yl) oxy) pyridin-2-yl) piperidine-1-carboxylate (233 mg,0.60 mmol) was suspended in DCM (4 mL). Then, 4M HCl in dioxane (0.5 mL) was added and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to give 227mg (116%) of a pale yellow solid.
Intermediate 3-28:3- ((6- (piperazin-1-yl) pyridin-3-yl) oxy) piperidine-2, 6-dione hydrochloride
Step 1: synthesis of tert-butyl 4- (5- (benzyloxy) pyridin-2-yl) piperazine-1-carboxylate
5- (Benzyloxy) -2-bromopyridine (640 mg,3.33 mmol), piperazine-1-carboxylic acid tert-butyl acetate (984 mg,4.00 mmol), pd 2(dba)3 (610 mg,0.67 mmol), BINAP (418 mg,0.67 mmol), and sodium tert-butoxide (640 mg,6.66 mmol) were suspended in toluene (40 mL) and stirred at 100deg.C for 16 h. Distilled water (100 mL) was added to the reaction solution and extracted with EtOAc (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (10-30% EtOAc/hexanes) to give 1.07g (87%) of a yellow solid.
Step 2: synthesis of tert-butyl 4- (5-hydroxypyridin-2-yl) piperazine-1-carboxylate
Tert-butyl 4- (5- (benzyloxy) pyridin-2-yl) piperazine-1-carboxylate (1.07 g,2.90 mmol) was suspended in MeOH (40 mL). Then, 10% Pd/C (0.15 g) was added and stirred under a hydrogen stream at room temperature for 16 hours. The reaction solution was filtered through celite and concentrated under reduced pressure to give 0.83g (102%) of a gray solid.
Step 3: synthesis of tert-butyl 4- (5- ((2, 6-dioxopiperidin-3-yl) oxy) pyridin-2-yl) piperazine-1-carboxylate
Tert-butyl 4- (5-hydroxypyridin-2-yl) piperazine-1-carboxylate (400 mg,1.43 mmol) was suspended in THF (25 mL). Then NaH (115 mg,2.86 mmol) was added and stirred for 10 minutes. 3-bromopiperidine-2, 6-dione (330 mg,1.72 mmol) was added and stirred at 60℃for 2 hours. Distilled water (80 mL) was added to the reaction solution and extracted with EtOAc (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (1-4% MeOH/DCM) and 258mg (46%) of a bright yellow solid was obtained.
Step 4: synthesis of 3- ((6- (piperazin-1-yl) pyridin-3-yl) oxy) piperidine-2, 6-dione hydrochloride
Tert-butyl 4- (5- ((2, 6-dioxopiperidin-3-yl) oxy) pyridin-2-yl) piperazine-1-carboxylate (258 mg,0.66 mmol) was suspended in DCM (4 mL). 4M HCl in dioxane (0.5 mL) was added and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to give 281mg (130%) of a white solid.
Intermediate 3-29:1- (4- (2, 4-dioxotetrahydropyrimidine-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde
Step 1: synthesis of (1- (4-nitrophenyl) piperidin-4-yl) methanol
1-Fluoro-4-nitrobenzene (3.0 g,21.26 mmol), piperidin-4-ylmethanol (2.93 g,25.50 mmol) and DIPEA (7.40 mL,42.52 mmol) were suspended in DMF (5 mL) and stirred in a microwave oven at 120℃for 2 hours. Distilled water (40 mL) was added to the reaction solution and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was triturated (EtOAc/hexanes) to give 4.90g (98%) of a yellow solid.
Step 2: synthesis of (1- (4-nitrophenyl) piperidin-4-yl) methyl acetate
(1- (4-Nitrophenyl) piperidin-4-yl) methanol (2.50 g,8.98 mmol) and acetyl chloride (0.81 mL,11.42 mmol) were suspended in EtOH (45 mL). Then TEA (2.65 mL,19.0 mmol) was slowly added and stirred at room temperature for 1 hour. Distilled water (50 mL) was added to the reaction solution and extracted with EtOAc (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (0-40% EtOAc/hexanes) to give 2.5g (85%) of a yellow solid.
Step 3: synthesis of (1- (4-aminophenyl) piperidin-4-yl) methyl acetate
(1- (4-Nitrophenyl) piperidin-4-yl) methyl acetate (2.50 g,8.98 mmol) was dissolved in EtOH (45 mL). Then, 10% Pd/C (250 mg) was added and stirred at room temperature under a hydrogen stream for 16 hours. The reaction solution was filtered through celite and concentrated under reduced pressure. The resulting residue was triturated (ether/hexane) to give 1.78g (80%) of a brown solid.
Step 4: synthesis of (1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl acetate
(1- (4-Aminophenyl) piperidin-4-yl) methyl acetate (1.78 g,7.16 mmol) was dissolved in toluene (12 mL). Then, acrylic acid (0.60 mL,8.60 mmol) was added and stirred at 50℃for 16 hours. Urea (2.15 g,35.8 mmol) and AcOH (10 mL) were added to the reaction solution and stirred at 105℃for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was MPLC (0-100% EtOAc/hexane) to give 860mg (35%) of a bright powder solid.
Step 5: synthesis of 1- (4- (4- (hydroxymethyl) piperidin-1-yl) phenyl) dihydropyrimidine-2, 4 (1H, 3H) -dione
(1- (4- (2, 4-Dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl acetate (850 mg,2.46 mmol) was suspended in 2N HCl (12 mL) and stirred at 100deg.C for 2 hours. The reaction solution was neutralized with aqueous NaHCO 3 and the resulting solid was filtered to give 630mg (84%) of a pink solid.
Step 6: synthesis of 1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde
1- (4- (4- (Hydroxymethyl) piperidin-1-yl) phenyl) dihydropyrimidine-2, 4 (1H, 3H) -dione (90 mg,0.29 mmol) was suspended in DCM (2 mL). Then, DMP (150 mg,4.23 mmol) was added and stirred at room temperature for 15 minutes. Aqueous NaHCO 3 (80 mL) was added to the reaction solution and extracted with DCM (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was treated with MPLC (0-90% EtOAc/hexanes) to give 55mg (62%) of a pink solid.
Intermediates 3-30 to 3-31 were synthesized using the same method as the synthesis of intermediate 3-29.
Intermediate 3-32:1- (3- (piperidin-4-yl) phenyl) dihydropyrimidine-2, 4 (1H, 3H) -dione
Step 1: synthesis of 1- (3-iodophenyl) dihydropyrimidine-2, 4 (1H, 3H) -dione
3-Iodoaniline (3.0 g,13.69 mmol) was suspended in toluene (23 mL). Then, acrylic acid (1.12 mL,16.43 mmol) was added and stirred at 70℃for 48 hours. AcOH (34 mL) and urea (2.46 g,13.69 mmol) were added to the reaction solution and stirred at 105℃for 16 hours. The reaction solution was concentrated under reduced pressure, distilled water (60 mL) was added, and extracted with EtOAc (30 ml×4). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (0-100% EtOAc/hexanes) to give 2.20g (51%) of a white solid.
Step 2: synthesis of tert-butyl 4- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate
1- (3-Iodophenyl) dihydropyrimidine-2, 4 (1H, 3H) -dione (200 mg,0.63 mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (216 mg,0.70 mmol), pd (dppf) Cl 2 (22 mg,0.03 mmol) and K 2CO3 (174 mg,1.26 mmol) were suspended in 1, 4-dioxan-e: H 2 O=5:1 (2 mL) and stirred at 100℃for 1.5 hours. The reaction solution was filtered through celite and concentrated under reduced pressure. The resulting residue was MPLC (0-70% EtOAc/hexanes) to give 190mg (81%) of a white solid.
Step 3: synthesis of tert-butyl 4- (3- (2, 4-dioxotetrahydropyrimidine-1 (2H) -yl) phenyl) piperidine-1-carboxylate
4- (3- (2, 4-Dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (188 mg,0.50 mmol) was dissolved in EtOH (15 mL). Then, 10% Pd/C (18 mg) was added and stirred at room temperature under a hydrogen stream for 16 hours. The reaction solution was filtered through celite and concentrated under reduced pressure to give 147mg (78.7%) of a bright yellow solid.
Step 4: synthesis of 1- (3- (piperidin-4-yl) phenyl) dihydropyrimidine-2, 4 (1H, 3H) -dione
Tert-butyl 4- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidine-1-carboxylate (147 mg,0.39 mmol) and TFA (0.9 mL) were suspended in DCM (6 mL) and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain 104mg (72%) of a pale yellow solid.
Intermediate 3-33 was synthesized using the same method as the synthesis of intermediate 3-32.
Example 1: n- (4- (2- ((2- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Step 1: synthesis of tert-butyl 7- ((4- (4- ((3-isopropoxyazetidine-1-carboxamido) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate
N- (4- (2-Chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy-azetidine-1-carboxamide (intermediate 1-1,0.15g,0.40 mmol), 7-amino-3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester (0.12 g,0.48 mmol), pd (OAc) 2 (0.02 g,0.08 mmol), BINAP (0.05 g,0.08 mmol) and Cs 2CO3 (0.33 g,0.80 mmol) were suspended in dioxane (3 mL) and stirred at 100℃for 16 hours. Distilled water (30 mL) was added to the reaction solution, followed by extraction with EtOAc (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (80-100% EtOAc/hexanes) to give 0.11g (46%) of a yellow solid.
Step 2: synthesis of 3-isopropoxy-N- (2-methyl-4- (2- ((1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) pyrimidin-4-yl) benzyl) azetidine-1-carboxamide
7- ((4- (4- ((3-Isopropoxyazetidine-1-carboxamido) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) -3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester (107 mg,0.18 mmol) was suspended in DCM (2 mL). Then, 4M HCl in dioxane (2 mL,8.10 mmol) was added and stirred at room temperature for 4 hours. The reaction solution was filtered and concentrated under reduced pressure to give 79mg (89%) of a yellow solid.
Step 3: synthesis of N- (4- (2- ((2- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
3-Isopropoxy-N- (2-methyl-4- (2- ((1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) pyrimidin-4-yl) benzyl) azetidine-1-carboxamide (79 mg,0.16 mmol) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1,72mg,0.19 mmol) were suspended in DCM (4 mL). Then, naBH (OAc) 3 (103 mg,0.49 mmol) was added and stirred at room temperature for 2 hours. Aqueous NaHCO 3 (30 mL) was added to the reaction solution and extracted with DCM (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (2-6% MeOH/DCM) and gave 63mg (46%) of a yellow solid.
Example 2:1- (tert-butyl) -N- (4- (2- ((2- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide
Example 2 was synthesized using the same method as example 1, using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide (intermediate 1-4) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1).
Example 3:1- (tert-butyl) -N- (4- (2- ((2- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Example 3 was synthesized using the same method as example 1 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1).
Example 4: n- (3- (2- ((2- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) amino) pyrimidin-4-yl) -5-fluoro-2-methylphenyl) -3-isopropoxy azetidine-1-carboxamide
Example 4 was synthesized using the same method as example 1 using N- (3- (2-chloropyrimidin-4-yl) -5-fluoro-2-methylphenyl) -3-isopropoxy-azetidine-1-carboxamide (intermediate 1-8) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy-azetidine-1-carboxamide (intermediate 1-1).
Example 5:1- (tert-butyl) -N- (3- (2- ((2- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) amino) pyrimidin-4-yl) -5-fluoro-2-methylphenyl) -1H-pyrazole-4-carboxamide
Example 5 was synthesized using the same method as example 1, using 1- (tert-butyl) -N- (3- (2-chloropyrimidin-4-yl) -5-fluoro-2-methylphenyl) -1H-pyrazole-4-carboxamide (intermediate 1-9) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1).
