CN114149409B - (hetero) aryl amide compound with protein kinase inhibition activity - Google Patents

(hetero) aryl amide compound with protein kinase inhibition activity Download PDF

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CN114149409B
CN114149409B CN202111400594.1A CN202111400594A CN114149409B CN 114149409 B CN114149409 B CN 114149409B CN 202111400594 A CN202111400594 A CN 202111400594A CN 114149409 B CN114149409 B CN 114149409B
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hydrogen
chlorodifluoromethoxy
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CN114149409A (en
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韩进松
崔文禹
黄慧
刘宇航
缪顺童
李飞
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China Pharmaceutical University
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Abstract

The invention relates to (hetero) aryl amide compounds shown in a formula I and capable of inhibiting the tyrosine kinase enzyme activity of Abelson protein (Abl 1), abelson related protein (Abl 2) and related chimeric proteins, in particular Bcr-Abl1, or pharmaceutically acceptable stereoisomers thereof, or crystal forms, pharmaceutically acceptable salts, solvates or hydrates thereof, a preparation method of the compounds, a pharmaceutical composition containing the compounds, and application of the compounds or the compositions in preparation of medicines. The compound of the invention has better Bcr-Abl kinase inhibition activity and pharmacodynamic performance, and can be used for treating and/or preventing Bcr-Abl caused diseases in subjects.

Description

(hetero) aryl amide compound with protein kinase inhibition activity
Technical Field
The invention belongs to the field of medicines. In particular, the present invention relates to (hetero) aryl amides capable of inhibiting the tyrosine kinase activity of Abelson protein (Abl 1), abelson related protein (Abl 2) and related chimeric proteins, in particular Bcr-Abl1, pharmaceutical compositions comprising them, and methods for their preparation and use.
Background
The known (hetero) aryl amide compounds are Bcr-Abl kinase inhibitory active compounds and are allosteric inhibitors of Bcr-Abl tyrosine kinase. For example, in WO2013171639 and WO2018133826, a class of (hetero) arylamide structural derivatives are disclosed, as well as the use thereof for Bcr-Abl kinase mediated cancers, for example in chronic myeloid leukemia and other diseases in which Bcr-Abl kinase inhibition is required.
The Bcr-Abl fusion gene is caused by the reciprocal translocation between chromosomes 9 and 22 in human hematopoietic stem cells, and the fusion of Bcr and Abl1 genes on Philadelphia chromosome (Ph). The expressed tyrosine kinase enables a series of signal paths for regulating cell growth, differentiation and death to be abnormally activated, so that the proliferation, adhesion and survival properties of cells are changed, and various tumors are generated, and the Bcr-Abl tyrosine kinase is inhibited, so that the growth of the tumors can be effectively inhibited.
(hetero) aryl amides such as ABL001 (also known as Asciminib, chemical name (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (1H-pyrazol-5-yl) nicotinamide, having the following formula) are ABL1 kinase allosteric inhibitors developed by nova pharmaceutical company, targeting the allosteric site myristoyl pocket of ABL1 for its inactivation, and the combination with ATP-competitive Bcr-ABL tyrosine kinase inhibitors are effective in preventing the emergence of ATP competitive inhibitors and/or resistance to the use of allosteric inhibitors. ABL-001 has been shown to act in combination with the second generation Bcr-ABL inhibitor nilotinib to radically treat CML in a mouse model (Andrew A. Wylei et al (2017) Nature 543, 733-737). North is developing a therapeutic regimen for ABL001 in combination with a number of ATP-competitive Bcr-ABL inhibitors, including imatinib, nilotinib, and dasatinib. The drug candidate is currently in phase III clinical trials.
TGRX-678 is the first and fastest developing fourth-generation Bcr-Abl1 allosteric inhibitor in China developed by Tajiri pharmaceutical company, and is also the second-generation Bcr-Abl1 allosteric inhibitor worldwide, and has obtained Chinese clinical permissions for 9 months, and is actively preparing clinical trials. The results of the preclinical in-vitro and in-vivo studies show that compared with ABL001, TGRX-678 has higher activity and selectivity on Bcr-AblT315I cells, better oral bioavailability and better in-vivo animal safety than ABL001.
However, there remains a need in the art to develop compounds that have inhibitory activity, or better pharmacodynamic properties, against Bcr-Abl kinase.
Disclosure of Invention
The invention aims to provide a novel (hetero) aryl amide compound or a pharmaceutically acceptable stereoisomer thereof, or a crystal form, a pharmaceutically acceptable salt, a solvate or a hydrate thereof, which has better Bcr-Abl kinase inhibition activity and pharmacodynamic performance and can be used for treating/preventing Bcr-Abl caused diseases in a subject.
The invention also provides a preparation method of the (hetero) aryl amide compound and an intermediate thereof.
The invention also provides a pharmaceutical composition comprising at least one compound of the invention or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, and a pharmaceutically acceptable excipient.
The invention also provides the use of the compound of the invention or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof or the pharmaceutical composition of the invention for the preparation of a medicament.
In this regard, the technical scheme adopted by the invention is as follows:
in a first aspect of the present invention there is provided a (hetero) aryl amide compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, water-soluble or hydrated form thereof:
wherein: y is selected from CH or N;
R 1 independently selected from hydrogen, halogen, nitrile, hydroxy, which may be mono-, di-or polysubstituted;
R 2 selected from-CF 2 -Y 1 ；
Y 1 Selected from hydrogen, chlorine, fluorine, methyl, difluoromethyl or trifluoromethyl;
z is selected from the group consisting of a bond, O or S (O) 0-2 ；
or-Z-R 2 Together represent-SF 5 ；
Het is pyrrolidinyl, wherein the pyrrolidinyl is substituted with 1 or more R a Group substitution;
R a independently selected from hydrogen, hydroxy, methyl, halogen, methoxy, hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl, cyano, or amino-carbonyl;
l is O, S or NR b ；
R 3 Selected from the group consisting of
Wherein X is 1 -X 9 Independently selected from CR c Or N, and X 6 ，X 7 ,，X 8 And X 9 One of them being a C atom, X, bound to the parent nucleus 10 Selected from O, S or NR b ，X 11 Selected from O, S, NR b Or C (R) c ) 2 ；
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3, 4, 5, 6 or 7;
R b independently selected from hydrogen, acetyl, C 1-6 Alkyl or C 1-6 A haloalkyl group;
r and R c Independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, aldehyde, carboxyl, acetamido, ethoxycarbonyl, aminoacyl, -NH 2 、-NHC 1-6 Alkyl, -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 Heteroaryl;
or two R groups on the same atom or on adjacent atoms may together form C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 Heteroaryl;
the halogen is F, cl or Br.
In certain preferred embodiments, formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, is disclosed:
wherein:
R 1 independently selected from: hydrogen, halogen, nitrile, hydroxy, which may be mono-, di-or polysubstituted; preferably, R 1 Independently selected from hydrogen or halogen;
R a independently selected from: hydrogen, hydroxy, halogen, nitrile, carboxyl, which may be mono-, di-or poly-substituted; preferably, R a Independently selected from: hydrogen or hydroxy;
l is O, S or NR b The method comprises the steps of carrying out a first treatment on the surface of the Preferably, L is NR b ；
R 3 Selected from the group consisting of
Wherein X is 1 -X 9 Independently selected from CR c Or N, and X 6 ,X 7 ,X 8 And X 9 One of them being a C atom, X, bound to the parent nucleus 10 Selected from O, S or NR b ，X 11 Selected from O, S, NR b Or C (R) c ) 2 ；
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3, 4, 5, 6 or 7;
R b independently selected from hydrogen, acetyl, C 1-6 Alkyl or C 1-6 A haloalkyl group; preferably, R b Independently selected from hydrogen, acetyl, C 1-3 Alkyl or C 1-3 A haloalkyl group;
r and R c Independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, aldehyde, carboxyl, acetamido, ethoxycarbonyl, aminoacyl, -NH 2 、-NHC 1-6 Alkyl, -N (C) 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 Heteroaryl;
preferably, R and R c Independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, aldehyde, carboxyl, acetamido, ethoxycarbonyl, aminoacyl, -NH 2 、-NHC 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 、C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 Heteroaryl;
or two R groups on the same atom or on adjacent atoms may together form C 3-7 Cycloalkyl, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 Heteroaryl;
the halogen is F, cl or Br.
In certain preferred embodiments, formula (III), or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, is disclosed:
Wherein:
R 1 independently selected from hydrogen or halogen; preferably, R 1 Is hydrogen;
R a independently selected from hydrogen or hydroxy; preferably, R a Is hydroxyl;
R 3 selected from the following groups optionally substituted with one, two or three R:
R b independently selected from hydrogen, acetyl or C 1-3 An alkyl group;
r is independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, aldehyde, carboxyl, acetamido, ethoxycarbonyl, aminoacyl, -NH 2 、-NHC 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 、C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 Heteroaryl; preferably, R is independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, aldehyde, carboxyl, acetamido, ethoxycarbonyl, aminoacyl, -NH 2 、-NHC 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 、C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-7 Heterocycloalkyl, C 6-10 Aryl or C 5-10 Heteroaryl groups.
In certain more preferred embodiments, the (hetero) arylamide compounds of the present invention are any one of the compounds in table 1 below, or a pharmaceutically acceptable salt, stereoisomer, hydrate, or solvate thereof:
table 1 shows some of the compounds of the present invention:
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in yet another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient. In a specific embodiment, the compounds of the present invention are provided in the pharmaceutical composition in an effective amount. In particular embodiments, the compounds of the present invention are provided in a therapeutically effective amount. In particular embodiments, the compounds of the present invention are provided in a prophylactically effective amount.
In yet another aspect, the present invention provides a process for the preparation of a compound according to formula (III) and intermediates thereof, comprising the steps of:
(1) Preparation of intermediate (V)
Dissolving 5-bromo-6-chloronicotinic acid (IV) in anhydrous DMF, adding 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethyl urea Hexafluorophosphate (HATU) and N, N-Diisopropylethylamine (DIPEA), stirring at room temperature for reacting for 1 hour, adding corresponding substituted aniline, and stirring at room temperature for reacting to obtain an intermediate (V);
(2) Preparation of intermediate (VI)
Dissolving the intermediate (V) in anhydrous DMSO, adding DIPEA and corresponding substituted pyrrolidine, and heating for reaction to obtain an intermediate (VI);
(3) Preparation of the target product (III)
Buchwald coupling reaction, comprising dissolving intermediate (VI) in anhydrous toluene, adding t-BuXPhos and t-Buona (or XantPhos and Cs) 2 CO 3 ) And palladium catalyst, adding various substituted aromatic amines, and heating under the protection of inert gas to obtain the target product (III).