Example 6:1- (tert-butyl) -N- (3- (2- ((2- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) -1,2,3, 4-tetrahydroisoquinolin-7-yl) amino) pyrimidin-4-yl) -5-fluoro-2-methylphenyl) -1H-1,2, 3-triazole-4-carboxamide
Example 6 was synthesized using the same method as example 1, using 1- (tert-butyl) -N- (3- (2-chloropyrimidin-4-yl) -5-fluoro-2-methylphenyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-10) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1).
Example 7: n- (4- (2- ((4- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Step 1: synthesis of tert-butyl 4- (4- ((4- (4- ((3-isopropoxy azetidine-1-carboxamido) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) phenyl) piperazine-1-carboxylate
N- (4- (2-Chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy-azetidine-1-carboxamide (intermediate 1-1,40mg,0.11 mmol), tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1,33mg,0.12 mmol), pd 2(dba)3 (10 mg,0.01 mmol), S-phos (9 mg,0.02 mmol) and Cs 2CO3 (70 mg,0.21 mmol) were suspended in dioxane (2 mL) and stirred in a microwave oven at 100deg.C for 1 hour. Distilled water (30 mL) was added to the reaction solution, followed by extraction with EtOAc (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (80-100% EtOAc/hexanes) to give 29mg (44%) of a yellow solid.
Step 2: synthesis of 3-isopropoxy-N- (2-methyl-4- (2- ((4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) benzyl) azetidine-1-carboxamide
Tert-butyl 4- (4- ((4- (4- ((3-isopropoxyazetidine-1-carboxamido) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) phenyl) piperazine-1-carboxylate (29 mg,0.05 mmol) was suspended in DCM (2 mL). TFA (0.5 mL) was then added and stirred at room temperature for 16 hours. The reaction solution was filtered and concentrated under reduced pressure to give 36mg of a yellow solid.
Step 3: synthesis of N- (4- (2- ((4- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
3-Isopropoxy-N- (2-methyl-4- (2- ((4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) benzyl) azetidine-1-carboxamide (36 mg,0.07 mmol) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1,31mg,0.08 mmol) were suspended in DCM (4 mL). Then, naBH (OAc) 3 (44 mg,0.21 mmol) was added and stirred at room temperature for 16 hours. Aqueous NaHCO 3 (30 mL) was added to the reaction solution and extracted with DCM (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (2-5% MeOH/DCM) to give 8.8mg (22%, two-step yield) of a yellow solid.
Example 8:1- (tert-butyl) -N- (4- (2- ((4- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide
Example 8 was synthesized using the same method as example 7 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide (intermediate 1-4) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1).
Example 9:1- (tert-butyl) -N- (4- (2- ((4- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Example 9 was synthesized using the same method as example 7 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1).
Example 10: n- (4- (2- ((4- (4- ((1- (6- (2, 6-dioxopiperidin-3-yl) -5-oxo-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 10 was synthesized using the same method as example 7 using 1- (6- (2, 6-dioxopiperidin-3-yl) -5-oxo-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) piperidine-4-carbaldehyde (intermediate 3-6) instead of 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1).
Example 11: n- (4- (2- ((4- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 11 was synthesized using the same method as example 7 using 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidine-3-carbaldehyde (intermediate 3-2) instead of 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1).
Example 12: n- (4- (2- ((4- (4- ((1- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 12 was synthesized using the same method as example 7 using 1- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-4) instead of 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1).
Example 13: n- (4- (2- ((4- (4- ((1- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 13 was synthesized using the same method as example 7 using 1- (2, 6-dioxopiperidin-3-yl) -6-fluoro-1, 3-dioxoisoindolin-5-yl) azetidine-3-carbaldehyde (intermediate 3-5) instead of 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1).
Example 14: n- (4- (2- ((4- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) -3-methylazetidin-3-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 14 was synthesized using the same method as example 7 using 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) -3-methylazetidine-3-carbaldehyde (intermediate 3-3) instead of 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1).
Example 15: n- (4- (2- ((4- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 15 was synthesized using the same method as example 7, using tert-butyl 4- (4-aminophenyl) piperidine-1-carboxylate (intermediate 2-5) instead of tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1).
Example 16: n- (4- (2- ((4- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methyl) piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 16 was synthesized using the same method as in example 7, except that 4- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (intermediate 2-5) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidine-3-carbaldehyde (intermediate 3-2) were used instead of 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 17: n- (4- (2- ((6- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 17 was synthesized using the same method as example 7, using tert-butyl 4- (5-aminopyridin-2-yl) piperazine-1-carboxylate (intermediate 2-2) instead of tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1).
Example 18: n- (4- (2- ((6- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methyl) piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 18 was synthesized using the same method as example 7, except that 4- (5-aminopyridine-2-yl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-2) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidine-3-carbaldehyde (intermediate 3-2) were used instead of 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 19: n- (4- (2- ((6- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) pyridin-3-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 19 was synthesized using the same method as example 7, using tert-butyl 4- (5-aminopyridin-2-yl) piperidine-1-carboxylate (intermediate 2-6) instead of tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1).
Example 20: n- (4- (2- ((6- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methyl) piperidin-4-yl) pyridin-3-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 20 was synthesized using the same method as example 7, except that 4- (5-aminopyridine-2-yl) piperidine-1-carboxylic acid tert-butyl ester (intermediate 2-6) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidine-3-carbaldehyde (intermediate 3-2) were used instead of 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 21: n- (4- (2- ((1- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 21 was synthesized using the same method as example 7 using tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate (intermediate 2-7) instead of tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1).
Example 22: n- (4- (2- ((1- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 22 was synthesized using the same method as example 7, except that 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (intermediate 2-7) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidine-3-carbaldehyde (intermediate 3-2) were used instead of 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 23: n- (3- (2- ((4- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -5-fluoro-2-methylphenyl) -3-isopropoxy azetidine-1-carboxamide
Example 23 was synthesized using the same method as example 7 using N- (3- (2-chloropyrimidin-4-yl) -5-fluoro-2-methylphenyl) -3-isopropoxy-azetidine-1-carboxamide (intermediate 1-8) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy-azetidine-1-carboxamide (intermediate 1-1).
Example 24:1- (tert-butyl) -N- (3- (2- ((4- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -5-fluoro-2-methylphenyl) -1H-pyrazole-4-carboxamide
Example 24 was synthesized using the same method as example 7, using 1- (tert-butyl) -N- (3- (2-chloropyrimidin-4-yl) -5-fluoro-2-methylphenyl) -1H-pyrazole-4-carboxamide (intermediate 1-9) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1).
Example 25:1- (tert-butyl) -N- (3- (2- ((4- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -5-fluoro-2-methylphenyl) -1H-1,2, 3-triazole-4-carboxamide
Example 25 was synthesized using the same method as example 7, using 1- (tert-butyl) -N- (3- (2-chloropyrimidin-4-yl) -5-fluoro-2-methylphenyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-10) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1).
Example 26: n- (3- (2- ((4- (4- ((1- (6- (2, 6-dioxopiperidin-3-yl) -5-oxo-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -5-fluoro-2-methylphenyl) -3-isopropoxy azetidine-1-carboxamide
Example 26 was synthesized using the same method as example 7, using N- (3- (2-chloropyrimidin-4-yl) -5-fluoro-2-methylphenyl) -3-isopropoxy-azetidine-1-carboxamide (intermediate 1-8) and 1- (6- (2, 6-dioxopiperidin-3-yl) -5-oxo-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) piperidine-4-carbaldehyde (intermediate 3-6) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy-azetidine-1-carboxamide (intermediate 1-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 27: n- (3- (2- ((4- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -5-fluoro-2-methylphenyl) -3-isopropoxy azetidine-1-carboxamide
Example 27 was synthesized using the same method as example 7, using N- (3- (2-chloropyrimidin-4-yl) -5-fluoro-2-methylphenyl) -3-isopropoxyiazetidine-1-carboxamide (intermediate 1-8) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidine-3-carbaldehyde (intermediate 3-2) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxyiazetidine-1-carboxamide (intermediate 1-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 28: n- (3- (2- ((4- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -5-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 28 was synthesized using the same method as example 7, using N- (3- (2-chloropyrimidin-4-yl) -5-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-2) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1).
Example 29: n- (3- (2- ((4- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -5-methylphenyl) -3-isopropoxy azetidine-1-carboxamide
Example 29 was synthesized using the same method as example 7 using N- (3- (2-chloropyrimidin-4-yl) -5-methylphenyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-3) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1).
Example 30:4- (2- ((4- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl 3-isopropoxy azetidine-1-carboxylic acid ester
Example 30 was synthesized using the same method as example 7, using 4- (2-chloropyrimidin-4-yl) -2-methylbenzyl 3-isopropoxy azetidine-1-carboxylic acid ester (intermediate 1-11) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1).
Example 31:1- (tert-butyl) -N- (4- (2- ((4- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide
Example 31 was synthesized using the same method as example 7, except that 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide (intermediate 1-4) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidine-3-carbaldehyde (intermediate 3-2) were used instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 32:1- (tert-butyl) -N- (4- (2- ((4- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Example 32 was synthesized using the same method as example 7, using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidine-3-carbaldehyde (intermediate 3-2) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 33: n- (4- (2- ((4- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide
Example 33 was synthesized using the same method as example 7 using N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide (intermediate 1-6) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1).
Example 34: n- (4- (2- ((4- (4- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide
Example 34 was synthesized using the same method as example 7, using N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide (intermediate 1-6) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidine-3-carbaldehyde (intermediate 3-2) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 35: n- (4- (2- ((1- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide
Example 35 was synthesized using the same method as example 7, using N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide (intermediate 1-6) and 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (intermediate 2-7) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxyiazetidine-1-carboxamide (intermediate 1-1) and 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1), respectively.
Example 36: n- (4- (2- ((1- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide
The same procedures used in example 7 were repeated except for using N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide (intermediate 1-6), tert-butyl 4- (4-amino-1H-pyrazole-1-yl) piperidine-1-carboxylate (intermediate 2-7), and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidine-3-carbaldehyde (intermediate 3-2) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1), and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-3-carbaldehyde (intermediate 3-2) to synthesize example 36.
Example 37:1- (tert-butyl) -N- (4- (2- ((1- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide
Example 37 was synthesized using the same method as example 7, using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide (intermediate 1-4) and 4- (4-amino-1H-pyrazole-1-yl) piperidine-1-carboxylic acid tert-butyl ester (intermediate 2-7) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxyiazetidine-1-carboxamide (intermediate 1-1) and 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1), respectively.
Example 38:1- (tert-butyl) -N- (4- (2- ((1- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide
The same procedures used in example 7 were repeated except for using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide (intermediate 1-4), 4- (4-amino-1H-pyrazole-1-yl) piperidine-1-carboxylic acid tert-butyl ester (intermediate 2-7), and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidine-3-carbaldehyde (intermediate 3-2) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1), and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-3-carbaldehyde (intermediate 3-2) to synthesize example 38.
Example 39:1- (tert-butyl) -N- (4- (2- ((1- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Example 39 was synthesized using the same procedure as in example 7 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5) and 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (intermediate 2-7) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1) and 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1), respectively.
Example 40:1- (tert-butyl) -N- (4- (2- ((1- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
The same procedures used in example 7 were repeated using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5), 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester (intermediate 2-7), and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidine-3-carbaldehyde (intermediate 3-2) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1), and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-carbaldehyde (intermediate 3-2) in place of N- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-5-carbaldehyde).
Example 41: n- (4- (2- ((4- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) methyl) azetidin-3-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 41 was synthesized using the same method as example 7, using 3- (4-aminophenyl) azetidine-1-carboxylic acid tert-butyl ester instead of 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1).
Example 42: n- (4- (2- ((4- (4- ((1- (3- ((2, 6-dioxopiperidin-3-yl) oxy) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 42 was synthesized using the same method as example 7 using 1- (3- ((2, 6-dioxopiperidin-3-yl) oxy) phenyl) piperidine-4-carbaldehyde (intermediate 3-16) instead of 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1).
Example 43: n- (4- (2- ((4- (4- ((1- (4- ((2, 6-dioxopiperidin-3-yl) oxy) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 43 was synthesized using the procedure similar to example 7 using 1- (4- ((2, 6-dioxopiperidin-3-yl) oxy) phenyl) piperidine-4-carbaldehyde (intermediate 3-15) instead of 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1).
Example 44: n- (4- (2- ((4- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methyl) piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide
The same procedures used in example 7 were repeated except for using N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide (intermediate 1-6), tert-butyl 4- (4-aminophenyl) piperidine-1-carboxylate (intermediate 2-5), and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidine-3-carbaldehyde (intermediate 3-2) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1), and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1) to synthesize example 44.
Example 45:1- (tert-butyl) -N- (4- (2- ((4- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methyl) piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide
The same procedures used in example 7 were repeated except for using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide (intermediate 1-4), 4- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (intermediate 2-5), and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidine-3-carbaldehyde (intermediate 3-2) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1), and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1) to synthesize example 45.
Example 46:1- (tert-butyl) -N- (4- (2- ((4- (1- ((1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidin-3-yl) methyl) piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
The same procedures used in example 7 were repeated using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5), 4- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (intermediate 2-5) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) azetidine-3-carbaldehyde (intermediate 3-2) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-2) to give 46.
Example 47: n- (4- (2- ((4- (1- ((1- (4- ((2, 6-dioxopiperidin-3-yl) oxy) phenyl) piperidin-4-yl) methyl) piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 47 was synthesized using the same procedure as in example 7 using tert-butyl 4- (4-aminophenyl) piperidine-1-carboxylate (intermediate 2-5) and 1- (4- ((2, 6-dioxopiperidin-3-yl) oxy) phenyl) piperidine-4-carbaldehyde (intermediate 3-15) instead of tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 48: n- (4- (2- ((4- (4- ((1- (4- ((2, 6-dioxopiperidin-3-yl) oxy) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide
Example 48 was synthesized using the same method as example 7, using N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide (intermediate 1-6) and 1- (4- ((2, 6-dioxopiperidin-3-yl) oxy) phenyl) piperidine-4-carbaldehyde (intermediate 3-15) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 49: n- (4- (2- ((4- (1- ((1- (4- ((2, 6-dioxopiperidin-3-yl) oxy) phenyl) piperidin-4-yl) methyl) piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide
Example 49 was synthesized using the same procedure as in example 7 using N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide (intermediate 1-6), tert-butyl 4- (4-aminophenyl) piperidine-1-carboxylate (intermediate 2-5) and 1- (4- ((2, 6-dioxopiperidin-3-yl) oxy) phenyl) piperidine-4-carbaldehyde (intermediate 3-15) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 50: n- (4- (2- ((4- (4- ((1- (5- ((2, 6-dioxopiperidin-3-yl) oxy) pyridin-2-yl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 50 was synthesized using the same method as example 7, using 1- (5- ((2, 6-dioxopiperidin-3-yl) oxy) pyridin-2-yl) piperidine-4-carbaldehyde (intermediate 3-18) instead of 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1).
Example 51: n- (4- (2- ((4- (1- ((1- (5- ((2, 6-dioxopiperidin-3-yl) oxy) pyridin-2-yl) piperidin-4-yl) methyl) piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 51 was synthesized using the same method as example 7, except that 4- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (intermediate 2-5) and 1- (5- ((2, 6-dioxopiperidin-3-yl) oxy) pyridine-2-yl) piperidine-4-carbaldehyde (intermediate 3-18) were used instead of 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 52: n- (4- (2- ((4- (4- ((1- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
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Using the same method as example 7, example 52 was synthesized using 1- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperidine-4-carbaldehyde (intermediate 3-23) instead of 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1).
Example 53: n- (4- (2- ((4- (1- ((1- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperidin-4-yl) methyl) piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 53 was synthesized using the same procedure as in example 7 using tert-butyl 4- (4-aminophenyl) piperidine-1-carboxylate (intermediate 2-5) and 1- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperidine-4-carbaldehyde (intermediate 3-23) in place of tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 54: n- (4- (2- ((4- (4- ((1- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 54 was synthesized using the same procedure as example 7 using 1- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidine-4-carbaldehyde (intermediate 3-25) instead of 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1).
Example 55: n- (4- (2- ((4- (4- ((1- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 55 was synthesized using the same procedure as in example 7 using 1- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidine-4-carbaldehyde (intermediate 3-24) instead of 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1).
Example 56: n- (4- (2- ((4- (1- ((1- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidin-4-yl) methyl) piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 56 was synthesized using the same method as in example 7, except that 4- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (intermediate 2-5) and 1- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidine-4-carbaldehyde (intermediate 3-24) were used instead of 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 57: n- (4- (2- ((4- (4- ((1- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide
Example 57 was synthesized using the same procedure as in example 7 using N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide (intermediate 1-6) and 1- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidine-4-carbaldehyde (intermediate 3-25) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 58: n- (4- (2- ((4- (4- ((1- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide
Example 58 was synthesized using the same method as example 7, using N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide (intermediate 1-6) and 1- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperidine-4-carbaldehyde (intermediate 3-23) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 59:1- (tert-butyl) -N- (4- (2- ((4- (4- ((1- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide
Example 59 was synthesized using the same procedure as example 7 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide (intermediate 1-4) and 1- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidine-4-carbaldehyde (intermediate 3-25) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 60:1- (tert-butyl) -N- (4- (2- ((4- (4- ((1- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide
Example 60 was synthesized using the same method as example 7, using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide (intermediate 1-4) and 1- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperidine-4-carbaldehyde (intermediate 3-23) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 61:1- (tert-butyl) -N- (4- (2- ((4- (4- ((1- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Example 61 was synthesized using the same procedure as in example 7 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5) and 1- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidine-4-carbaldehyde (intermediate 3-25) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 62:1- (tert-butyl) -N- (4- (2- ((4- (4- ((1- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Example 62 was synthesized using the same method as example 7, using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5) and 1- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperidine-4-carbaldehyde (intermediate 3-23) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxyiazetidine-1-carboxamide (intermediate 1-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 63: n- (4- (2- ((4- ((4- ((1- (3- ((2, 6-dioxopiperidin-3-yl) oxy) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) methyl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 63 was synthesized using the same procedure as in example 7 using tert-butyl 4- (4-aminobenzyl) piperazine-1-carboxylate (intermediate 2-13) and 1- (3- ((2, 6-dioxopiperidin-3-yl) oxy) phenyl) piperidine-4-carbaldehyde (intermediate 3-16) instead of tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 64: n- (4- (2- ((4- ((4- ((1- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) methyl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 64 was synthesized using the same procedure as in example 7 using tert-butyl 4- (4-aminobenzyl) piperazine-1-carboxylate (intermediate 2-13) and 1- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidine-4-carbaldehyde (intermediate 3-25) instead of tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 65: n- (4- (2- ((4- (4- ((1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 65 was synthesized using the same method as example 7, and using 1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde (intermediate 3-30) instead of 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1).
Example 66: n- (4- (2- ((4- (4- ((1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 66 was synthesized using the same method as example 7 using 1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde (intermediate 3-29) instead of 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1).
Example 67: n- (4- (2- ((4- ((4- ((1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) methyl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 67 was synthesized using the same procedure as in example 7 using tert-butyl 4- (4-aminobenzyl) piperazine-1-carboxylate (intermediate 2-13) and 1- (3- (2, 4-dioxotetrahydropyrimidine-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde (intermediate 3-30) instead of tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 68: n- (4- (2- ((4- ((4- ((1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) methyl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 68 was synthesized using the same procedure as example 7 using tert-butyl 4- (4-aminobenzyl) piperazine-1-carboxylate (intermediate 2-13) and 1- (4- (2, 4-dioxotetrahydropyrimidine-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde (intermediate 3-29) instead of tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 69:1- (tert-butyl) -N- (4- (2- ((4- ((4- ((1- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) methyl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Example 69 was synthesized using the same procedure as example 7 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5), tert-butyl 4- (4-aminobenzyl) piperazine-1-carboxylate (intermediate 2-13) and 1- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidine-4-carbaldehyde (intermediate 3-25) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 70:1- (tert-butyl) -N- (4- (2- ((4- (4- ((1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Example 70 was synthesized using the same method as example 7, except that 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5) and 1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde (intermediate 3-30) were used instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxyetidine-1-carboxamide (intermediate 1-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 71:1- (tert-butyl) -N- (4- (2- ((4- (4- ((1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Example 71 was synthesized using the same procedure as example 7 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5) and 1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde (intermediate 3-29) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxyiazetidine-1-carboxamide (intermediate 1-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 72:1- (tert-butyl) -N- (4- (2- ((4- (4- ((1- (4- ((2, 6-dioxopiperidin-3-yl) amino) -2-fluorophenyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Example 72 was synthesized using the same method as example 7, except that 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5) and 1- (4- ((2, 6-dioxopiperidin-3-yl) amino) -2-fluorophenyl) piperidine-4-carbaldehyde (intermediate 3-26) were used instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxyiazetidine-1-carboxamide (intermediate 1-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 73:1- (tert-butyl) -N- (4- (2- ((4- (4- ((1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-fluorophenyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Example 73 was synthesized using the same procedure as in example 7 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5) and 1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-fluorophenyl) piperidine-4-carbaldehyde (intermediate 3-31) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxyiazetidine-1-carboxamide (intermediate 1-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 74:1- (tert-butyl) -N- (4- (2- ((4- ((4- ((1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) methyl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Example 74 was synthesized using the same method as in example 7, using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5), 4- (4-aminobenzyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-13), and 1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde (intermediate 3-30) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1), and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 75:1- (tert-butyl) -N- (4- (2- ((4- ((4- ((1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) methyl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Using the same method as in example 7, example 75 was synthesized using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5), 4- (4-aminobenzyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-13), and 1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde (intermediate 3-29) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1), and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 76:1- (tert-butyl) -N- (4- (2- ((6- (4- ((1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Using the same method as in example 7, example 76 was synthesized using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5), 4- (5-aminopyridine-2-yl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-2), and 1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde (intermediate 3-30) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1), and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-yl) piperidine-4-carbaldehyde (intermediate 3-30), respectively.
Example 77:1- (tert-butyl) -N- (4- (2- ((6- (4- ((1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
The same procedures used in example 7 were repeated except for using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5), 4- (5-aminopyridine-2-yl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-2), and 1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde (intermediate 3-29) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1), and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-yl) piperidine-4-carbaldehyde (intermediate 3-1) to synthesize example 77.
Example 78:1- (tert-butyl) -N- (4- (2- ((4- (1- ((1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Using the same method as in example 7, example 78 was synthesized using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5), 4- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (intermediate 2-5) and 1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde (intermediate 3-30) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 79:1- (tert-butyl) -N- (4- (2- ((4- (1- ((1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
The procedure of example 7 was followed using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5), tert-butyl 4- (4-aminophenyl) piperidine-1-carboxylate (intermediate 2-5) and 1- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde (intermediate 3-29) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-yl) piperidine-4-carbaldehyde (intermediate 3-1) to synthesize example 79.