In yet another aspect, the present invention provides a process for the preparation of a compound according to formula (III) and intermediates thereof, comprising the steps of:
(1) Preparation of intermediate (VIII)
Dissolving 6-chloro-5-nitronicotinic acid (VII) in anhydrous DCM, adding thionyl chloride (SOCl) 2 ) Heating and stirring for reaction for 4 hours, vacuum drying, adding anhydrous DCM for dissolution, then adding corresponding substituted aniline, and stirring at room temperature for reaction to obtain an intermediate (VIII);
(2) Preparation of Intermediate (IX)
Dissolving the intermediate (VIII) in anhydrous DMSO, adding DIPEA and corresponding substituted pyrrolidine, and heating for reaction to obtain an Intermediate (IX);
(3) Preparation of intermediate (X)
Intermediate (IX) was dissolved in anhydrous MeOH, palladium on carbon (Pd/C) was added to the mixture at H 2 Heating and reacting under the condition to obtain an intermediate (X);
(4) Preparation of the target product (III)
Buchwald coupling reaction, comprising the steps of dissolving intermediate (X) in anhydrous toluene, adding XantPhos and Cs 2 CO 3 And palladium catalyst, adding various substituted aromatic amines, and heating under the protection of inert gas to obtain a target product (III);
or reductive amination reaction, which comprises dissolving intermediate (X) in anhydrous methanol, adding various substituted cycloalkyl ketones, heating and stirring for 2 hr, and adding sodium cyanoborohydride (NaBH) 3 CN), heating to obtain the target product (III).
The invention also provides kits comprising a compound of the invention, and other therapeutic agents, in combination with a pharmaceutically acceptable carrier, adjuvant or vehicle.
The invention also provides the use of the compound of the invention in the preparation of a medicament for the treatment and/or prophylaxis of Bcr-Abl caused diseases.
The invention provides the use of a compound of the invention or a composition of the invention in the manufacture of a medicament for the treatment and/or prophylaxis of a Bcr-Abl caused disease.
In particular embodiments, the disease may be selected from: solid tumors, sarcomas, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, gastrointestinal stromal tumors, thyroid cancer, gastric cancer, rectal cancer, multiple myeloma, neoplasia, and other proliferative or proliferative diseases.
In specific embodiments, the Bcr-Abl caused disease is chronic granulocytic leukemia, gastrointestinal stromal tumor, acute granulocytic leukemia, thyroid, metastatic invasive cancer, or a combination thereof.
The compounds of the invention are useful for the treatment and/or prophylaxis of diseases or disorders associated with aberrant activated kinase activity of wild-type Abl, including non-malignant diseases or disorders such as CNS diseases, in particular neurodegenerative diseases (e.g. alzheimer's disease, parkinson's disease), motor neuron diseases (amyotrophic lateral sclerosis), muscular dystrophy, autoimmune diseases and inflammatory diseases (diabetes and pulmonary fibrosis), viral infections, ruan virus diseases.
In particular embodiments, the compounds are administered orally, subcutaneously, intravenously or intramuscularly. In particular embodiments, the compound is administered chronically.
Other objects and advantages of the present invention will be apparent to those skilled in the art from the detailed description, examples, and examples that follow.
Definition of the definition
Chemical definition
The definition of specific functional groups and chemical terms is described in more detail below.
When numerical ranges are listed, it is intended to include each and every value and subrange within the range. For example "C 1-6 Alkyl "includes C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 And C 5-6 An alkyl group.
It will be appreciated that any of the moieties defined below may be substituted with a number of substituents, and that the corresponding definitions are within their scope as set out below, including such substituted moieties, when described herein. Unless otherwise indicated, the term "substituted" is defined below.
“C 1-6 Alkyl "refers to a straight or branched saturated hydrocarbon group having from l to 6 carbon atoms, also referred to herein as" lower alkyl ". In some embodiments, C 1-4 Alkyl groups are particularly preferred. Examples of such alkyl groups include, but are not limited to: methyl (C) 1 ) Ethyl (C) 2 ) N-propyl (C) 3 ) Isopropyl (C) 3 ) N-butyl (C) 4 ) Tert-butyl (C) 4 ) Sec-butyl (C) 4 ) Isobutyl (C) 4 ) N-pentyl (C) 5 ) 3-pentyl (C) 5 ) Amyl (C) 5 ) Neopentyl (C) 5 ) 3-methyl-2-butyl (C) 5 ) Tert-amyl (C) 5 ) And n-hexyl (C) 6 ). Unless otherwise indicated, each of the alkyl groups is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents; for example, 1 to 5 substituents, l to 3 substituents or l substituents. In some embodiments, the alkyl is unsubstituted C 1-6 Alkyl (e.g., -CH) 3 ). In some embodiments, the alkyl is substituted C 1-6 An alkyl group.
“C 1-6 Alkoxy "refers to the group-OR, wherein R is a substituted OR unsubstituted C 1-6 An alkyl group. In some embodiments, C 1-4 Alkoxy groups are particularly preferred. Specific such alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1, 2-dimethylbutoxy.
"halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). In some embodiments, the halogen group is F, cl or Br. In some embodiments, the halogen group is Cl. In some embodiments, the halogen group is F. In some embodiments, the halogen group is Br.
Thus, "C 1-6 Haloalkyl "means" C "as described above 1-6 Alkyl ", substituted with one or more halo groups.
In some embodiments, C 1-4 Haloalkyl is particularly preferred, more preferably C 1-2 A haloalkyl group. Exemplary such haloalkyl groups include, but are not limited to: -CF 3 、-CH 2 F、-CHF 2 、-CClF 2 、-CHFCH 2 F、-CH 2 CHF 2 、-CF 2 CF 3 、-CF 2 CClF 2 、-CF 2 CH 3 、-CCl 3 、-CH 2 Cl、-CHCl 2 2, 2-trifluoro-1, 1-dimethyl-ethyl, and the like.
“C 3-7 Cycloalkyl "means having 3 to 7 ring carbon atomsA child and zero heteroatoms of a non-aromatic cyclic hydrocarbon group. In some embodiments, C 3-6 Cycloalkyl is particularly preferred, more preferably C 5-6 Cycloalkyl groups. Cycloalkyl also includes ring systems in which the cycloalkyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary such cycloalkyl groups include, but are not limited to: cyclopropyl (C) 3 ) Cyclopropenyl (C) 3 ) Cyclobutyl (C) 4 ) Cyclobutenyl (C) 4 ) Cyclopentyl (C) 5 ) Cyclopentenyl (C) 5 ) Cyclohexyl (C) 6 ) Cyclohexenyl (C) 6 ) Cyclohexadienyl (C) 6 ) Cycloheptyl (C) 7 ) Cycloheptenyl (C) 7 ) Cycloheptadienyl (C) 7 ) Cycloheptatrienyl (C) 7 ) And so on. Unless otherwise indicated, each cycloalkyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted by one or more substituents ("substituted cycloalkyl"). In some embodiments, cycloalkyl is unsubstituted C 3-7 Cycloalkyl groups. In some embodiments, the carbocyclyl is substituted C 3-7 Cycloalkyl groups.
“C 3-7 Heterocycloalkyl "or refers to a group of a 3 to 7 membered non aromatic ring system having a ring carbon atom and l to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, sulfur, boron, phosphorus and silicon. In heterocycloalkyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as the valency permits. In some embodiments, C 3-6 Heterocycloalkyl groups are particularly preferred, which are 3 to 6 membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably C 5-6 Heterocycloalkyl, which is a 5 to 6 membered non-aromatic ring system having a ring carbon atom and l to 3 ring heteroatoms. Unless otherwise indicated, each heterocycloalkyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocycloalkyl") or substituted with one or more substituents ("substituted heterocycloalkyl"). In some embodiments, the heterocycloalkyl is unsubstituted C 3-7 Heterocycloalkyl group. In some embodiments, the heterocycloalkyl is a substituted C 3-7 A heterocycloalkyl group. Heterocycloalkyl also includes ring systems in which the above heterocycloalkyl ring is fused with one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or ring systems in which the above heterocycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocycloalkyl ring; and in such cases the number of ring members continues to represent the number of ring members in the heterocycloalkyl ring system. Exemplary 3-membered heterocycloalkyl groups containing one heteroatom include, but are not limited to: aziridinyl, oxetanyl, thietanyl (thio). Exemplary 4-membered heterocycloalkyl groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocycloalkyl groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocycloalkyl groups containing two heteroatoms include, but are not limited to: dioxolanyl, oxathiolanyl (oxathiolanyl), dithiolanyl (disulfuranyl) and oxazolidin-2-one. Exemplary 5-membered heterocycloalkyl groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6-membered heterocycloalkyl groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl and thianyl (thianyl). Exemplary 6-membered heterocycloalkyl groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiocyclohexenyl, and dioxanyl. Exemplary 6-membered heterocycloalkyl groups containing three heteroatoms include, but are not limited to: hexahydrotriazinyl (triazinyl). Exemplary 7-membered heterocycloalkyl groups containing one heteroatom include, but are not limited to: azepanyl, oxepinyl, and thiepanyl. Exemplary 5-membered heterocycloalkyl groups fused to a C6 aryl ring (also referred to herein as 5, 6-bicyclic heterocycloalkyl) include, but are not limited to: indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary AND C 6 Aryl ringFused 6-membered heterocycloalkyl (also referred to herein as 6, 6-bicyclic heterocycloalkyl) includes, but is not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
“C 6-10 Aryl "refers to a group of a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) having 6 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C 6 Aryl "; for example, phenyl). In some embodiments, aryl groups have ten ring carbon atoms ("C 10 Aryl "; for example, naphthyl groups, such as 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which the above aryl ring is fused to one or more cycloalkyl or heterocycloalkyl groups and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Unless otherwise indicated, each of the aryl groups is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents. In some embodiments, the aryl is unsubstituted C 6-10 Aryl groups. In some embodiments, aryl is substituted C 6-10 Aryl groups.
“C 5-10 Heteroaryl "refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as the valency permits. The heteroaryl bicyclic ring system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above heteroaryl ring is fused to one or more cycloalkyl or heterocycloalkyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, C 5-6 Heteroaryl groups are particularly preferred which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic rings having ring carbon atoms and l-4 ring heteroatomsA system. Unless otherwise indicated, each heteroaryl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted by one or more substituents ("substituted heteroaryl"). In some embodiments, the heteroaryl is an unsubstituted 5-10 membered heteroaryl. In some embodiments, the heteroaryl is a substituted 5-10 membered heteroaryl. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: a pyridyl group. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to: triazinyl and tetrazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azetidinyl, azepanyl, and thiepinyl. Exemplary 5, 6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazole, benzothienyl, isobenzothienyl, benzofuranyl, benzisotofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiadiazolyl, indenazinyl and purinyl. Exemplary 6, 6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl.
"cyano" means the group-CN.
"nitro" means a group-NO 2 。
Other definitions
The term "pharmaceutically acceptable salts" refers to those salts which, within the scope of sound medical judgment, are suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail in Berge et al, J.pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the invention include salts derived from suitable inorganic and organic acids and bases.
The "subject" to be administered includes, but is not limited to: a human (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle aged adults, or senior adults)) and/or a non-human animal, e.g., a mammal, such as a primate (e.g., cynomolgus monkey, rhesus monkey), cow, pig, horse, sheep, goat, rodent, cat, and/or dog. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably herein.