Example 80: n- (4- (2- ((4- (4- ((1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide
Example 80 was synthesized using the same method as example 7, using N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide (intermediate 1-6) and 1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde (intermediate 3-30) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 81:1- (tert-butyl) -N- (4- (2- ((4- (4- ((1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide
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Example 81 was synthesized using the same procedure as example 7 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide (intermediate 1-4) and 1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde (intermediate 3-30) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 82: n- (4- (2- ((6- (4- ((1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide
Example 82 was synthesized using the same method as example 7, using N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide (intermediate 1-6), 4- (5-aminopyridine-2-yl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-2), and 1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde (intermediate 3-30) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1), and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 83:1- (tert-butyl) -N- (4- (2- ((6- (4- ((1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperazin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide
Example 83 was synthesized using the same procedure as in example 7 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide (intermediate 1-4), 4- (5-aminopyridine-2-yl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-2), and 1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde (intermediate 3-30) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1), and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 84: n- (4- (2- ((4- (1- ((1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide
Example 84 was synthesized using the same method as example 7, using N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide (intermediate 1-6), tert-butyl 4- (4-aminophenyl) piperidine-1-carboxylate (intermediate 2-5) and 1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde (intermediate 3-30) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 85:1- (tert-butyl) -N- (4- (2- ((4- (1- ((1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-4-yl) methyl) piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide
Example 85 was synthesized using the same method as example 7, using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide (intermediate 1-4), 4- (4-aminophenyl) piperidine-1-carboxylic acid tert-butyl ester (intermediate 2-5) and 1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidine-4-carbaldehyde (intermediate 3-30) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1) and 1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidine-4-carbaldehyde (intermediate 3-1), respectively.
Example 86: n- (4- (2- ((4- (4- ((1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -4-methoxybenzoyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Step 1: synthesis of tert-butyl 4- ((4- (4- ((4- (4- ((3-isopropoxy azetidine-1-carboxamido) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) phenyl) piperazin-1-yl) methyl) piperidine-1-carboxylate
3-Isopropoxy-N- (2-methyl-4- (2- ((4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) benzyl) azetidine-1-carboxamide (100 mg,0.19 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (50 mg,0.23 mmol) were suspended in DCM (4 mL). Then, naBH (OAc) 3 (123 mg,0.58 mmol) was added and stirred at room temperature for 2 hours. Aqueous NaHCO 3 (30 mL) was added to the reaction solution and extracted with DCM (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (5-8% MeOH/DCM) to give 129mg (93%) of a yellow solid.
Step 2: synthesis of 3-isopropoxy-N- (2-methyl-4- (2- ((4- (4- (piperidin-4-ylmethyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) benzyl) azetidine-1-carboxamide
Tert-butyl 4- ((4- (4- ((4- (4- ((3-isopropoxyazetidine-1-carboxamido) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) phenyl) piperazin-1-yl) methyl) piperidine-1-carboxylate (128 mg,0.18 mmol) was suspended in DCM (8 mL). TFA (2 mL) was then added and stirred at room temperature for 2 hours. Aqueous NaHCO 3 (30 mL) was added to the reaction solution and extracted with DCM (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 125mg of an orange solid.
Step 3: synthesis of N- (4- (2- ((4- (4- ((1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -4-methoxybenzoyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
3- (2, 4-Dioxotetrahydropyrimidin-1 (2H) -yl) -4-methoxybenzoic acid (intermediate 3-12, 16mg,0.06 mmol) was suspended in DMF (0.5 mL). HOBT (10 mg,0.07 mmol), TBTU (24 mg,0.07 mmol) and DIPEA (0.03 mL,0.15 mmol) were then added. 3-isopropoxy-N- (2-methyl-4- (2- ((4- (4- (piperidin-4-ylmethyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) benzyl) azetidine-1-carboxamide (30 mg,0.05 mmol) was dissolved in DMF (0.5 mL), added and stirred at room temperature for 16 hours. Aqueous NHCl 4 (30 mL) was added to the reaction solution, followed by extraction with EtOAc (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (3-8% MeOH/DCM) and 22mg (52%) of a yellow solid was obtained.
Example 87: n- (4- (2- ((4- (4- ((1- (3- ((2, 6-dioxopiperidin-3-yl) amino) benzoyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 87 was synthesized using the same procedure as in example 86 using 3- ((2, 6-dioxopiperidin-3-yl) amino) benzoic acid (intermediate 3-8) instead of 3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -4-methoxybenzoic acid (intermediate 3-12).
Example 88: n- (4- (2- ((4- (4- ((1- (3- ((2, 6-dioxopiperidin-3-yl) amino) benzoyl) azetidin-3-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 88 was synthesized using the same procedure as example 86 using 3-formylazetidine-1-carboxylic acid tert-butyl ester and 3- ((2, 6-dioxopiperidin-3-yl) amino) benzoic acid (intermediate 3-8) in place of 4-formylpiperidine-1-carboxylic acid tert-butyl ester and 3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -4-methoxybenzoic acid (intermediate 3-12), respectively.
Example 89: n- (4- (2- ((4- (4- ((1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) benzoyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 89 was synthesized using the same procedure as in example 86 using 3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) benzoic acid (intermediate 3-11) instead of 3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -4-methoxybenzoic acid (intermediate 3-12).
Example 90: n- (3- (2- ((4- (4- ((1- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -4-methoxybenzoyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -5-fluoro-2-methylphenyl) -3-isopropoxy azetidine-1-carboxamide
Example 90 was synthesized using the same method as step 1 and step 2 of example 7 and example 86 using N- (3- (2-chloropyrimidin-4-yl) -5-fluoro-2-methylphenyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-8) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1).
Example 91: n- (4- (2- ((1- (1- ((1- (3- ((2, 6-dioxopiperidin-3-yl) amino) benzoyl) piperidin-4-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 91 was synthesized using the same procedure as steps 1 and 2 of example 7 and example 86 using tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate (intermediate 2-7) and 3- ((2, 6-dioxopiperidin-3-yl) amino) benzoic acid (intermediate 3-8) in place of tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1) and 3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -4-methoxybenzoic acid (intermediate 3-12), respectively.
Example 92: n- (4- (2- ((1- (1- ((1- (3- ((2, 6-dioxopiperidin-3-yl) amino) benzoyl) azetidin-3-yl) methyl) piperidin-4-yl) -1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 92 was synthesized using the same method as steps 1 and 2 of example 7 and example 86, using tert-butyl 4- (4-amino-1H-pyrazol-1-yl) piperidine-1-carboxylate (intermediate 2-7), tert-butyl 3-formylazetidine-1-carboxylate and 3- ((2, 6-dioxopiperidin-3-yl) amino) benzoic acid (intermediate 3-8) in place of tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1), tert-butyl 4-formylpiperidine-1-carboxylate and 3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -4-methoxybenzoic acid (intermediate 3-12), respectively.
Example 93: n- (4- (2- ((4- (4- ((1- (3- ((2, 6-dioxopiperidin-3-yl) amino) benzoyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide
Example 93 was synthesized using the same procedure as in steps 1 and 2 of example 7 and example 86 using N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide (intermediate 1-6) and 3- ((2, 6-dioxopiperidin-3-yl) amino) benzoic acid (intermediate 3-8) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxyiazetidine-1-carboxamide (intermediate 1-1) and 3- (2, 4-dioxotetrahydropyrimidine-1 (2H) -yl) -4-methoxybenzoic acid (intermediate 3-12), respectively.
Example 94: n- (4- (2- ((4- (4- ((1- (3- ((2, 6-dioxopiperidin-3-yl) amino) benzoyl) azetidin-3-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide
Example 94 was synthesized using the same procedure as steps 1 and 2 of example 7 and example 86 using N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide (intermediate 1-6), 3-formylazetidine-1-carboxylic acid tert-butyl ester and 3- ((2, 6-dioxopiperidin-3-yl) amino) benzoic acid (intermediate 3-8) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy-azetidine-1-carboxamide (intermediate 1-1), 4-formylpiperidine-1-carboxylic acid tert-butyl ester and 3- (2, 4-dioxotetrahydropyrimidine-1 (2H) -yl) -4-methoxybenzoic acid (intermediate 3-12), respectively.
Example 95:1- (tert-butyl) -N- (4- (2- ((4- (4- ((1- (3- ((2, 6-dioxopiperidin-3-yl) amino) benzoyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide
Example 95 was synthesized using the same procedure as in steps 1 and 2 of example 7 and example 86 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide (intermediate 1-4) and 3- ((2, 6-dioxopiperidin-3-yl) amino) benzoic acid (intermediate 3-8) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1) and 3- (2, 4-dioxotetrahydropyrimidine-1 (2H) -yl) -4-methoxybenzoic acid (intermediate 3-12), respectively.
Example 96:1- (tert-butyl) -N- (4- (2- ((4- (4- ((1- (3- ((2, 6-dioxopiperidin-3-yl) amino) benzoyl) azetidin-3-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide
Example 96 was synthesized using the same procedure as in steps 1 and 2 of example 7 and example 86 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide (intermediate 1-4), 3-formylazetidine-1-carboxylic acid tert-butyl ester and 3- ((2, 6-dioxopiperidin-3-yl) amino) benzoic acid (intermediate 3-8) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), 4-formylpiperidine-1-carboxylic acid tert-butyl ester and 3- (2, 4-dioxotetrahydropyrimidine-1 (2H) -yl) -4-methoxybenzoic acid (intermediate 3-12), respectively.
Example 97:1- (tert-butyl) -N- (4- (2- ((4- (4- ((1- (3- ((2, 6-dioxopiperidin-3-yl) amino) benzoyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
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Example 97 was synthesized using the same procedures as in steps 1 and 2 of example 7 and example 86 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5) and 3- ((2, 6-dioxopiperidin-3-yl) amino) benzoic acid (intermediate 3-8) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxyiazetidine-1-carboxamide (intermediate 1-1) and 3- (2, 4-dioxotetrahydropyrimidine-1 (2H) -yl) -4-methoxybenzoic acid (intermediate 3-12), respectively.
Example 98:1- (tert-butyl) -N- (4- (2- ((4- (4- ((1- (3- ((2, 6-dioxopiperidin-3-yl) amino) benzoyl) azetidin-3-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Example 98 was synthesized using the same methods as step 1 and step 2 of example 7 and example 86 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5), 3-formylazetidine-1-carboxylic acid tert-butyl ester and 3- ((2, 6-dioxopiperidin-3-yl) amino) benzoic acid (intermediate 3-8) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxyetidine-1-carboxamide (intermediate 1-1), 4-formylpiperidine-1-carboxylic acid tert-butyl ester and 3- (2, 4-dioxotetrahydropyrimidine-1 (2H) -yl) -4-methoxybenzoic acid (intermediate 3-12), respectively.
Example 99: n- (4- (2- ((4- (1- ((1- (3- ((2, 6-dioxopiperidin-3-yl) amino) benzoyl) piperidin-4-yl) methyl) piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 99 was synthesized using the same procedure as step 1 and step 2 of example 7 and example 86 using tert-butyl 4- (4-aminophenyl) piperidine-1-carboxylate (intermediate 2-5) and 3- ((2, 6-dioxopiperidin-3-yl) amino) benzoic acid (intermediate 3-8) in place of tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1) and 3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -4-methoxybenzoic acid (intermediate 3-12), respectively.
Example 100: n- (4- (2- ((4- (1- ((1- (3- ((2, 6-dioxopiperidin-3-yl) amino) benzoyl) azetidin-3-yl) methyl) piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 100 was synthesized using the same method as steps 1 and 2 of example 7 and example 86, using tert-butyl 4- (4-aminophenyl) piperidine-1-carboxylate (intermediate 2-5), tert-butyl 3-formylazetidine-1-carboxylate and 3- ((2, 6-dioxopiperidin-3-yl) amino) benzoic acid (intermediate 3-8) instead of tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1), tert-butyl 4-formylpiperidine-1-carboxylate and 3- (2, 4-dioxotetrahydropyrimidine-1 (2H) -yl) -4-methoxybenzoic acid (intermediate 3-12), respectively.
Example 101: n- (4- (2- ((4- (1- ((1- (3- ((2, 6-dioxopiperidin-3-yl) amino) benzoyl) piperidin-4-yl) methyl) azetidin-3-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 101 was synthesized using the same method as steps 1 and 2 of example 7 and example 86, using 3- (4-aminophenyl) azetidine-1-carboxylic acid tert-butyl ester and 3- ((2, 6-dioxopiperidin-3-yl) amino) benzoic acid (intermediate 3-8) instead of 4- (4-aminophenyl) piperazine-1-carboxylic acid tert-butyl ester (intermediate 2-1) and 3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -4-methoxybenzoic acid (intermediate 3-12), respectively.
Example 102: n- (4- (2- ((4- (4- ((1- (3- ((2, 6-dioxopiperidin-3-yl) oxy) benzoyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 102 was synthesized using the same method as example 86, using 3- ((2, 6-dioxopiperidin-3-yl) oxy) benzoic acid (intermediate 3-14) instead of 3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -4-methoxybenzoic acid (intermediate 3-12).
Example 103: n- (4- (2- ((4- (4- (1- (3- ((2, 6-dioxopiperidin-3-yl) amino) benzoyl) piperidin-4-yl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 103 was synthesized using the same method as in example 86, using tert-butyl 4-oxopiperidine-1-carboxylate and 3- ((2, 6-dioxopiperidin-3-yl) amino) benzoic acid (intermediate 3-8) instead of tert-butyl 4-formylpiperidine-1-carboxylate and 3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -4-methoxybenzoic acid (intermediate 3-12), respectively.
Example 104: n- (4- (2- ((4- (1 '- (3- ((2, 6-dioxopiperidin-3-yl) amino) benzoyl) - [1,4' -bipiperidin ] -4-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 104 was synthesized using the same method as steps 1 and 2 of example 7 and example 86, using tert-butyl 4- (4-aminophenyl) piperidine-1-carboxylate (intermediate 2-5), tert-butyl 4-oxopiperidine-1-carboxylate and 3- ((2, 6-dioxopiperidin-3-yl) amino) benzoic acid (intermediate 3-8) in place of tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1), tert-butyl 4-formylpiperidine-1-carboxylate and 3- (2, 4-dioxotetrahydropyrimidine-1 (2H) -yl) -4-methoxybenzoic acid (intermediate 3-12), respectively.
Example 105: n- (4- (2- ((4- (4- ((1- (2- ((3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) amino) -2-oxoethyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
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Step 1:2- (4- ((4- (4- ((4- (4- ((3-isopropoxy azetidine-1-carboxamide) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) phenyl) piperazin-1-yl) methyl) piperidin-1-yl) acetic acid methyl ester
3-Isopropoxy-N- (2-methyl-4- (2- ((4- (4- (piperidin-4-ylmethyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) benzyl) azetidine-1-carboxamide (50 mg,0.08 mmol) and methyl 2-bromoacetate (15 mg,0.10 mmol) were suspended in DCM (10 mL). Then, triethylamine (0.03 mL,0.25 mmol) was added at 0deg.C and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and the resulting residue was MPLC (5-8% MeOH/DCM) to give 41mg (73%) of a yellow solid.
Step 2: synthesis of 2- (4- ((4- (4- ((4- (4- ((3-isopropoxy azetidine-1-carboxamido) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) phenyl) piperazin-1-yl) methyl) piperidin-1-yl) acetic acid
Methyl 2- (4- ((4- (4- ((4- (4- ((3-isopropoxyetidine-1-carboxamido) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) phenyl) piperazin-1-yl) methyl) piperidin-1-yl) acetate (41 mg,0.06 mmol) was suspended in EtOH (2 mL). Then, lithium hydroxide (5 mg,0.12 mmol) was added and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to give 34mg of a yellow solid.
Step 3: synthesis of N- (4- (2- ((4- (4- ((1- (2- ((3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) amino) -2-oxoethyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
3- ((3-Aminophenyl) amino) piperidine-2, 6-dione (intermediate 3-7, 33mg,0.05 mmol) was suspended in DMF (0.5 mL). HOBT (8 mg,0.06 mmol), TBTU (19 mg,0.06 mmol) and DIPEA (0.03 mL,0.15 mmol) were then added. 2- (4- ((4- (4- ((4- (3-isopropoxy azetidine-1-carboxamido) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) phenyl) piperazin-1-yl) methyl) piperidin-1-yl) acetic acid (33 mg,0.05 mmol) dissolved in DMF (0.5 mL) was added and stirred at room temperature for 16 hours. Aqueous NHCl 4 (30 mL) was added to the reaction solution, followed by extraction with EtOAc (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (5-8% MeOH/DCM) to give 8mg (15% two-step yield) of a yellow solid.
Example 106: n- (3- (2- ((4- (4- ((1- (2- ((3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) amino) -2-oxoethyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -5-fluoro-2-methylphenyl) -3-isopropoxy azetidine-1-carboxamide
Example 106 was synthesized using the same method as step 1 and step 2 of example 7, step 1 and step 2 of example 86, and example 105 using N- (3- (2-chloropyrimidin-4-yl) -5-fluoro-2-methylphenyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-8) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1).
Example 107: n- (4- (2- ((4- (4- ((1- (6- (2, 6-dioxopiperidin-3-yl) -5-oxo-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) azetidin-3-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Step 1: synthesis of tert-butyl 3- ((4- (4- ((4- (4- ((3-isopropoxy azetidine-1-carboxamido) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) phenyl) piperazin-1-yl) methyl) azetidine-1-carboxylate
3-Isopropoxy-N- (2-methyl-4- (2- ((4- (piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) benzyl) azetidine-1-carboxamide (50 mg,0.10 mmol) and tert-butyl 3-formylazetidine-1-carboxylate (22 mg,0.12 mmol) were suspended in DCM (2 mL). Then, naBH (OAc) 3 (64 mg,0.30 mmol) was added and stirred at room temperature for 2 hours. Aqueous NaHCO 3 (30 mL) was added to the reaction solution and extracted with DCM (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (5-8% MeOH/DCM) and gave 65mg (98%) of a yellow solid.
Step 2: synthesis of N- (4- (2- ((4- (4- (azetidin-3-ylmethyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
3- ((4- (4- ((4- (4- ((3-Isopropoxy azetidine-1-carboxamido) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) phenyl) piperazin-1-yl) methyl) azetidine-1-carboxylic acid tert-butyl ester (65 mg,0.10 mmol) was suspended in DCM (4 mL). TFA (1 mL) was then added and stirred at room temperature for 2 hours. Aqueous NaHCO 3 (30 mL) was added to the reaction solution and extracted with DCM (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 53mg (95%) of a yellow solid.
Step 3: synthesis of N- (4- (2- ((4- (4- ((1- (6- (2, 6-dioxopiperidin-3-yl) -5-oxo-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) azetidin-3-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
N- (4- (2- ((4- (4- (azetidin-3-ylmethyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy-azetidine-1-carboxamide (33 mg,0.06 mmol), 3- (2-chloro-5-oxo-5, 7-dihydro-6H-pyrrolo [3,4-b ] pyridin-6-yl) piperidine-2, 6-dione (25 mg,0.09 mmol) and DIPEA (0.03 mL,0.18 mmol) were suspended in DMSO (2 mL) and stirred at 120℃for 16H. Aqueous NH 4 Cl (30 mL) was added to the reaction solution, followed by extraction with EtOAc (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (5-8% MeOH/DCM) and 19mg (41%) of a yellow solid was obtained.
Example 108: n- (3- (2- ((4- (4- ((1- (6- (2, 6-dioxopiperidin-3-yl) -5-oxo-6, 7-dihydro-5H-pyrrolo [3,4-b ] pyridin-2-yl) azetidin-3-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -5-fluoro-2-methylphenyl) -3-isopropoxy azetidine-1-carboxamide
Example 108 was synthesized using the same method as step 1 and step 2 of example 7 and example 107 using N- (3- (2-chloropyrimidin-4-yl) -5-fluoro-2-methylphenyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-8) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1).
Example 109: n- (4- (2- ((4- (4- (1- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperidin-4-yl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 109 was synthesized using the procedure described for example 107, starting from tert-butyl 4-oxopiperidine-1-carboxylate and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione, instead of tert-butyl 3-formylazetidine-1-carboxylate and 3- (2-chloro-5-oxo-5, 7-dihydro-6H-pyrrolo [3,4-b ] pyridin-6-yl) piperidine-2, 6-dione.
Example 110: n- (4- (2- ((4- (1 '- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) - [1,4' -bipiperidin ] -4-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 110 was synthesized using the same method as steps 1 and 2 of example 7 and example 107, using tert-butyl 4- (4-aminophenyl) piperidine-1-carboxylate (intermediate 2-5), tert-butyl 4-oxopiperidine-1-carboxylate and 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione instead of tert-butyl 4- (4-aminophenyl) piperazine-1-carboxylate (intermediate 2-1), tert-butyl 3-formylazetidine-1-carboxylate and 3- (2-chloro-5-oxo-5, 7-dihydro-6H-pyrrolo [3,4-b ] pyridin-6-yl) piperidine-2, 6-dione, respectively.
Example 111: n- (4- (2- ((4- (4- ((4- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperazin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Step 1: synthesis of tert-butyl 4- ((1- (4- ((4- (4- ((3-isopropoxy azetidine-1-carboxamido) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) phenyl) piperidin-4-yl) methyl) piperazine-1-carboxylate
N- (4- (2-Chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy-azetidine-1-carboxamide (intermediate 1-1,53mg,0.14 mmol), tert-butyl 4- ((1- (4-aminophenyl) piperidin-4-yl) methyl) piperazine-1-carboxylate (intermediate 2-8,58mg,0.15 mmol), pd 2(dba)3 (13 mg,0.01 mmol), S-phos (12 mg,0.03 mmol) and Cs 2CO3 (91.2 mg,0.28 mmol) were suspended in dioxane (2 mL) and stirred at 100℃for 3 hours. The reaction solution was filtered and concentrated under reduced pressure, and the resulting residue was MPLC (80-100% EtOAc/hexanes) to give 47mg (47%) of a yellow solid.
Step 2: synthesis of 3-isopropoxy-N- (2-methyl-4- (2- ((4- (4- (piperazin-1-ylmethyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) benzyl) azetidine-1-carboxamide
Tert-butyl 4- ((1- (4- ((4- (4- ((3-isopropoxyazetidine-1-carboxamido) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) phenyl) piperidin-4-yl) methyl) piperazine-1-carboxylate (47 mg,0.06 mmol) was suspended in DCM (2 mL). TFA (0.2 mL) was then added and stirred at room temperature for 3 hours. The reaction solution was diluted with DCM (2 mL), then aqueous sodium bicarbonate (ph=8-9) was added and extracted with DCM (20 ml×2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 28mg (70%) of a yellow solid.
Step 3: synthesis of N- (4- (2- ((4- (4- ((4- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperazin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
3-Isopropoxy-N- (2-methyl-4- (2- ((4- (4- (piperazin-1-ylmethyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) benzyl) azetidine-1-carboxamide (20 mg,0.03 mmol), 2- (2, 6-dioxopiperidin-3-yl) -5-fluoroisoindoline-1, 3-dione (11 mg,0.04 mmol) and DIPEA (0.015 mL,0.09 mmol) were suspended in DMSO (1.15 mL) and stirred at 100deg.C for 16 hours. Distilled water (30 mL) was added to the reaction solution and extracted with EtOAc (20 mL x 2). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (50-100% EA/Hex) to give 10mg (38%) of a yellow solid.