"disease," "disorder," and "condition" are used interchangeably herein.
As used herein, unless otherwise indicated, the term "treating" includes an effect that occurs when a subject has a particular disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or delays or slows the progression of the disease, disorder, or condition ("therapeutic treatment"), as well as an effect that occurs before the subject begins to have the particular disease, disorder, or condition ("prophylactic treatment").
In general, an "effective amount" of a compound refers to an amount sufficient to elicit a biological response of interest. As will be appreciated by those of ordinary skill in the art, the effective amount of the compounds of the present invention may vary depending on the following factors: for example, biological targets, pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age health and symptoms of the subject. Effective amounts include therapeutically and prophylactically therapeutically effective amounts.
As used herein, unless otherwise indicated, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to the amount of therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder or condition. The term "therapeutically effective amount" may include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of other therapeutic agents.
As used herein, unless otherwise indicated, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to the amount of therapeutic agent used alone or in combination with other agents, which provides a prophylactic benefit in preventing a disease, disorder or condition. The term "prophylactically effective amount" may include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic efficacy of other prophylactic agents.
"Bcr-Abl1" refers to a fusion protein formed by the N-terminal exon of the split cluster region (BCR) gene and the main C-terminal part (exons 2-11) of the Abelson (Abl 1) gene. The most common fusion transcript encodes the 210-kDa protein (p 210Bcr-Abl 1), the rarer transcript encoding the 190-kDa protein (pl 190Bcr-Abl 1) and the 230-kDa protein (p 230 Bcr-Abl 1). The Abl1 sequence of these proteins comprises an Abl1 tyrosine kinase domain that is tightly regulated in wild-type proteins, but constitutively activated in Bcr-Abl1 fusion proteins. The deregulated tyrosine kinase interacts with a variety of cellular cell signaling pathways that lead to deregulation of cell transformation and proliferation.
"Bcr-Abl1 mutant" refers to a plurality of single site mutations in Bcr-Abl1, including: glu255, lys, glu255, val, thr315, ile, met244, val, phe317, leu248, val, met343, thr, gly250, ala, met351, thr, gly250, glu355, gly, gln252, his, phe358, ala, gln252, arg, phe359, val, tyr253, his, val379, ile, tyr253, phe382, leu, glu255, lys, leu387, met 255, val, his396, pro, phe311, ile, his396, arg, phe311, leu, ser417, tyr, thr315, ile, glu459, lys, and Phe 486.
"c-Abl" refers to the full length gene product of a non-mutated wild-type Abl 1.
The compounds of the invention may include one or more asymmetric centers and thus may exist in a variety of stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms. For example, the compounds of the invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. The isomers may be separated from the mixtures by methods known to those skilled in the art, including: chiral High Pressure Liquid Chromatography (HPLC), formation and crystallization of chiral salts; alternatively, preferred isomers may be prepared by asymmetric synthesis.
Those skilled in the art will appreciate that many organic compounds may form complexes with a solvent in or from which they react or precipitate or crystallize. These complexes are referred to as "solvates". When the solvent is water, the complex is referred to as a "hydrate". The present invention encompasses all solvates of the compounds of the present invention.
Pharmacology and efficacy
The compounds of the invention show therapeutic efficacy especially for diseases or disorders that depend on the activity of Bcr-Abll. In particular, the compounds of the invention inhibit the ATP binding site of Bcr-Abll (including wild-type Bcr-Abll and/or mutations thereof (including T315I mutations)).
Extracellular matrix is degraded during cancer cell tumor invasion and metastasis by invasion pseudopodia (invapodia). Abl kinase activity is required for Src-induced invasive pseudopodogenesis, which regulates the different stages and functions of invasive pseudopodium assembly. Thus, the compounds of the present invention as Abl inhibitors have potential as therapeutics for the treatment of metastatic invasive cancer.
Inhibitors of c-Abl kinase may be useful in the treatment of brain cancers: including glioblastomas, which are the most common and aggressive malignant primary brain tumors, wherein c-Abl expression is detectable by immunohistochemical techniques in a subset of patients. Thus, new c-Abl inhibitors with high brain exposure represent solid treatment approaches to glioblastomas and other brain cancers.
The compounds of the invention may be used for the treatment of viruses. For example, viral infection may be mediated by Abl1 kinase activity, as in the case of poxviruses and ebola viruses. Imatinib and nilotinib have been shown to stop the release of ebola virus particles from infected cells in vitro. Compounds of the invention that inhibit c-Abl kinase are therefore expected to be useful in reducing the replication capacity of pathogens.
Parkinson's disease is the second most common chronic neurodegenerative disease, with the most common familial autosomal recessive form caused by mutations in the E3 ubiquitin protein ligase (parkin). Recent studies have shown that activated c-ABL is found in the striatum of sporadic parkinson's disease patients. Meanwhile, parkin is tyrosine-phosphorylated, causing loss of its ubiquitin ligase and cytoprotective activity as indicated by accumulation of parkin substrate.
The compounds or compositions of the invention are also useful for treating the following diseases, disorders or conditions mediated by Bcr-Abl kinase: respiratory diseases, allergies, rheumatoid arthritis, osteoarthritis, rheumatic disorders, psoriasis, ulcerative colitis, crohn's disease, septic shock, proliferative disorders, atherosclerosis, allograft rejection after implantation, diabetes, stroke, obesity or restenosis, leukemia, stromal tumors, thyroid cancer, systemic mastocytosis, eosinophilic syndrome, fibrosis, polyarthritis, scleroderma, lupus erythematosus, graft-versus-host disease, neurofibromatosis, pulmonary hypertension, alzheimer's disease, seminomas, atheroma, mast cell tumors, lung cancer, bronchogenic carcinoma, asexual cell tumor, testicular intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma, papillary/follicular parathyroid hyperplasia/adenoma, colon cancer, colorectal adenoma, ovarian cancer, prostate cancer, glioblastoma, brain tumor, malignant glioma, pancreatic cancer, malignant pleural mesothelioma, angioblastoma, hemangioma, renal cancer, liver cancer, adrenal cancer, bladder cancer, gastric cancer, rectal cancer, vaginal cancer, cervical cancer, endometrial cancer, multiple myeloma, neck and head tumors, neoplasias, and other proliferative or proliferative disorders, or a combination thereof.
Pharmaceutical compositions, formulations and kits
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.
Pharmaceutically acceptable excipients for use in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the co-formulated contents. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.
The invention also includes kits (e.g., pharmaceutical packages). Kits provided can include a compound of the invention, other therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and/or dispersible packages or other suitable containers) containing a compound of the invention, other therapeutic agent. In some embodiments, the provided kits may also optionally include a third container containing pharmaceutically acceptable excipients for diluting or suspending the compounds of the invention and/or other therapeutic agents. In some embodiments, the compounds of the invention and other therapeutic agents provided in the first and second containers are combined to form one unit dosage form.
The following formulation examples illustrate representative pharmaceutical compositions that may be prepared according to the present invention. However, the present invention is not limited to the following pharmaceutical compositions.
Exemplary formulation 1-tablet: the compounds of the present invention in dry powder form may be combined with a dry gel binder at a ratio of about 1:2 weight ratio. A lesser amount of magnesium stearate was added as a lubricant. The mixture is formed into tablets of 0.3-30mg (each tablet containing 0.1-10mg of active compound) in a tablet press.
Exemplary formulation 2-tablet: the compounds of the present invention in dry powder form may be combined with a dry gel binder at a ratio of about 1:2 weight ratio. A lesser amount of magnesium stearate was added as a lubricant. The mixture is formed into tablets of 30-90mg (each tablet containing 10-30mg of active compound) in a tablet press.
Exemplary formulation 3-tablet: the compounds of the present invention in dry powder form may be combined with a dry gel binder at a ratio of about 1:2 weight ratio. A lesser amount of magnesium stearate was added as a lubricant. The mixture is formed into tablets of 90-150mg (each tablet containing 30-50mg of active compound) in a tablet press.
Exemplary formulation 4-tablet: the compounds of the present invention in dry powder form may be combined with a dry gel binder at a ratio of about 1:2 weight ratio. A lesser amount of magnesium stearate was added as a lubricant. The mixture is formed into 150-240mg tablets (each tablet containing 50-80mg of active compound) in a tablet press.
Exemplary formulation 5-tablet: the compounds of the present invention in dry powder form may be combined with a dry gel binder at a ratio of about 1:2 weight ratio. A lesser amount of magnesium stearate was added as a lubricant. The mixture is formed into 240-270mg tablets (each tablet containing 80-90mg of active compound) in a tablet press.
Exemplary formulation 6-tablet: the compounds of the present invention in dry powder form may be combined with a dry gel binder at a ratio of about 1:2 weight ratio. A lesser amount of magnesium stearate was added as a lubricant. The mixture is formed into 270-450mg tablets (each tablet containing 90-150mg of active compound) in a tablet press.
Exemplary formulation 7-tablet: the compounds of the present invention in dry powder form may be combined with a dry gel binder at a ratio of about 1:2 weight ratio. A lesser amount of magnesium stearate was added as a lubricant. The mixture is formed into 450-900mg tablets (each tablet containing 150-300mg of active compound) in a tablet press.
Exemplary formulation 8-capsule: the compounds of the present invention in dry powder form may be mixed with the starch diluent in a weight ratio of about 1:1. The mixture was filled into 250mg capsules (each capsule containing 125mg of active compound).
Exemplary formulation 9-liquid: the compound of the present invention (125 mg) may be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture may be blended, passed through a No.10 mesh U.S. sieve, and then mixed with an aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) prepared in advance. Sodium benzoate (10 mg), flavouring and colouring agents were diluted with water and added with stirring. Sufficient water may then be added to give a total volume of 5 mL.
Exemplary formulation 10-injection: the compounds of the present invention may be dissolved or suspended in buffered sterile saline injectable aqueous medium to a concentration of about 5 mg/mL.
Administration of drugs
The pharmaceutical compositions provided herein may be administered by a number of routes including, but not limited to: oral, parenteral, inhalation, topical, rectal, nasal, buccal, vaginal, by implantation or other means of administration. For example, parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intramuscularly, and intracranial injection or infusion techniques.
Typically, an effective amount of a compound provided herein is administered. The amount of the compound actually administered may be determined by a physician, according to the circumstances involved, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.
When used to prevent a disorder of the present invention, a subject at risk of developing the disorder is administered a compound provided herein, typically based on physician recommendations and administered under the supervision of a physician, at a dosage level as described above. Subjects at risk for developing a particular disorder generally include subjects having a family history of the disorder, or those subjects determined by genetic testing or screening to be particularly susceptible to developing the disorder.
The pharmaceutical compositions provided herein may also be administered chronically ("chronically"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over a prolonged period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue administration indefinitely, e.g., for the remainder of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, e.g., within a therapeutic window.