Example 112: n- (4- (2- ((4- (3- ((4- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperazin-1-yl) methyl) azetidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 112 was synthesized using the same method as example 111 using tert-butyl 4- ((1- (4-aminophenyl) azetidin-3-yl) methyl) piperazine-1-carboxylate (intermediate 2-9) instead of tert-butyl 4- ((1- (4-aminophenyl) piperidin-4-yl) methyl) piperazine-1-carboxylate (intermediate 2-8).
Example 113: n- (4- (2- ((4- (3- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) benzoyl) piperazin-1-yl) methyl) azetidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Step 1: synthesis of tert-butyl 4- ((1- (4- ((4- (4- ((3-isopropoxy azetidine-1-carboxamido) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) phenyl) azetidin-3-yl) methyl) piperazine-1-carboxylate
N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy-azetidine-1-carboxamide (intermediate 1-1, 150mg,0.40 mmol), tert-butyl 4- ((1- (4-aminophenyl) azetidin-3-yl) methyl) piperazine-1-carboxylate (intermediate 2-9,166mg,0.48 mmol), pd 2(dba)3 (37 mg,0.04 mmol), S-phos (33 mg,0.08 mmol) and Cs 2CO3 (326 mg,1.00 mmol) were suspended in dioxane (8 mL) and stirred at 100℃for 16 hours. Distilled water (50 mL) was added to the reaction solution and extracted with EtOAc (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (50-100% EtOAc/hexane, 2-4% MeOH/DCM) to give 167mg (61%) of a brown solid.
Step 2: synthesis of 3-isopropoxy-N- (2-methyl-4- (2- ((4- (3- (piperazin-1-ylmethyl) azetidin-1-yl) phenyl) amino) pyrimidin-4-yl) benzyl) azetidine-1-carboxamide
4- ((1- (4- ((4- (4- ((3-Isopropoxy azetidine-1-carboxamido) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) azetidin-3-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester (167 mg,0.24 mmol) and TFA (0.25 mL) were suspended in DCM (0.75 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give 124mg (87%) of a brown solid.
Step 3: synthesis of N- (4- (2- ((4- (3- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) benzoyl) piperazin-1-yl) methyl) azetidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
3- ((2, 6-Dioxopiperidin-3-yl) amino) benzoic acid (intermediate 3-8, 20mg,0.08 mmol) was suspended in DMF (2 mL). HATU (10 mg,0.07 mmol) and DIPEA (0.04 ml,0.21 mmol) were then added and 3-isopropoxy-N- (2-methyl-4- (2- ((4- (3- (piperazin-1-ylmethyl) azetidin-1-yl) phenyl) amino) pyrimidin-4-yl) benzyl) azetidine-1-carboxamide (40 mg,0.07 mmol) was slowly added to the reaction solution. The mixture was stirred at room temperature for 16 hours, distilled water (30 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (15 ml×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (amine silica, 1-3% MeOH/DCM) to give 26mg (47%) of a yellow solid.
Example 114: n- (4- (2- ((4- (4- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) benzoyl) piperazin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 114 was synthesized using the same method as example 113 using tert-butyl 4- ((1- (4-aminophenyl) piperidin-4-yl) methyl) piperazine-1-carboxylate (intermediate 2-8) instead of tert-butyl 4- ((1- (4-aminophenyl) azetidin-3-yl) methyl) piperazine-1-carboxylate (intermediate 2-9). .
Example 115: n- (4- (2- ((4- (4- ((1- (3- ((2, 6-dioxopiperidin-3-yl) amino) benzyl) piperidin-4-yl) methyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
3-Isopropoxy-N- (2-methyl-4- (2- ((4- (4- (piperidin-4-ylmethyl) piperazin-1-yl) phenyl) amino) pyrimidin-4-yl) benzyl) azetidine-1-carboxamide (20 mg,0.03 mmol), 3- ((3- (bromomethyl) phenyl) amino) piperidine-2, 6-dione (intermediate 3-13, 14mg,0.05 mmol) and K 2CO3 (9 mg,0.07 mmol) were suspended in DMF (1 mL) and stirred at 80℃for 16 hours. Distilled water (30 mL) was added to the reaction solution, followed by extraction with EtOAc (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (NH silica, 1-2% MeOH/DCM) to give 6.2mg (23%) of a yellow solid.
Example 116: n- (4- (2- ((4- (4- (4- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidine-1-carbonyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Step 1: synthesis of tert-butyl 1- (4- ((4- (4- ((3-isopropoxy azetidine-1-carboxamido) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) phenyl) piperidine-4-carboxylate
N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1, 300mg,0.80 mmol), tert-butyl 1- (4-aminophenyl) piperidine-4-carboxylate (intermediate 2-10, 442mg,1.60 mmol), pd 2(dba)3 (147 mg,0.16 mmol), S-Phos (99 mg,0.24 mmol) and Cs 2CO3 (782 mg,2.40 mmol) were suspended in 1, 4-dioxane (5 mL) and stirred at 100℃for 16 hours. The reaction solution was filtered through celite and concentrated under reduced pressure. The resulting residue was MPLC (0-100% EtOAc/hexanes) to give 266mg (54%) of a brown solid.
Step 2: synthesis of 1- (4- ((4- (4- ((3-isopropoxy azetidine-1-carboxamido) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) phenyl) piperidine-4-carboxylic acid
Tert-butyl 1- (4- ((4- (4- ((3-isopropoxyazetidine-1-carboxamido) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) phenyl) piperidine-4-carboxylate (260 mg,0.42 mmol) and TFA (2 mL) were suspended in DCM (6 mL) and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to give 230mg (97%) of a yellow solid.
Step 3: synthesis of N- (4- (2- ((4- (4- (4- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidine-1-carbonyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
1- (4- ((4- (4- ((3-Isopropoxyazetidine-1-carboxamido) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) phenyl) piperidine-4-carboxylic acid (60 mg,0.10 mmol), 3- ((3- (piperidin-4-yl) phenyl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-10,40mg,0.14 mmol), HATU (61 mg,0.16 mmol) and DIPEA (0.1 mL,0.50 mmol) were suspended in DMF (2 mL) and stirred at room temperature for 16 hours. Distilled water (30 mL) was added to the reaction solution and extracted with EtOAc (20 mL x 2). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. PTLC (7% MeOH/DCM) was performed on the resulting residue to give 41mg (46%) of a yellow solid.
Example 117: n- (4- (2- ((4- (4- (4- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidine-1-carbonyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 117 was synthesized using the same method as example 116 using 3- ((4- (piperidin-4-yl) phenyl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-9) instead of 3- ((3- (piperidin-4-yl) phenyl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-10).
Example 118: n- (4- (2- ((4- (4- (4- (4- ((2, 6-dioxopiperidin-3-yl) oxy) phenyl) piperidine-1-carbonyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 118 was synthesized using the same procedure as example 116 using 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17) instead of 3- ((3- (piperidin-4-yl) phenyl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-10).
Example 119: n- (4- (2- ((4- (4- ((4- (4- ((2, 6-dioxopiperidin-3-yl) oxy) phenyl) piperidin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Step 1: synthesis of N- (4- (2- ((4- (4- (1, 3-dioxolan-2-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
N- (4- (2-Chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy-azetidine-1-carboxamide (intermediate 1-1,100mg,0.27 mmol), 4- (4- (1, 3-dioxolan-2-yl) piperidin-1-yl) aniline (intermediate 2-11,133mg,0.53 mmol), pd 2(dba)3 (49 mg,0.053 mmol), S-phos (33 mg,0.08 mmol) and Cs 2CO3 (174 mg,0.53 mmol) were suspended in dioxane (4 mL) and stirred at 100℃for 16 hours. Distilled water (30 mL) was added to the reaction solution, followed by extraction with EtOAc (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (50-100% EtOAc/hexanes) to give 87mg (56%) of a yellow solid.
Step 2: synthesis of N- (4- (2- ((4- (4-formylpiperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
N- (4- (2- ((4- (4- (1, 3-dioxolan-2-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (87 mg,0.15 mmol) was suspended in DCM (2 mL). TFA (2 mL) was then added and stirred at 50 ℃ for 16 hours. The reaction solution was concentrated under reduced pressure and the resulting residue was MPLC (5-8% MeOH/DCM) to give 44mg (55%) of a yellow solid.
Step 3: synthesis of N- (4- (2- ((4- (4- ((4- (4- ((2, 6-dioxopiperidin-3-yl) oxy) phenyl) piperidin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
N- (4- (2- ((4- (4-formylpiperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy-azetidine-1-carboxamide (22 mg,0.04 mmol) and 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17, 16mg,0.05 mmol) were suspended in DCM (2 mL) and stirred for 10 min. NaBH (OAc) 3 (17 mg,0.08 mmol) was added and stirred at room temperature for 16 hours. Aqueous NaHCO 3 (30 mL) was added to the reaction solution and extracted with DCM (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (2-8% MeOH/DCM) and 11mg (32%) of a yellow solid was obtained.
Example 120: n- (4- (2- ((4- (4- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperazin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 120 was synthesized using the same method as example 119 using 3- ((3- (piperazin-1-yl) phenyl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-21) instead of 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17).
Example 121: n- (4- (2- ((4- (4- ((4- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperazin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 121 was synthesized using the same method as example 119 using 3- ((4- (piperazin-1-yl) phenyl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-22) instead of 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17).
Example 122: n- (4- (2- ((4- (4- ((4- (3- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 122 was synthesized using the same method as example 119 using 3- ((3- (piperidin-4-yl) phenyl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-10) instead of 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17).
Example 123: n- (4- (2- ((4- (4- ((4- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 123 was synthesized using the same procedure as example 119 using 3- ((4- (piperidin-4-yl) phenyl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-9) instead of 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17).
Example 124: n- (4- (2- ((4- (4- ((4- (5- ((2, 6-dioxopiperidin-3-yl) oxy) pyridin-2-yl) piperidin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 124 was synthesized using the same procedure as example 119 using 3- ((6- (piperidin-4-yl) pyridin-3-yl) oxy) piperidine-2, 6-dione hydrochloride (intermediate 3-27) instead of 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17).
Example 125: n- (4- (2- ((4- (4- ((4- (5- ((2, 6-dioxopiperidin-3-yl) oxy) pyridin-2-yl) piperazin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 125 was synthesized using the same procedure as example 119 using 3- ((6- (piperazin-1-yl) pyridin-3-yl) oxy) piperidine-2, 6-dione hydrochloride (intermediate 3-28) instead of 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17).
Example 126: n- (4- (2- ((4- (4- ((4- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperidin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 126 was synthesized using the same method as example 119 using 3- ((6- (piperidin-4-yl) pyridin-3-yl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-19) instead of 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17).
Example 127: n- (4- (2- ((4- (4- ((4- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperazin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 127 was synthesized using the same procedure as in example 119 using 3- ((6- (piperazin-1-yl) pyridin-3-yl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-20) instead of 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17).
Example 128: n- (4- (2- ((4- (4- ((4- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperidin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide
Example 128 was synthesized using the same procedure as in example 119 using N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide (intermediate 1-6) and 3- ((6- (piperidin-4-yl) pyridin-3-yl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-19) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1) and 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17), respectively.
Example 129: n- (4- (2- ((4- (4- ((4- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperazin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide
Example 129 was synthesized using the same procedure as in example 119 using N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide (intermediate 1-6) and 3- ((6- (piperazin-1-yl) pyridin-3-yl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-20) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1) and 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17), respectively.