Various methods of administration may be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, the pharmaceutical composition may be administered as a bolus, e.g., in order to raise the concentration of the compound in the blood to an effective level. Bolus doses depend on the targeted systemic level of active ingredient through the body, e.g., intramuscular or subcutaneous bolus doses cause slow release of the active ingredient, whereas bolus injections delivered directly to veins (e.g., by IV intravenous drip) can be delivered more rapidly, causing the concentration of the active ingredient in the blood to rise rapidly to effective levels. In other embodiments, the pharmaceutical composition may be administered in the form of a continuous infusion, for example, by IV intravenous drip, thereby providing a steady state concentration of the active ingredient in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.
Oral compositions may take the form of bulk liquid solutions or suspensions or bulk powders. More typically, however, the compositions are provided in unit dosage form in order to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable for producing the desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules and the like. In such compositions, the compound is typically a minor component (about 0.1 to about 50 wt.%, or preferably about 1 to about 40 wt.%) with the remainder being various carriers or excipients and processing aids useful for forming the desired administration form.
For oral doses, a typical regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses. Using these modes of dosing, each dose provides from about 0.01 to about 20mg/kg of a compound of the invention, with preferred doses each providing from about 0.1 to about 10mg/kg, especially from about 1 to about 5mg/kg.
In order to provide similar blood levels to, or lower than, the use of an injected dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.
From about 1 to about 120 hours, especially 24 to 96 hours, the injected dosage level is in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour. To achieve adequate steady state levels, a preloaded bolus of about 0.1mg/kg to about 10mg/kg or more may also be administered. For human patients of 40 to 80kg, the maximum total dose cannot exceed about 2 g/day.
Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous carriers, buffers, suspending and dispersing agents, colorants, flavors, and the like. Solid forms may include, for example, any of the following components, or compounds having similar properties: binders, for example microcrystalline cellulose, gum tragacanth or gelatin; excipients, for example, starch or lactose; disintegrants, for example alginic acid, primogel or corn starch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silicon dioxide; sweeteners, for example, sucrose or saccharin; or a flavoring agent, for example, peppermint, methyl salicylate, or orange flavoring.
Injectable compositions are typically based on sterile saline or phosphate buffered saline for injectable use, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, the remainder being an injectable excipient or the like.
Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient. When formulated as ointments, the active ingredients are typically combined with a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and compositions are included within the scope provided by the present invention.
The compounds of the invention may also be administered via a transdermal device. Transdermal administration may thus be achieved using a reservoir (reservoir) or porous membrane type, or a variety of solid matrix patches.
The above components of the compositions for oral administration, injection or topical administration are merely representative. Other materials and processing techniques, etc. are set forth in Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania, section 8, incorporated herein by reference.
The compounds of the present invention may also be administered in sustained release form, or from a sustained release delivery system. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.
The invention also relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α -, β -and γ -cyclodextrins consisting of 6, 7 and 8 α -1, 4-linked glucose units, respectively, optionally including one or more substituents on the linked sugar moiety, including but not limited to: methylated, hydroxyalkylated, acylated and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β -cyclodextrin, e.g., sulfobutyl ether β -cyclodextrin, also known as Captisol. See, for example, U.S.5,376,645. In some embodiments, the formulation comprises hexapropyl- β -cyclodextrin (e.g., 10-50% in water).
Treatment of
The compounds of the invention are also useful for treating the following diseases, disorders or conditions mediated by Bcr-Abl kinase: respiratory diseases, allergies, rheumatoid arthritis, osteoarthritis, rheumatic disorders, psoriasis, ulcerative colitis, crohn's disease, septic shock, proliferative disorders, atherosclerosis, allograft rejection after implantation, diabetes, stroke, obesity or restenosis, leukemia, stromal tumors, thyroid cancer, systemic mastocytosis, eosinophilic syndrome, fibrosis, polyarthritis, scleroderma, lupus erythematosus, graft-versus-host disease, neurofibromatosis, pulmonary hypertension, alzheimer's disease, seminomas, asexual cytomas, mast cell swelling, lung cancer, bronchogenic carcinoma, asexual cell tumor, testicular intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma, papillary/follicular parathyroid hyperplasia/adenoma, colon cancer, colorectal adenoma, ovarian cancer, prostate cancer, glioblastoma, brain tumor, malignant glioma, pancreatic cancer, malignant pleural mesothelioma, hemangioblastoma, hemangioma, renal cancer, liver cancer, adrenal cancer, bladder cancer, stomach cancer, rectal cancer, vaginal cancer, cervical cancer, endometrial cancer, multiple myeloma, neck and head tumors, neoplasias, and other proliferative or proliferative disorders, or a combination thereof.
The present invention thus provides compounds of the invention for use in therapy, particularly in the treatment of diseases and conditions mediated by inappropriate Bcr-Abl activity.
Inappropriate Bcr-Abl activity as referred to herein is any Bcr-Abl activity that deviates from the expected normal Bcr-Abl activity in a particular mammalian subject. Inappropriate Bcr-Abl activity can take the form of, for example: abnormal increase in activity, or aberrations in timing and or control of Bcr-Abl activity. Such inappropriate activity could then be caused, for example, by overexpression or mutation of the protein kinase resulting in inappropriate or uncontrolled activation.
In another embodiment, the invention relates to a method of modulating, regulating or inhibiting Bcr-Abl for the prevention and/or treatment of a disorder associated with deregulated or inappropriate Bcr-Abl activity.
In another embodiment, the disorder mediated by Bcr-Abl activity is a respiratory disease. In another embodiment, the disorder is a proliferative disorder. In yet another embodiment, the disorder is cancer. In another embodiment, the disorder is leukemia.
In another embodiment, the compounds of the invention may also be used to treat neurodegeneration. While the native C-ABL tyrosine kinase remains relatively stationary in healthy adult brains, it can be activated in brains of CNS disease patients including neurodegenerative diseases such as Alzheimer's Disease (AD), parkinson's disease (AD), frontotemporal dementia (frontotemporal dementia) (FTD), pick's disease, niemann-pick's disease type C (NPC) and other degenerative, inflammatory and autoimmune diseases and aging.
The effective amount of the compound of the present invention is generally in the range of 0.01mg to 50mg compound per kilogram of patient body weight, preferably 0.1mg to 25mg compound per kilogram of patient body weight, in single or multiple administrations. In general, the compounds of the invention may be administered to the patient in need of such treatment in a daily dosage range of from about l mg to about 3500mg, preferably from 10mg to 1000mg, per patient. For example, the daily dose per patient may be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800, 900 or 1000mg. The administration may be one or more times daily, weekly (or at intervals of days), or on an intermittent schedule. For example, the compounds may be administered on a weekly basis (e.g., once a week), once or more times a day, indefinitely or for a few weeks, e.g., 4-10 weeks. Alternatively, the administration may be continued for several days (e.g., 2-10 days) and then several days (e.g., 1-30 days) without administration of the compound, with the cycle being repeated indefinitely or for a given number of cycles, e.g., 4-10 cycles. For example, the compounds of the invention may be administered daily for 5 days, then intermittently for 9 days, then daily for another 5 days, then intermittently for 9 days, and so on, with the cycle being repeated indefinitely or for a total of 4-10 times.
Detailed Description
The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods and compounds claimed herein are carried out, prepared, and evaluated, and are intended to be merely illustrative of the invention and are not intended to limit the scope of what is claimed.
Synthesis method
The compounds of the present invention may be prepared according to methods conventional in the art, using suitable reagents, starting materials and purification methods known to those skilled in the art.
The following more specifically describes the preparation method of the compound of the present invention, but these specific methods do not limit the present invention in any way. The compounds of the present invention may also be conveniently prepared by optionally combining the various synthetic methods described in this specification or known in the art, such combinations being readily apparent to those skilled in the art to which the present invention pertains.
Typically, in the preparation, each reaction is carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ℃ C. To 100 ℃ C., preferably 0 ℃ C. To 80 ℃ C.). The reaction time is usually 0.1 hours to 60 hours, preferably 0.5 to 24 hours.
EXAMPLE 1 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((4 ] Methoxyphenyl) amino) nicotinamide (compound 1)
Step 1: synthesis of 5-bromo-6-chloro-N- (4- (chlorodifluoromethoxy) phenyl) nicotinamide (Compound 1 b).
To the reaction flask was added 5-bromo-6-chloronicotinic acid (1 a,25.0g,106.4 mmol), 4- (chlorodifluoromethoxy) aniline (20.0 g,103.6 mmol), dissolved in 300mL anhydrous DMF, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (HATU, 46.5g,122.3 mmol) and N, N-diisopropylethylamine (DIPEA, 26.3g,203.4 mmol) were added and reacted at room temperature for 18 hours with stirring, diluted with excess water, extracted 3-4 times with ethyl acetate, the combined organic phases washed with saturated brine, concentrated, purified by column chromatography, dried in vacuo to give the product 20.1g, yield: 46.1%.
Step 2: synthesis of (R) -5-bromo-N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (Compound 1 c).
To the reaction flask was added compound 1b (19.0 g,46.3 mmol) and (R) -3 hydroxypyrrolidine (4.84 g,55.5 mmol), 150mL anhydrous DMSO was added, DIPEA (11.98 g,92.6 mmol) was added, the reaction was heated to 100deg.C and stirred for 2 hours, excess water was added to dilute, ethyl acetate was extracted 3-4 times, the organic phases were combined, washed with saturated brine, concentrated, purified by column chromatography, and dried in vacuo to give 17.1g of the product, yield: 80.0%.
Step 3: synthesis of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((4-methoxyphenyl) amino) nicotinamide (Compound 1).