Example 130:1- (tert-butyl) -N- (4- (2- ((4- (4- ((4- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperidin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide
Example 130 was synthesized using the same method as example 119 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide (intermediate 1-4) and 3- ((6- (piperidin-4-yl) pyridin-3-yl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-19) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1) and 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17), respectively.
Example 131:1- (tert-butyl) -N- (4- (2- ((4- (4- ((4- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperazin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide
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Example 131 was synthesized using the same procedure as example 119 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide (intermediate 1-4) and 3- ((6- (piperazin-1-yl) pyridin-3-yl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-20) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1) and 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17), respectively.
Example 132:1- (tert-butyl) -N- (4- (2- ((4- (4- ((4- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperidin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Example 132 was synthesized using the same procedure as example 119 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5) and 3- ((6- (piperidin-4-yl) pyridin-3-yl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-19) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxyiazetidine-1-carboxamide (intermediate 1-1) and 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17), respectively.
Example 133:1- (tert-butyl) -N- (4- (2- ((4- (4- ((4- (5- ((2, 6-dioxopiperidin-3-yl) amino) pyridin-2-yl) piperazin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Example 133 was synthesized using the same procedure as example 119 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5) and 3- ((6- (piperazin-1-yl) pyridin-3-yl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-20) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxyiazetidine-1-carboxamide (intermediate 1-1) and 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17), respectively.
Example 134: n- (4- (2- ((4- (4- ((4- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide
Example 134 was synthesized using the same procedure as example 119 using N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1-isopropyl-1H-pyrazole-4-carboxamide (intermediate 1-6) and 3- ((4- (piperidin-4-yl) phenyl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-9) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxyiazetidine-1-carboxamide (intermediate 1-1) and 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17), respectively.
Example 135:1- (tert-butyl) -N- (4- (2- ((4- (4- ((4- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide
Example 135 was synthesized using the same procedure as in example 119 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-pyrazole-4-carboxamide (intermediate 1-4) and 3- ((4- (piperidin-4-yl) phenyl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-9) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1) and 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17), respectively.
Example 136:1- (tert-butyl) -N- (4- (2- ((4- (4- ((4- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Example 136 was synthesized using the same procedure as example 119 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5) and 3- ((4- (piperidin-4-yl) phenyl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-9) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1) and 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17), respectively.
Example 137:1- (tert-butyl) -N- ((5- (2- ((4- (4- ((4- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -3-methylpyridin-2-yl) methyl) -1H-1,2, 3-triazole-4-carboxamide
Example 137 was synthesized using the same procedure as example 119 using 1- (tert-butyl) -N- ((5- (2-chloropyrimidin-4-yl) -3-methylpyridin-2-yl) methyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-7) and 3- ((4- (piperidin-4-yl) phenyl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-9) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxyiazetidine-1-carboxamide (intermediate 1-1) and 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17), respectively.
Example 138:1- (tert-butyl) -N- (4- (2- ((4- (4- ((4- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Example 138 was synthesized using the same procedure as example 119 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5) and 1- (3- (piperidin-4-yl) phenyl) dihydropyrimidine-2, 4 (1H, 3H) -dione (intermediate 3-32) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxyetidine-1-carboxamide (intermediate 1-1) and 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17), respectively.
Example 139:1- (tert-butyl) -N- (4- (2- ((4- (4- ((4- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Example 139 was synthesized using the same procedure as in example 119, using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5) and 1- (4- (piperidin-4-yl) phenyl) dihydropyrimidine-2, 4 (1H, 3H) -dione (intermediate 3-33) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxyetidine-1-carboxamide (intermediate 1-1) and 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17), respectively.
Example 140:1- (tert-butyl) -N- (4- (2- ((4- ((4- ((4- (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-1-yl) methyl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
The same procedures used in example 119 were repeated using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5), 4- ((4- (1, 3-dioxolan-2-yl) piperidin-1-yl) methyl) aniline (intermediate 2-14) and 1- (3- (piperidin-4-yl) phenyl) dihydropyrimidine-2, 4 (1H, 3H) -dione (intermediate 3-32) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), 4- (4- (1, 3-dioxolan-2-yl) piperidin-1-yl) aniline (intermediate 2-11) and 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17) respectively to synthesize example 140.
Example 141:1- (tert-butyl) -N- (4- (2- ((4- ((4- ((4- (4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) phenyl) piperidin-1-yl) methyl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
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The same procedures used in example 119 were repeated using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5), 4- ((4- (1, 3-dioxolan-2-yl) piperidin-1-yl) methyl) aniline (intermediate 2-14) and 1- (4- (piperidin-4-yl) phenyl) dihydropyrimidine-2, 4 (1H, 3H) -dione (intermediate 3-33) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), 4- (4- (1, 3-dioxolan-2-yl) piperidin-1-yl) aniline (intermediate 2-11) and 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17) respectively to synthesize example 141.
Example 142:1- (tert-butyl) -N- (4- (2- ((4- ((4- ((4- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidin-1-yl) methyl) phenyl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Example 142 was synthesized using the same method as in example 119, using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5), 4- ((4- (1, 3-dioxolan-2-yl) piperidin-1-yl) methyl) aniline (intermediate 2-14) and 3- ((4- (piperidin-4-yl) phenyl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-9) in place of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1), 4- (4- (1, 3-dioxolan-2-yl) piperidin-1-yl) aniline (intermediate 2-11) and 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17), respectively.
Example 143:1- (tert-butyl) -N- (4- (2- ((4- (4- ((4- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidin-1-yl) methyl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) -2- (hydroxymethyl) benzyl) -1H-1,2, 3-triazole-4-carboxamide
Example 143 was synthesized using the same procedure as example 119 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2- (hydroxymethyl) benzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-12) and 3- ((4- (piperidin-4-yl) phenyl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-9) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1) and 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17), respectively.
Example 144: n- (4- (2- ((6- (4- ((4- (4- ((2, 6-dioxopiperidin-3-yl) oxy) phenyl) piperidin-1-yl) methyl) piperidin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Step 1: synthesis of N- (4- (2- ((6- (4- (hydroxymethyl) piperidin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
N- (4- (2-Chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy-azetidine-1-carboxamide (intermediate 1-1,300mg,0.80 mmol), (1- (5-aminopyridin-2-yl) piperidin-4-yl) methanol (intermediate 2-4,245mg,1.18 mmol), pd 2(dba)3 (147 mg,0.16 mmol), S-phos (99 mg,0.24 mmol) and Cs 2CO3 (521 mg,1.60 mmol) were suspended in dioxane (8 mL) and stirred at 90℃for 24 hours. Distilled water (70 mL) was added to the reaction solution and extracted with EtOAc (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (50-100% EtOAc/hexane, 5-8% MeOH/DCM) to give 300mg (69%) of a yellow solid.
Step 2: synthesis of (1- (5- ((4- (4- ((3-isopropoxy azetidine-1-carboxamido) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) pyridin-2-yl) piperidin-4-yl) methyl 4-methylbenzenesulfonate
N- (4- (2- ((6- (4- (hydroxymethyl) piperidin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (146 mg,0.27 mmol) was suspended in DCM (10 mL) and TsCl (103 mg,0.54 mmol) was added thereto. Triethylamine (0.11 mL,0.81 mmol) was slowly added to the reaction solution and stirred at room temperature for 16 hours. Distilled water (30 mL) was added to the reaction solution and extracted with DCM (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (2-3% MeOH/DCM) to give 88mg (47%) of a yellow solid.
Step 3: synthesis of N- (4- (2- ((6- (4- ((4- (4- ((2, 6-dioxopiperidin-3-yl) oxy) phenyl) piperidin-1-yl) methyl) piperidin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
(1- (5- ((4- (4- ((3-Isopropoxyetidine-1-carboxamido) methyl) -3-methylphenyl) pyrimidin-2-yl) amino) piperidin-4-yl) methyl 4-methylbenzenesulfonate (88 mg,0.13 mmol), 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17, 52mg,0.16 mmol), DIPEA (0.07 mL,0.378 mmol) and KI (10 mg,0.06 mmol) were suspended in MeCN (2 mL) and stirred at 85 ℃ for 2 hours. The reaction solution was concentrated under reduced pressure, distilled water (30 mL) was added, and extracted with DCM (10 ml×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was MPLC (2-8% MeOH/DCM) and 28mg (28%) of a yellow solid was obtained.
Example 145: n- (4- (2- ((6- (4- ((4- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidin-1-yl) methyl) piperidin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide
Example 145 was synthesized using the same procedure as example 144 using 3- ((4- (piperidin-4-yl) phenyl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-9) instead of 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17).
Example 146:1- (tert-butyl) -N- (4- (2- ((6- (4- ((4- (4- ((2, 6-dioxopiperidin-3-yl) amino) phenyl) piperidin-1-yl) methyl) piperidin-1-yl) pyridin-3-yl) amino) pyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide
Example 146 was synthesized using the same procedure as example 144 using 1- (tert-butyl) -N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -1H-1,2, 3-triazole-4-carboxamide (intermediate 1-5) and 3- ((4- (piperidin-4-yl) phenyl) amino) piperidine-2, 6-dione hydrochloride (intermediate 3-9) instead of N- (4- (2-chloropyrimidin-4-yl) -2-methylbenzyl) -3-isopropoxy azetidine-1-carboxamide (intermediate 1-1) and 3- (4- (piperidin-4-yl) phenoxy) piperidine-2, 6-dione hydrochloride (intermediate 3-17), respectively.
The NMR and mass results of the compounds obtained in examples 1 to 146 are summarized in Table 2 below.
TABLE 2
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Evaluation of the Compounds of the invention
Experimental example 1: measurement of BTK protein degradation Capacity
TMD-8, RAMOS or 293T BTK MUT (C481S) cells were treated with the synthesized compounds and then Western blot detection was used to measure the amount of BTK protein present in the cells. The protocol for the experiments performed using TMD-8 cells was as follows:
culture TMD-8 cells were resuspended in RPMI1640 MEDIUM (Hyclone, SH 30027.01), 10% FBS (Hyclone, SV 30207.02) and 1% penicillin-streptomycin (Welgene, LS 202-02) MEDIUM and 1mL of the suspension was seeded into 12 well plates at a cell concentration of 1X 10 6/mL.
Compound treatment 12-well plates were treated as follows: 10mM stock was serially diluted 1/10 with DMSO (3. Mu.L+27. Mu. LDMSO) and cells were treated with 0.1, 1, 10. Mu.M or 0.0001, 0.001, 0.01, 0.1. Mu.M of compound at final concentration and harvested after 24 hours. In the negative control group, 1/10 of the diluted DMSO was added to the medium (3. Mu.L DMSO+27. Mu.L medium).
[ Harvesting ] Each well was pipetted into a 1.5mL microtube and collected and centrifuged (500 g, 5min, 4 ℃). After removal of the supernatant, it was washed with PBS and centrifuged again (500 g, 5min, 4 ℃). The supernatant was removed and the precipitate collected.
[ Cell lysis and sample preparation ] lysis buffer was prepared as follows: 60-70. Mu.L of RIPA buffer (Biosesang, RC 2038-050-00), 0.5mM PMSF (SIGMA, P7626) and 1 Xprotease/phosphatase inhibitor (CELL SIGNALING, 5872S) were added per well and left on ice for 30 minutes (vortexing at 0 and 30 minutes respectively), followed by sonication (10 second pulse, 30 second stop, 5 cycles, 70% amplification) and centrifugation (15000 g,15 minutes, 4 ℃). Only the supernatant was collected and transferred to a new microtube. Samples were diluted 1/2 in 96-well plates with RIPA buffer. 200 μ L BCA Protein Assay Kit (iNtRON, 21071) of mixture a: b=50:1 was added each, left at 37 ℃ for 30 minutes and cooled for 10 minutes. Absorbance was then measured at 562nm using a SYNERGY H1 microplate reader of BioTek. The protein was quantified using the measured value to prepare a sample, which was then boiled at 70℃for 10 minutes. The sample buffer used at this time was a mixture of NuPAGE or Bolt 4x sample buffer (Invitrogen) and 10x sample reducing agent each depending on the gel to be used. RIPA buffer was used for protein dilution.
Western blot detection method equal amounts of samples were loaded onto NuPAGE or Bolt Bis-tris 4-12% gradient gels and run (200V, 35 min). Transfer to 0.2mm NC membrane (1.3A constant, 25V restriction, 15 min) using Trans-blot Turbo (BIO-RAD). For blocking, skim milk or INTERCEPT BLOCKING BUFFER (LI-COR, 927-60001) was used at room temperature for 1 hour with 0.1% TBST=1:1. anti-BTK rabbits (1:1,000 in 5% skim milk/0.2% TBST, size: 77kDa,Cell Signaling Technology) were reacted at 4℃for 16 hours or at room temperature for 2 hours. anti-GAPDH rabbits (1:10,000 in 5% BSA/0.2% TBST, size: 36kDa, GENETEX) and anti- β -actin mice (1:10,000 in 5% BSA/0.2% TBST, RT, size: 43kDa, GENETEX) were reacted at room temperature for 1 or 3 hours. The samples were washed 3 times for 5 minutes with 0.5% tbst. Based on the addition of secondary antibody per sample, anti-rabbit IgG (1:5,000 in 5% skim milk/TBST, CST),800CW goat anti-rabbit IgG secondary antibody (1:10,000 in 5% skim milk/TBST, RT 45 min),/>680RD goat anti-mouse IgG secondary antibody (1:10,000 in 5% skim milk/TBST, RT 45 min) and reacted on a shaker at room temperature for 45 min. Samples were washed 5 times with 0.5% TBST for 5 minutes each and tested with LI-COR's Odyssey. At this time, BTK was detected using SuperSignal West Pico PLUS Chemiluminescent Substrate or SuperSignal West femto Maximum Sensitivity Substrate, and the housekeeping gene was detected as it is.
The results of evaluating the BTK protein degradation ability of the compounds of the present invention in TMD-8 cells are summarized in table 3 below.
TABLE 3
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As shown in table 3, the compounds of the present invention exhibit excellent activity in degrading BTK protein.

Claims (13)

1. A compound of formula 1 or a pharmaceutically acceptable salt thereof:
[ chemical formula 1]
In the chemical formula 1 described above, a compound having the formula,
A is a carbocycle, heterocycle, aryl or heteroaryl,
R 1a and R 1b are each independently H, halogen, C 1-6 alkyl, C 1-6 alkoxy or carbocycle, wherein one or more hydrogens of the alkyl, the alkoxy or the carbocycle are optionally substituted with one or more selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy and C 1-6 hydroxyalkyl,
R 2a and R 2b are each independently H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxy or C 1-6 hydroxyalkyl,
R 3 is H, halogen, C 1-6 alkyl, C 1-6 haloalkyl or-NH 2,
X 1 and X 2 are each independently CH or N,
Y 1 is NH or O, and the group consisting of,
N is an integer of 0,1 or 2,
L is a compound represented by the following chemical formula 2,
[ Chemical formula 2]
In the chemical formula 2 described above, the chemical formula,
B is aryl or heteroaryl, wherein one or more hydrogens in the aryl or heteroaryl are optionally substituted with one or more selected from the group consisting of C 1-6 alkyl, halogen, and C 1-6 haloalkyl,
C 1 and C 2 are each independently a direct bond, a carbocycle or a heterocycle, wherein one or more hydrogens in the carbocycle or the heterocycle are optionally substituted with one or more selected from the group consisting of C 1-6 alkyl, halogen, C 1-6 haloalkyl and hydroxy,
D 1 and D 2 are each independently a direct bond, -O-, -N (R 4) - -, C (O) - -, -CC-, -C (O) NH-, or-NHC (O) - -, where R 4 is H, C 1-6 alkyl or C 1-6 haloalkyl,
Q 1、q2、q3 and q 4 are each independently integers from 0 to 3,
E is the following chemical formula 3 or chemical formula 4,
[ Chemical formula 3]
[ Chemical formula 4]
In the chemical formula 3 and the chemical formula 4,
X 3、X4、X5 and X 6 are each independently CH or N,
Y 2 is -C(R6a)(R6b)-、-C(O)-、-C(R6a)(R6b)-C(R6a)(R6b)-、-C(R6a)＝C(R6b)-、-C(R6a)＝N-、-N＝C(R6a)- or-n=n-,
Z is a direct bond, -C (R 6a)(R6b)-、-N(R6a) -, -O-, or-C (O) NH-,
R 5a and R 5b are each independently H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or C 1-6 haloalkoxy,
R 6a and R 6b are each independently H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein in the chemical formula 1:
a is a carbocycle, heterocycle, aryl or heteroaryl,
R 1a and R 1b are each independently H, halogen, C 1-6 alkyl or C 1-6 alkoxy, wherein one or more hydrogens of the alkyl or the alkoxy are optionally substituted with one or more selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 haloalkyl, hydroxy and C 1-3 hydroxyalkyl,
R 2a and R 2b are each independently H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxy or C 1-6 hydroxyalkyl,
R 3 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl or-NH 2,
X 1 and X 2 are each independently CH or N,
Y 1 is NH or O, and the group consisting of,
N is an integer of 0,1 or 2,
L is a compound represented by the following chemical formula 2,
[ Chemical formula 2]
In the chemical formula 2 described above, the chemical formula,
B is aryl or heteroaryl, wherein one or more hydrogens in the aryl or heteroaryl are optionally substituted with one or more selected from the group consisting of C 1-3 alkyl, halogen, and C 1-3 haloalkyl,
C 1 and C 2 are each independently a direct bond, a carbocycle or a heterocycle, wherein one or more hydrogens in the carbocycle or the heterocycle are optionally substituted with one or more selected from the group consisting of C 1-3 alkyl, halogen and hydroxy,
D 1 and D 2 are each independently a direct bond, -O-, -N (R 4) -C (O) -, -CC-, -C (O) NH-, or-NHC (O) -, wherein R 4 is H, C 1-3 alkyl or C 1-3 haloalkyl,
Q 1、q2、q3 and q 4 are each independently integers from 0 to 3,
E is the following chemical formula 3 or chemical formula 4,
[ Chemical formula 3]
[ Chemical formula 4]
In the chemical formula 3 and the chemical formula 4,
X 3、X4、X5 and X 6 are each independently CH or N,
Y 2 is -C(R6a)(R6b)-、-C(O)-、-C(R6a)＝C(R6b)-、-C(R6a)＝N-、-N＝C(R6a)- or-n=n-,
Z is a direct bond, -C (R 6a)(R6b)-、-N(R6a) -, -O-, or-C (O) NH-,
R 5a and R 5b are each independently H, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl or C 1-6 haloalkoxy,
R 6a and R 6b are each independently H, halogen, C 1-3 alkyl or C 1-3 haloalkyl.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein in the chemical formula 1:
a is azetidine, pyrrolidine, piperidine, piperazine, benzene, pyridine, pyrimidine, pyrazole, triazole, oxazole, thiazole, oxadiazole or thiadiazole,
R 1a and R 1b are each independently H, halogen, C 1-6 alkyl or C 1-6 alkoxy, wherein one or more hydrogens of the alkyl or the alkoxy are optionally substituted with one or more selected from the group consisting of halogen, C 1-3 alkyl and hydroxy,
R 2a and R 2b are each independently H, halogen, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 hydroxyalkyl,
R 3 is H or halogen, and the halogen,
X 1 is CH or N, and,
X 2 is a group of CH (CH),
Y 1 is NH or O, and the group consisting of,
N is an integer of 0,1 or 2,
L is a compound represented by the following chemical formula 2,
[ Chemical formula 2]
In the chemical formula 2 described above, the chemical formula,
B is benzene, pyridine, pyrimidine, pyrazine, pyridazine, tetrahydroisoquinoline, pyrazole, triazole or tetrahydropyrazolopyrazine,
C 1 and C 2 are each independently a direct bond, a cyclobutane, a cyclohexane, an azetidine, a pyrrolidine, a piperidine, or a piperazine, wherein one or more hydrogens of the cyclobutane, the cyclohexane, the azetidine, the pyrrolidine, the piperidine, or the piperazine are optionally substituted with one or more selected from the group consisting of C 1-3 alkyl, halogen, and hydroxy,
D 1 and D 2 are a direct bond, -O-, -NH-, -C (O) NH-, or-NHC (O) -,
Q 1、q2、q3 and q 4 are each independently integers from 0 to 3,
E is the following chemical formula 3 or chemical formula 4,
[ Chemical formula 3]
[ Chemical formula 4]
In the chemical formula 3 and the chemical formula 4,
X 3、X4、X5 and X 6 are each independently CH or N,
Y 2 is-CH 2 -or-C (O) -,
Z is a direct bond, -NH-or-O-,
R 5a or R 5b are each independently H, halogen, C 1-3 alkyl or C 1-3 alkoxy.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is any one of:
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is any one of the following:
6. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is any one of the following:
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7. A composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
8. A pharmaceutical composition for degrading or inhibiting Bruton's Tyrosine Kinase (BTK), comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient.
9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is for use in the treatment or prevention of an autoimmune disease or cancer.
10. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is for use in the treatment or prevention of leukemia, lymphoma, solid tumors, autoimmune diseases, fahrenheit macroglobulinemia, B-cell malignancy, recurrent mature B-cell tumors, multiple myeloma, multiple sclerosis, graft-versus-host disease, agaropectinemia, hepatitis, neuromyelitis optica, myelodysplastic syndrome (MDS), plasmacytoma, asthma, chronic Obstructive Pulmonary Disease (COPD), transplant rejection, gout, atherosclerosis, inflammatory bowel disease, pancreatitis, B-cell mediated hyperacute disease, thromboembolic disease, pulmonary embolism, polycythemia vera, primary thrombocythemia, myelofibrosis with myelometaplasia, or acute inflammatory disease.
11. A method for treating or preventing a Bruton's Tyrosine Kinase (BTK) related disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.
12. The method of claim 11, wherein the Bruton's Tyrosine Kinase (BTK) related disease is an autoimmune disease or cancer.
13. The method of claim 11, wherein the Bruton's Tyrosine Kinase (BTK) related disease is leukemia, lymphoma, solid tumors, autoimmune diseases, fahrenheit macroglobulinemia, B-cell malignancy, recurrent mature B-cell tumor, multiple myeloma, multiple sclerosis, graft-versus-host disease, agaropectinemia, hepatitis, neuromyelitis optica, myelodysplastic syndrome (MDS), plasmacytoma, asthma, chronic Obstructive Pulmonary Disease (COPD), transplant rejection, gout, atherosclerosis, inflammatory bowel disease, pancreatitis, B-cell mediated hyperacute disease, thromboembolic disease, pulmonary embolism, polycythemia vera, primary thrombocythemia, myelofibrosis with myelometaplasia, or acute inflammatory disease.
CN202280071497.9A 2021-11-05 2022-11-04 Compound with BTK protein degradation activity and medical application thereof Pending CN118159532A (en)

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KR10-2021-0151162 2021-11-05
KR10-2022-0034349 2022-03-18
KR20220034349 2022-03-18
PCT/KR2022/017291 WO2023080732A1 (en) 2021-11-05 2022-11-04 Compound having btk protein degradation activity, and medical uses thereof

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