Into a reaction flask was charged compound 1c (230.0 mg,0.5 mmol), 4-methoxyaniline (123.0 mg,1.0 mmol), pd 2 (dba) 3 (45.8 mg,0.05 mmol), t-BuXPhos (31.8 mg,0.075 mmol) and t-BuONa (96 mg,1.0 mmol) were dissolved in 3mL dry toluene,at N 2 Heating to 100 ℃ under protection, stirring and reacting for 12 hours, detecting that the raw materials are reacted by TLC, vacuum drying, adding excessive water for dilution, extracting by ethyl acetate for 3-4 times, combining organic phases, washing by saturated saline water, concentrating, purifying by silica gel column chromatography, vacuum drying, purifying by reverse phase column chromatography, vacuum drying to obtain 45.3mg of a product, and obtaining the yield: 18.0%. LC-MS (ESI) m/z=505.12 [ M+H ]] + ； 1 H NMR(300MHz,DMSO-d 6 )δ10.15(s,1H),8.56(d,J＝2.2Hz,1H),7.86(d,J＝2.3Hz,1H),7.84(d,J＝2.3Hz,1H),7.82(d,J＝2.2Hz,1H),7.34(t,J＝1.1Hz,1H),7.31(d,J＝1.1Hz,1H),7.17(s,1H),6.83-6.76(m,2H),6.66-6.59(m,2H),4.87(d,J＝3.3Hz,1H),4.26(s,1H),3.73-3.52(m,3H),3.67(s,3H),3.42(d,J＝11.6Hz,1H),1.83(ddd,J＝19.8,10.2,5.8Hz,2H)。
EXAMPLE 2 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-fluorophenyl) amino) -6- (3-hydroxy) Pyrrolidin-1-yl) nicotinamide (compound 2)
Referring to the procedure of example 1, substituting 4-methoxyaniline for 2-fluoroaniline produced compound 2: LC-MS (ESI) m/z=493.17 [ M+H ]] + ； 1 H NMR(300MHz,DMSO-d6)δ10.14(s,1H),8.67(d,J＝2.2Hz,1H),7.88(d,J＝2.0Hz,2H),7.85(d,J＝2.2Hz,1H),7.48(d,J＝1.9Hz,1H),7.34(t,J＝1.1Hz,1H),7.32(q,J＝1.2Hz,1H),7.14(ddd,J＝12.1,8.1,1.4Hz,1H),7.01-6.91(m,1H),6.74-6.64(m,1H),6.39(ddd,J＝9.4,8.0,1.6Hz,1H),4.89(d,J＝3.3Hz,1H),4.25(s,1H),3.75-3.59(m,3H),3.46(d,J＝11.6Hz,1H),1.90-1.69(m,2H)。
EXAMPLE 3 preparation of (R) -5- ((3-chloro-4-fluorophenyl) amino) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3- Hydroxypyrrolidin-1-yl) nicotinamide (compound 3)
Referring to the procedure of example 1, substituting 4-methoxyaniline with 3-chloro-4-fluoroaniline produced compound 3: LC-MS (ESI) m/z=527.06 [ M+H ]] + ； 1 H NMR(300MHz,DMSO-d6)δ10.15(s,1H),8.66(d,J＝2.2Hz,1H),7.91(d,J＝2.3Hz,1H),7.87(d,J＝2.2Hz,1H),7.85(d,J＝2.2Hz,1H),7.76(s,1H),7.35(d,J＝1.2Hz,1H),7.32(q,J＝1.2Hz,1H),7.20(t,J＝9.1Hz,1H),6.64(dd,J＝6.3,2.8Hz,1H),6.52(ddd,J＝9.0,3.9,2.8Hz,1H),4.90(d,J＝3.3Hz,1H),4.27(s,1H),3.78-3.52(m,3H),3.41(d,J＝11.8Hz,1H),1.94-1.70(m,2H)。
Example 4 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((3, 4, 5-trimethoxyphenyl) amino) nicotinamide (compound 4)
Referring to the procedure of example 1, substituting 4-methoxyaniline with 3,4, 5-trimethoxyaniline produced compound 4: LC-MS (ESI) m/z=565.13 [ M+H ]] + ； 1 H NMR(300MHz,DMSO-d6)δ10.15(s,1H),8.60(d,J＝2.2Hz,1H),7.92(d,J＝2.3Hz,1H),7.87(d,J＝2.2Hz,1H),7.85(d,J＝2.2Hz,1H),7.40(s,1H),7.34(d,J＝1.2Hz,1H),7.33-7.30(m,1H),5.93(s,2H),4.89(d,J＝3.3Hz,1H),4.28(s,1H),3.73-3.52(m,3H),3.65(s,6H),3.56(s,3H),3.48-3.38(m,1H),1.97-1.71(m,2H)。
EXAMPLE 5 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((4-cyanophenyl) amino) -6- (3-hydroxy) Pyrrolidin-1-yl) nicotinamide (compound 5)
Referring to the procedure of example 1, substituting 4-methoxyaniline with 4-aminobenzonitrile produced compound 5: LC-MS (ESI) m/z=500.17 [ M+H ]] + ； 1 H NMR(300MHz,DMSO-d6)δ10.15(s,1H),8.71(d,J＝2.3Hz,1H),8.48(s,1H),7.97(d,J＝2.2Hz,1H),7.91-7.82(m,2H),7.62-7.52(m,2H),7.34(dt,J＝9.0,1.1Hz,2H),6.69-6.59(m,2H),4.91(d,J＝3.3Hz,1H),4.27(s,1H),3.73-3.52(m,3H),3.40(d,J＝11.7Hz,1H),1.93-1.71(m,2H)。
EXAMPLE 6 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((4-fluorophenyl) amino) -6- (3-hydroxy) Pyrrolidin-1-yl) nicotinamide (compound 6)
Referring to the procedure of example 1, substituting 4-methoxyaniline for 4-fluoroaniline produced compound 6: LC-MS (ESI) m/z=493.18 [ M+H ]] + ； 1 H NMR(300MHz,DMSO-d6)δ10.15(s,1H),8.62(d,J＝2.2Hz,1H),7.88(q,J＝2.2Hz,2H),7.84(d,J＝2.2Hz,1H),7.50(s,1H),7.33(dt,J＝9.0,1.1Hz,2H),7.00(t,J＝8.9Hz,2H),6.66-6.55(m,2H),4.88(d,J＝3.3Hz,1H),4.26(s,1H),3.66(m,3H),3.42(d,J＝11.7Hz,1H),1.93-1.70(m,2H)。
EXAMPLE 7 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (p-methyl) Anilino) nicotinamide (compound 7)
Referring to the procedure of example 1, substituting 4-methoxyaniline for p-toluidine produced compound 7: LC-MS (ESI) m/z=489.14 [ M+H ]] + ； 1 H NMR(300MHz,DMSO-d6)δ10.15(s,1H),8.60(d,J＝2.2Hz,1H),7.87(d,J＝2.0Hz,2H),7.84(d,J＝2.2Hz,1H),7.34(s,2H),7.31(t,J＝1.1Hz,1H),6.96(d,J＝8.2Hz,2H),6.58-6.49(m,2H),4.87(d,J＝3.3Hz,1H),4.25(s,1H),3.77-3.56(m,3H),3.42(d,J＝11.7Hz,1H),1.93-1.70(m,2H)。
EXAMPLE 8 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (m-methyl) Phenylamino) nicotinamide (Compound 8)
Referring to the procedure of example 1, substituting m-toluidine for 4-methoxyaniline produced compound 8: LC-MS (ESI) m/z=489.10 [ M+H ]] + ； 1 H NMR(300MHz,DMSO-d6)δ10.15(s,1H),8.62(d,J＝2.2Hz,1H),7.90(d,J＝2.3Hz,1H),7.87(d,J＝2.2Hz,1H),7.85(d,J＝2.2Hz,1H),7.43(s,1H),7.34(d,J＝1.2Hz,1H),7.31(t,J＝1.0Hz,1H),7.02(t,J＝7.7Hz,1H),6.51-6.46(m,1H),6.43(s,1H),6.38(d,J＝8.0Hz,1H),4.88(d,J＝3.3Hz,1H),4.26(s,1H),3.77-3.54(m,3H),3.43(d,J＝11.6Hz,1H),2.19(s,3H),1.94-1.70(m,2H)。
EXAMPLE 9 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (pyri-dine) Pyridin-4-ylamino) nicotinamide (compound 9)
Into a reaction flask was charged compound 1c (230.0 mg,0.5 mmol), pyridin-4-amine (94.0 mg,1.0 mmol), pd 2 (dba) 3 (45.8 mg,0.05 mmol), xantPhos (43.4 mg,0.075 mmol) and Cs 2 CO 3 (325.0 mg,1.0 mmol) was dissolved in 3mL of anhydrous toluene under N 2 Heating to 100 ℃ under protection, stirring and reacting for 12 hours, detecting that the raw materials are reacted by TLC, vacuum drying, adding excessive water for dilution, extracting by ethyl acetate for 3-4 times, combining organic phases, washing by saturated saline water, concentrating, purifying by silica gel column chromatography, vacuum drying, purifying by reverse phase column chromatography, vacuum drying to obtain 52.3mg of a product, and obtaining the yield: 22.0%. LC-MS (ESI) m/z=476.17 [ M+H ] ] + ； 1 H NMR(300MHz,DMSO-d6)δ10.44(s,1H),10.40(s,1H),8.61(s,1H),8.41-8.35(m,2H),7.81(d,J＝2.2Hz,1H),7.78(d,J＝2.2Hz,1H),7.35(d,J＝1.3Hz,2H),7.34-7.31(m,2H),6.42(s,1H),5.06(d,J＝3.4Hz,1H),4.42(s,1H),3.66-3.48(m,3H),3.42(m,1H),2.12-1.86(m,2H)。
EXAMPLE 10 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (pyri-dine Pyridin-3-ylamino) nicotinamide (compound 10)
Referring to the procedure of example 9, the substitution of pyridin-4-amine with pyridin-3-amine produced compound 10: LC-MS (ESI) m/z=476.13 [ M+H ]] + ； 1 H NMR(300MHz,DMSO-d6)δ10.16(s,1H),8.66(d,J＝2.2Hz,1H),8.02(d,J＝2.8Hz,1H),7.94(d,J＝2.2Hz,1H),7.90(dd,J＝4.6,1.4Hz,1H),7.87(d,J＝2.2Hz,1H),7.85(d,J＝2.2Hz,1H),7.81(s,1H),7.37-7.33(m,1H),7.32(d,J＝1.2Hz,1H),7.15(dd,J＝8.3,4.6Hz,1H),6.86(ddd,J＝8.3,2.9,1.4Hz,1H),4.89(d,J＝3.3Hz,1H),4.27(s,1H),3.77-3.54(m,3H),3.41(d,J＝11.6Hz,1H),1.93-1.71(m,2H)。
EXAMPLE 11 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (pyri-dine Pyridin-2-ylamino) nicotinamide (compound 11)
Referring to the procedure of example 9, the substitution of pyridin-4-amine with pyridin-2-amine produced compound 11: LC-MS (ESI) m/z=476.15 [ M+H ]] + ； 1 H NMR(300MHz,DMSO-d6)δ10.14(s,1H),8.64(d,J＝2.3Hz,1H),8.27(s,1H),8.02(ddd,J＝5.0,2.0,0.8Hz,1H),7.98(d,J＝2.2Hz,1H),7.88(d,J＝2.2Hz,1H),7.86(d,J＝2.2Hz,1H),7.50(ddd,J＝8.8,7.2,2.0Hz,1H),7.34(d,J＝1.2Hz,1H),7.32(q,J＝1.3Hz,1H),6.63(ddd,J＝7.1,5.0,0.9Hz,1H),6.50(dt,J＝8.3,0.9Hz,1H),4.89(d,J＝3.3Hz,1H),4.26(s,1H),3.75-3.55(m,3H),3.48–3.37(m,1H),1.95-1.69(m,2H)。
EXAMPLE 12 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-)Hydroxypyrrolidin-1-yl) -5- ((2 ] Methoxy pyrimidin-5-yl) amino) nicotinamide (compound 12)
Referring to the procedure of example 9, substituting pyridin-4-amine with 2-methoxypyrimidin-5-amine produced compound 12: LC-MS (ESI) m/z=507.11 [ M+H ]] + ； 1 H NMR(300MHz,DMSO-d6)δ10.16(s,1H),8.60(d,J＝2.2Hz,1H),8.04(s,2H),7.89-7.85(m,2H),7.84(d,J＝2.2Hz,1H),7.58(s,1H),7.35(d,J＝1.2Hz,1H),7.32(s,1H),4.89(d,J＝3.3Hz,1H),4.28(s,1H),3.83(s,3H),3.75-3.53(m,3H),3.38(d,J＝12.4Hz,1H),1.96-1.70(m,2H)。
EXAMPLE 13 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((2 ] Methylpyridin-3-yl) amino) nicotinamide (compound 13)
Referring to the procedure of example 9, substituting pyridin-4-amine with 2-methylpyridin-3-amine produced compound 13: LC-MS (ESI) m/z=490.12 [ M+H ]] + ； 1 H NMR(300MHz,DMSO-d6)δ10.15(s,1H),8.68(d,J＝2.2Hz,1H),7.87(d,J＝2.1Hz,2H),7.85(d,J＝2.3Hz,1H),7.82(dd,J＝4.7,1.4Hz,1H),7.34(q,J＝1.1Hz,1H),7.32(q,J＝1.3Hz,1H),7.16(s,1H),6.99(dd,J＝8.1,4.7Hz,1H),6.47(dd,J＝8.1,1.4Hz,1H),4.87(d,J＝3.3Hz,1H),4.23(d,J＝4.9Hz,1H),3.73-3.52(m,3H),3.47-3.37(m,1H),2.51(p,J＝1.9Hz,3H),1.90-1.63(m,2H)。
EXAMPLE 14 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((6 ] Methoxypyridin-3-yl) amino) nicotinamide (compound 14)
Referring to the procedure of example 9, substituting pyridin-4-amine with 6-methoxypyridine-3-amine produced compound 14: LC-MS (ESI) m/z=506.14 [ M+H ]] + ； 1 H NMR(300MHz,DMSO-d6)δ10.17(s,1H),8.57(d,J＝2.2Hz,1H),7.86(s,1H),7.84(d,J＝2.1Hz,1H),7.81(d,J＝2.2Hz,1H),7.57(d,J＝2.8Hz,1H),7.33(d,J＝8.8Hz,3H),7.11(dd,J＝8.8,2.9Hz,1H),6.70(d,J＝8.8Hz,1H),4.90(d,J＝3.3Hz,1H),4.27(s,1H),3.76(s,3H),3.66(m,3H),3.42(s,1H),1.94-1.74(m,2H)。
EXAMPLE 15 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((4-cyanopyridin-3-yl) amino) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 15)
Referring to the procedure of example 9, the substitution of pyridin-4-amine with 3-aminoisonicotinic nitrile produced compound 15: LC-MS (ESI) m/z=501.15 [ M+H ]] + ； 1 H NMR(300MHz,DMSO-d6)δ10.17(s,1H),8.74(d,J＝2.2Hz,1H),8.60(s,1H),8.05-7.98(m,2H),7.94(d,J＝0.7Hz,1H),7.90-7.82(m,2H),7.56(dd,J＝5.0,0.7Hz,1H),7.34(dq,J＝7.9,1.1Hz,2H),4.94(d,J＝3.3Hz,1H),4.28(s,1H),3.71-3.56(m,3H),3.49-3.40(m,1H),1.93-1.75(m,2H)。
EXAMPLE 16 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((5-fluoropyridin-3-yl) amino) -6 ] (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 16)
Referring to the procedure of example 9, substituting pyridin-4-amine with 5-fluoropyridine-3-amine produced compound 16: LC-MS (ESI) m/z=494.12 [ M+H ]] + ； 1 H NMR(300MHz,DMSO-d6)δ10.16(s,1H),8.68(d,J＝2.2Hz,1H),8.19(d,J＝1.4Hz,1H),7.97(d,J＝2.2Hz,1H),7.92-7.81(m,4H),7.34(d,J＝8.7Hz,2H),6.65(dt,J＝11.6,2.4Hz,1H),4.92(d,J＝3.2Hz,1H),4.28(s,1H),3.74-3.55(m,3H),3.42(s,1H),1.92-1.73(m,2H)。
EXAMPLE 17 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((6 ] Methylpyridin-3-yl) amino) nicotinamide (compound 17)
Referring to the procedure of example 9, substituting pyridin-4-amine with 6-methylpyridin-3-amine produced compound 17: LC-MS (ESI) m/z=490.17 [ M+H ]] + ； 1 H NMR(300MHz,DMSO-d6)δ10.16(s,1H),8.63(d,J＝2.2Hz,1H),7.97-7.80(m,4H),7.61(s,1H),7.33(dt,J＝8.9,1.0Hz,2H),7.02(d,J＝8.4Hz,1H),6.82(dd,J＝8.3,2.9Hz,1H),4.89(d,J＝3.3Hz,1H),4.26(s,1H),3.76-3.52(m,3H),3.40(m,1H),2.33(s,3H),1.92-1.70(m,2H)。
EXAMPLE 18 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((6 ] (trifluoromethyl) pyridin-3-yl) amino) nicotinamide (Compound 18)
Referring to the procedure of example 9, substituting pyridin-4-amine with 6- (trifluoromethyl) pyridin-3-amine produced compound 18: LC-MS (ESI) m/z=544.16 [ M+H ]] + ； 1 H NMR(300MHz,DMSO-d6)δ10.16(s,1H),8.71(d,J＝2.2Hz,1H),8.52(s,1H),8.13(d,J＝2.7Hz,1H),8.00(d,J＝2.2Hz,1H),7.90-7.79(m,2H),7.62(d,J＝8.7Hz,1H),7.34(d,J＝8.8Hz,2H),6.93(dd,J＝8.7,2.7Hz,1H),4.93(d,J＝3.3Hz,1H),4.28(s,1H),3.73-3.55(m,3H),3.41(s,1H),1.92-1.71(m,2H)。
EXAMPLE 19 preparation of (R) -5- ((1H-pyrazol-5-yl) amino) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3- Hydroxypyrrolidin-1-yl) nicotinamide (compound 19)
Referring to the procedure of example 9, substituting pyridin-4-amine with 1H-pyrazol-5-amine produced compound 19: LC-MS (ESI) m/z=465.18 [ M+H ]] + 。
EXAMPLE 20 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((3-hydroxy-1H-pyrazol-5-yl) ammonia Phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 20)
Referring to the procedure of example 9, substituting pyridin-4-amine with 5-amino-1H-pyrazol-3-ol produced compound 20: LC-MS (ESI) m/z=481.11 [ M+H ]] + 。
EXAMPLE 21 preparation of (R) -5- ((4-bromo-1H-pyrazol-5-yl) amino) -N- (4- (chlorodifluoromethoxy) phenyl) propanoic acid 6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 21)
Referring to the procedure of example 9, substituting pyridin-4-amine with 4-bromo-1H-pyrazol-5-amine produced compound 21: LC-MS (ESI) m/z=543.03 [ M+H ]] + 。
EXAMPLE 22 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((1 ] methyl-1H-pyrazol-5-yl) amino) nicotinamide (compound 22)
Referring to the procedure of example 9, substituting pyridin-4-amine with 1-methyl-1H-pyrazol-5-amine produced compound 22: LC-MS (ESI) m/z=479.11 [ M+H ]] + 。
EXAMPLE 23 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (iso- Thiazole-5-ylamino) nicotinamide (compound 23)
Referring to the procedure of example 9, substituting pyridin-4-amine with isothiazol-5-amine produced compound 23: LC-MS (ESI) m/z=482.02 [ M+H ]] + 。
Example 24 preparation of (R) -2- ((5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrazole) Pyrrolidin-1-yl) pyridin-3-yl amino) thiazole-4-carboxylic acid ethyl ester (compound 24)
Referring to the procedure of example 9, substituting pyridin-4-amine with ethyl 2-aminothiazole-4-carboxylate produced compound 24: LC-MS (ESI) m/z=554.12 [ M+H ]] + 。
EXAMPLE 25 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (thia-point) Azol-5-ylamino) nicotinamide (Compound 25)
Referring to the procedure of example 9, substituting pyridin-4-amine with thiazol-5-amine produced compound 25: LC-MS (ESI) m/z=482.01 [ M+H ]] + 。
EXAMPLE 26 preparation of (R) -2- ((5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) ) -2- (3-hydroxypyrazole) Pyrrolidin-1-yl) pyridin-3-yl amino) thiazole-4-carboxylic acid (compound 26)
Referring to the procedure of example 9, substituting pyridin-4-amine with 2-aminothiazole-4-carboxylic acid produced compound 26: LC-MS (ESI) m/z=526.01 [ M+H ]] + 。
EXAMPLE 27 preparation of (R) -5- ((1H-imidazol-5-yl) amino) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3- Hydroxypyrrolidin-1-yl) nicotinamide (compound 27)
Referring to the procedure of example 9, substituting pyridin-4-amine with 1H-imidazol-5-amine produced compound 27: LC-MS (ESI) m/z=465.17 [ M+H ]] + 。
EXAMPLE 28 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((1 ] methyl-1H-imidazol-5-yl) amino) nicotinamide (compound 28)
Referring to the procedure of example 9, substituting pyridin-4-amine with 1-methyl-1H-imidazol-5-amine produced compound 28: LC-MS (ESI) m/z=478.18 [ M+H ]] + 。
EXAMPLE 29 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (oxa-ne Azol-5-ylamino) nicotinamide (Compound 29)
Referring to the procedure of example 9, substituting pyridin-4-amine with oxazol-5-amine produced compound 29: LC-MS (ESI) m/z=466.14 [ M+H ]] + 。
EXAMPLE 30 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (iso- Thiazole-3-ylamino) nicotinamide (compound 30)
Referring to the procedure of example 9, substituting pyridin-4-amine with isothiazol-3-amine produced compound 30: LC-MS (ESI) m/z=482.03 [ M+H ]] + 。
EXAMPLE 31 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (iso- Thiazole-4-ylamino) nicotinamide (compound 31)
Referring to the procedure of example 9, substituting pyridin-4-amine with isothiazol-4-amine produced compound 31: LC-MS (ESI) m/z=482.04 [ M+H ]] + 。
EXAMPLE 32 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (thia-point) Azol-2-ylamino) nicotinamide (Compound 32)
Referring to the procedure of example 9, substituting pyridin-4-amine with thiazol-2-amine produced compound 32: LC-MS (ESI) m/z=482.05 [ M+H ]] + 。
EXAMPLE 33 preparation of (R) -5- ((1H-tetrazol-5-yl) amino) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-) Hydroxypyrrolidin-1-yl) nicotinamide (compound 33)
Referring to the procedure of example 9, substituting pyridin-4-amine with 1H-tetrazol-5-amine produced compound 33: LC-MS (ESI) m/z=467.11 [ M+H ]] + 。
Example 34 preparation of (R) -5- ((1H-1, 2, 3-triazol-5-yl) amino) -N- (4- (chlorodifluoromethoxy) benzene Phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 34)
Referring to the procedure of example 9, substituting pyridin-4-amine with 1H-1,2, 3-triazol-5-amine produced compound 34: LC-MS (ESI) m/z=466.12 [ M+H ]] + 。
EXAMPLE 35 preparation of (R) -5- ((1, 2, 4-thiadiazol-5-yl) amino) -N- (4- (chlorodifluoromethoxy) phenyl) propanoic acid 6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 35)
Referring to the procedure of example 9, substituting pyridin-4-amine with 1,2, 4-thiadiazol-5-amine produced compound 35: LC-MS (ESI) m/z=483.01 [ M+H ]] + 。
EXAMPLE 36 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-cyanophenyl) amino) -6- (3-)Hydroxypyrrolidin-1-yl) nicotinamide (compound 36)
With reference to the method of example 9,replacement of pyridin-4-amine with 2-aminobenzonitrile gives compound 36: LC-MS (ESI) m/z=500.11 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.73(d,J＝2.2Hz,1H),8.13(s,1H),7.96(d,J＝2.2Hz,1H),7.91-7.83(m,2H),7.59(dd,J＝7.8,1.6Hz,1H),7.40(ddd,J＝8.7,7.3,1.6Hz,1H),7.37-7.30(m,2H),6.78(td,J＝7.5,1.0Hz,1H),6.37(d,J＝8.4Hz,1H),4.93(d,J＝3.3Hz,1H),4.27(dt,J＝5.8,2.6Hz,1H),3.64(m,3H),3.47(m,1H),1.89-1.72(m,2H)。
EXAMPLE 37 preparation of (R) -5- ((4-chloro-2-cyanophenyl) amino) -N- (4- (chlorodifluoromethoxy) phenyl) -6 ] (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 37)
Referring to the procedure of example 9, substituting pyridin-4-amine with 2-amino-5-chlorobenzonitrile produced compound 37: LC-MS (ESI) m/z=534.02 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.73(d,J＝2.2Hz,1H),8.34(s,1H),7.96(d,J＝2.2Hz,1H),7.91-7.83(m,2H),7.74(d,J＝2.5Hz,1H),7.44(dd,J＝9.1,2.6Hz,1H),7.37-7.27(m,2H),6.37(d,J＝9.1Hz,1H),4.93(d,J＝3.3Hz,1H),4.28(s,1H),3.62(m,3H),3.49-3.40(m,1H),1.82(m,2H)。
EXAMPLE 38 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-cyano-4-fluorophenyl) amino) -6 ] (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 38)
Referring to the procedure of example 9, substituting pyridin-4-amine with 2-amino-5-fluorobenzonitrile produced compound 38: LC-MS (ESI) m/z=518.12 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.71(d,J＝2.2Hz,1H),8.11(s,1H),7.93(d,J＝2.2Hz,1H),7.90-7.83(m,2H),7.59(dd,J＝8.5,3.1Hz,1H),7.39-7.29(m,3H),6.39(dd,J＝9.3,4.5Hz,1H),4.92(d,J＝3.3Hz,1H),4.27(dp,J＝7.5,4.0,3.6Hz,1H),3.63(m,3H),3.49-3.43(m,1H),1.90-1.73(m,2H)。
EXAMPLE 39 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-cyano-4-nitrophenyl) amino) 6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 39)
Referring to the procedure of example 9, substituting pyridin-4-amine with 2-amino-5-nitrobenzonitrile produced compound 39: LC-MS (ESI) m/z=545.12 [ M+H ]] + 。
Example 40 preparation of (R) -4- ((5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrazole) Pyrrolidin-1-yl) pyridin-3-yl) amino) -3-cyanobenzoic acid (compound 40)
Referring to the procedure of example 9, substituting pyridin-4-amine with 4-amino-3-cyanobenzoic acid produced compound 40: LC-MS (ESI) m/z=544.11 [ M+H ]] + 。
EXAMPLE 41 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2, 4-dichloro-6-cyanophenyl) amino Phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 41)
Referring to the procedure of example 9, substituting pyridin-4-amine with 2-amino-3, 5-dichlorobenzonitrile produced compound 41: LC-MS (ESI) m/z=568.01 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.73(d,J＝2.2Hz,1H),8.30(d,J＝19.5Hz,1H),7.92-7.81(m,4H),7.67(s,1H),7.39-7.28(m,2H),4.95(s,1H),4.30(s,1H),3.92-3.43(m,4H),1.97-1.73(m,2H)。
EXAMPLE 42 preparation of (R) -5- ((3-chloro-2-cyanophenyl) amino) -N- (4- (chlorodifluoromethoxy) phenyl) -6 ] (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 42)
Referring to the procedure of example 9, substituting pyridin-4-amine with 2-amino-6-chlorobenzonitrile produced compound 42: LC-MS (ESI) m/z=534.01 [ M+H ]] + 。
EXAMPLE 43 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-cyano-3-fluorophenyl) amino) -6 ] (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 43)
Referring to the procedure of example 9, substituting pyridin-4-amine with 2-amino-6-fluorobenzonitrile produced compound 43: LC-MS (ESI) m/z=518.12 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.74(t,J＝1.8Hz,1H),8.52(s,1H),8.02-7.93(m,1H),7.87(dt,J＝8.9,1.7Hz,2H),7.48-7.38(m,1H),7.34(d,J＝8.6Hz,2H),6.68(t,J＝8.8Hz,1H),6.20(d,J＝8.6Hz,1H),4.94(dd,J＝3.3,1.5Hz,1H),4.29(s,1H),3.70-3.57(m,3H),3.47(d,J＝11.5Hz,1H),1.92-1.75(m,2H)。
EXAMPLE 44 preparation of (R) -5- ((5-chloro-2-cyanophenyl) amino) -N- (4- (chlorodifluoromethoxy) phenyl) -6 ] (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 44)
Referring to the procedure of example 9, pyridin-4-amine was replaced with 2-ammoniaBase-4-chlorobenzonitrile to afford compound 44: LC-MS (ESI) m/z=534.03 [ M+H ]] + 。
EXAMPLE 45 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-cyano-5-fluorophenyl) amino) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 45)
Referring to the procedure of example 9, substituting pyridin-4-amine with 2-amino-4-fluorobenzonitrile produced compound 45: LC-MS (ESI) m/z=518.14 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.74(d,J＝2.3Hz,1H),8.46(d,J＝1.7Hz,1H),7.98(d,J＝2.2Hz,1H),7.92-7.79(m,2H),7.70(dd,J＝8.7,6.4Hz,1H),7.38-7.28(m,2H),6.63(td,J＝8.4,2.5Hz,1H),6.07(dd,J＝11.8,2.5Hz,1H),4.95(d,J＝3.3Hz,1H),4.34-4.24(m,J＝3.0Hz,1H),3.64(m,3H),3.52-3.42(m,1H),1.94-1.74(m,2H)。
EXAMPLE 46 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-cyano-6-chlorophenyl) amino) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 46)
Referring to the procedure of example 9, substituting pyridin-4-amine with 2-amino-3-chlorobenzonitrile produced compound 46: LC-MS (ESI) m/z=534.01 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.72(d,J＝2.3Hz,1H),8.12(s,1H),7.92-7.82(m,3H),7.72(dd,J＝7.9,1.5Hz,1H),7.51(d,J＝7.9Hz,1H),7.37-7.30(m,2H),6.85(t,J＝7.9Hz,1H),4.95(d,J＝3.2Hz,1H),4.30(s,1H),3.69(m,4H),1.95-1.75(m,2H)。
EXAMPLE 47 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-cyano-6-fluorophenyl) amino) -6 ] (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 47)
Referring to the procedure of example 9, substituting pyridin-4-amine with 2-amino-3-fluorobenzonitrile produced compound 47: LC-MS (ESI) m/z=518.12 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.70(d,J＝2.2Hz,1H),8.27(d,J＝3.0Hz,1H),7.92-7.82(m,3H),7.48(ddd,J＝12.1,8.1,1.5Hz,1H),7.39-7.29(m,3H),6.82(td,J＝8.0,4.8Hz,1H),4.95(d,J＝3.3Hz,1H),4.30(s,1H),3.79-3.64(m,3H),3.56-3.45(m,1H),1.95-1.75(m,2H)。
EXAMPLE 48 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((3-cyanopyridin-4-yl) amino) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 48)
Referring to the procedure of example 9, the substitution of pyridin-4-amine with 4-aminonicotinonitrile produced compound 48: LC-MS (ESI) m/z=501.13 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.09(s,1H),8.77(d,J＝2.3Hz,1H),8.58(s,1H),8.25(d,J＝6.1Hz,1H),8.01(d,J＝2.3Hz,1H),7.90-7.83(m,2H),7.39-7.30(m,2H),6.33(d,J＝6.1Hz,1H),4.97(d,J＝3.3Hz,1H),4.29(s,1H),3.68-3.56(m,3H),3.47-3.41(m,1H),1.93-1.74(m,2H)。
EXAMPLE 49 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((3-cyanopyridin-2-yl) amino) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 49)
Step 1: synthesis of 6-chloro-N- (4- (chlorodifluoromethoxy) phenyl) -5-nitronicotinamide (Compound 49 b).
6-chloro-5-nitronicotinic acid (49 a,13.1g,65.0 mmol) was added to the flask, dissolved in 200mL anhydrous DCM, and thionyl chloride (SOCl) was added 2 200 mL), stirring at 80 ℃ for 4 hours, vacuum drying, adding 200mL of anhydrous DCM for dissolution, adding 4- (chlorodifluoromethoxy) aniline (12.6 g,65.0 mmol), stirring at room temperature for 1 hour, vacuum drying to obtain 18.7g of a product, and yield: 76.3%.
Step 2: synthesis of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5-nitronicotinamide (Compound 49 c).
To the reaction flask were added compound 49b (18.7 g,49.6 mmol) and (R) -3 hydroxypyrrolidine (5.2 g,59.5 mmol), 150mL anhydrous DMSO, DIPEA (12.8 g,99.2 mmol), heating to 100deg.C and stirring for 2 hours, diluting with excess water, ethyl acetate extraction 3-4 times, combining the organic phases, washing with saturated brine, concentrating, purifying by column chromatography, vacuum drying to give 16.9g of product, yield: 79.6%.
Step 3: synthesis of (R) -5-amino-N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (Compound 49 d).
Into a reaction flask was charged compound 49C (16.9 g,39.5 mmol) and palladium on carbon (Pd/C, 1 g), dissolved in 120mL anhydrous MeOH, under H 2 Heating to 40 ℃ under the condition of stirring and reacting for 12 hours, filtering, taking filtrate, and vacuum drying to obtain 12.9g of product, and the yield is: 82.1%.
Step 4: synthesis of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((3-cyanopyridin-2-yl) amino) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (Compound 49).
Into a reaction flask was charged compound 49d (199.0 mg,0.5 mmol), 2-bromonicotinonitrile (182.0 mg,1.0 mmol), pd 2 (dba) 3 (45.8 mg,0.05 mmol), xantPhos (43.4 mg,0.075 mmol) and Cs 2 CO 3 (325.0 mg,1.0 mmol) was dissolved in 3mL of anhydrous toluene under N 2 Heating to 100deg.C under protection, stirring for reaction for 12 hr, vacuum drying, diluting with excessive water, extracting with ethyl acetate for 3-4 times, mixing organic phases, washing with saturated saline solution, concentrating, purifying by silica gel column chromatography, vacuum drying, and reversingPurifying by phase column chromatography, vacuum drying to obtain 65.2mg of product, yield: 26.1%. LC-MS (ESI) m/z=501.11 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.98(s,1H),8.70(d,J＝2.3Hz,1H),8.26(dd,J＝4.9,1.9Hz,1H),8.05(dd,J＝7.7,1.9Hz,1H),7.92(d,J＝2.3Hz,1H),7.90-7.85(m,2H),7.33(dd,J＝8.4,5.5Hz,2H),6.80(dd,J＝7.7,4.9Hz,1H),4.94(d,J＝3.3Hz,1H),4.28(s,1H),3.63(m,3H),3.46(m,1H),1.91-1.70(m,2H)。
EXAMPLE 50 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-cyanopyridin-3-yl) amino) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 50)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromopyridine carbonitrile produced compound 50: LC-MS (ESI) m/z=501.11 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.74(d,J＝2.2Hz,1H),8.47(s,1H),8.04(dd,J＝4.3,1.3Hz,1H),8.00(d,J＝2.2Hz,1H),7.91-7.83(m,2H),7.43(dd,J＝8.7,4.3Hz,1H),7.34(dq,J＝7.9,1.0Hz,2H),6.84(dd,J＝8.7,1.3Hz,1H),4.94(d,J＝3.3Hz,1H),4.28(s,1H),3.70-3.56(m,3H),3.49-3.42(m,1H),1.92-1.74(m,2H)。
EXAMPLE 51 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-cyano-5-fluoropyridin-3-yl) ammonia Phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 51)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromo-5-fluoropyridine carbonitrile gave compound 51: LC-MS (ESI) m/z=519.14 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.84-8.74(m,2H),8.06(d,J＝2.4Hz,1H),8.01(d,J＝2.2Hz,1H),7.92-7.82(m,2H),7.40-7.29(m,2H),6.70(dd,J＝10.9,2.4Hz,1H),4.94(d,J＝3.3Hz,1H),4.29(s,1H),3.71-3.57(m,3H),3.49-3.40(m,1H),1.93-1.75(m,2H)。
Example 52 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-cyano-5-methylpyridin-3-yl) Amino) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 52)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromo-5-methylpyridinecarbonitrile gave compound 52: LC-MS (ESI) m/z=515.14 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.74(d,J＝2.3Hz,1H),8.35(s,1H),7.98(d,J＝2.3Hz,1H),7.91-7.83(m,2H),7.37-7.30(m,3H),6.79(dd,J＝1.8,0.9Hz,1H),4.94(d,J＝3.3Hz,1H),4.28(m,1H),3.64(m,3H),3.47-3.39(m,1H),2.22(s,3H),1.91-1.72(m,2H)。
Example 53 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-cyano-6-methylpyridin-3-yl) Amino) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 53)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromo-6-methylpyridinecarbonitrile gave compound 53: LC-MS (ESI) m/z=515.11 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.72(d,J＝2.3Hz,1H),8.27(s,1H),7.96(d,J＝2.2Hz,1H),7.92-7.83(m,2H),7.38-7.29(m,3H),6.79(d,J＝8.8Hz,1H),4.93(d,J＝3.3Hz,1H),4.27(m,1H),3.63(m,1H),3.43(dt,J＝11.7,1.5Hz,1H),2.36(s,3H),1.90-1.71(m,2H)。
EXAMPLE 54 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-cyano-4-methylpyridin-3-yl) Amino) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 54)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromo-4-methylpyridinecarbonitrile gives compound 54: LC-MS (ESI) m/z=515.12 [ M+H ]] + 。
EXAMPLE 55 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((4-cyano-5-fluoropyridin-3-yl) ammonia Phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 55)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromo-5-fluoroisonicotinic nitrile produced compound 55: LC-MS (ESI) m/z=519.12 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.06(s,1H),8.76(d,J＝2.2Hz,1H),8.10-8.01(m,2H),7.93-7.82(m,3H),7.39-7.30(m,2H),4.95(d,J＝3.3Hz,1H),4.30(m,1H),3.72-3.59(m,3H),3.46(dt,J＝11.4,1.7Hz,1H),1.93-1.73(m,2H)。
EXAMPLE 56 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((4-cyano-5-chloropyridin-3-yl) ammonia Phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 56)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromo-5-chloroisonicotinic nitrile produced compound 56: LC-MS (ESI) m/z=535.04 [ M+H ]] + 。
Example 57 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((4-cyano-5-bromopyridin-3-yl) ammonia Phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 57)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3, 5-dibromoisonicotinic nitrile produced compound 57: LC-MS (ESI) m/z=579.05 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.17(s,1H),8.88(s,1H),8.75(d,J＝2.3Hz,1H),8.19(s,1H),8.02(d,J＝2.2Hz,1H),7.91-7.83(m,3H),7.39-7.31(m,2H),4.95(d,J＝3.3Hz,1H),4.30(s,1H),3.74-3.58(m,3H),3.45(d,J＝11.7Hz,1H),1.94-1.74(m,2H)。
EXAMPLE 58 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-cyano-5-chloropyridin-3-yl) ammonia Phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 58)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromo-5-chloropyridine carbonitrile gave compound 58: LC-MS (ESI) m/z=535.10 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.82-8.73(m,2H),8.07(d,J＝2.0Hz,1H),8.01(d,J＝2.2Hz,1H),7.91-7.83(m,2H),7.34(dq,J＝8.0,1.0Hz,2H),6.91(d,J＝2.0Hz,1H),4.95(d,J＝3.3Hz,1H),4.34-4.24(m,1H),3.71-3.57(m,3H),3.43(dd,J＝11.5,2.0Hz,1H),1.93-1.75(m,2H)。
EXAMPLE 59 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((4-cyano-5-methylpyridin-3-yl) Amino) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 59)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromo-5-methylisonicotinonitrile produced compound 59: LC-MS (ESI) m/z=515.13 [ M+H ]] + 。
Examples60 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((4-cyano-5-methoxypyridine-3) Group) amino) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 60)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromo-5-methoxyisonicotinic nitrile produced compound 60: LC-MS (ESI) m/z=531.13 [ M+H ]] + 。
EXAMPLE 61 preparation of (R) -5- ((4-carbamoyl-5-fluoropyridin-3-yl) amino) -N- (4- (chlorodifluoromethoxy) Phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 61)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromo-5-fluoroisonicotinamide produced compound 61: LC-MS (ESI) m/z=537.12 [ M+H ]] + 。
Example 62 preparation of (R) -3- ((5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrazole) Pyrrolidin-1-yl) pyridin-3-yl) amino isonicotinic acid (compound 62)
Step 1: synthesis of methyl (R) -3- ((5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrolidin-1-yl) pyridin-3-yl) amino) picolinate (compound 62 a).
Into a reaction flask was charged compound 49d (800.0 mg,2.0 mmol), methyl 3-bromopyridine carboxylate (880.0 mg,4.0 mmol), pd 2 (dba) 3 (180.0 mg,0.2 mmol), xantPhos (184.0 mg,0.3 mmol) and Cs 2 CO 3 (1300.0 mg,4.0 mmol) is added6mL of anhydrous toluene was dissolved in N 2 Heating to 100 ℃ under protection, stirring and reacting for 12 hours, detecting that the raw materials are reacted by TLC, vacuum drying, adding excessive water for dilution, extracting by ethyl acetate for 3-4 times, combining organic phases, washing by saturated saline, concentrating, purifying by silica gel column chromatography, vacuum drying, purifying by reverse phase column chromatography, and vacuum drying to obtain 621.0mg of a product, wherein the yield is: 58.3%.
Step 2: synthesis of (R) -3- ((5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrolidin-1-yl) pyridin-3-yl) amino) isonicotinic acid (Compound 62).
To a reaction flask were added compound 62a (600.0 mg,1.1 mmol) and sodium hydroxide (NaOH, 88.0mg,2.2 mmol), 2mL of anhydrous MeOH and 2mL of water were added to dissolve, and the reaction was stirred at room temperature for 2 hours, adjusted to PH 7 by adding an appropriate amount of acetic acid, concentrated, purified by column chromatography, and dried under vacuum to give 251.0mg of product, yield: 44.0%. LC-MS (ESI) m/z=520.11 [ M+H ]] + ； 1 H NMR(300MHz,DMSO-d6)δ9.69(s,1H),9.42(s,1H),8.64(d,J＝1.4Hz,1H),8.40(dd,J＝3.5,1.7Hz,1H),7.73-7.39(m,4H),7.48(dd,J＝7.9,1.8Hz,1H),7.21-7.13(m,2H),4.96(m,1H),4.30(m，1H),3.81-3.59(m,3H),3.43-3.39(m,1H),2.01-1.71(m,2H)。
EXAMPLE 63 preparation of (R) -5- ((4-carbamoylpyridin-3-yl) amino) -N- (4- (chlorodifluoromethoxy) benzene Phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 63)
To a reaction flask were added compound 62 (104 mg,0.2 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (HATU, 92mg,0.24 mmol) and N, N-diisopropylethylamine (DIPEA, 52mg,0.4 mmol), dissolved in 1mL anhydrous DMF, stirred at room temperature for 1 hour, then added with ammonia in methanol (7M, 0.5 mL), stirred at room temperature for 12 hours, diluted with excess water, extracted with ethyl acetate for 3-4 times, the organic phases were combined, washed with saturated brine, concentrated, purified by column chromatography, dried in vacuo to give 14.1mg of the product,yield: 13.6%. LC-MS (ESI) m/z=519.11 [ M+H ]] + ； 1 H NMR(300MHz,DMSO-d6)δ9.72(s,1H),9.39(s,1H),8.55(d,J＝1.4Hz,1H),8.36(dd,J＝3.5,1.8Hz,1H),7.72-7.56(m,4H),7.43(d,J＝8.7Hz,3H),7.22-7.07(m,2H),4.91(d,J＝3.3Hz,1H),4.20(m,1H),3.97-3.69(m,3H),3.41(m,1H),2.03-1.69(m,2H)。
EXAMPLE 64 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((4-formylpyridin-3-yl) amino) 6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 64)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromoisonicotinal produced compound 64: LC-MS (ESI) m/z=504.10 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.55(s,1H),9.57(d,J＝2.8Hz,1H),9.49(dd,J＝3.4,1.9Hz,1H),8.59(dt,J＝6.3,1.8Hz,1H),8.53(d,J＝1.7Hz,1H),8.06-8.02(m,1H),7.98-7.92(m,2H),7.37(d,J＝8.7Hz,3H),5.10(s,1H),4.51(m,3H),4.01-3.76(m,2H),2.04(m,2H)。
EXAMPLE 65 preparation of (R) -2-amino-5- ((5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-) Hydroxypyrrolidin-1-yl) pyridin-3-yl) amino isonicotinic acid (compound 65)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 2-amino-5-bromoisonicotinic acid produced compound 65: LC-MS (ESI) m/z=535.1 [ M+H ] ] + 。
EXAMPLE 66 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((4 ] Nitropyridin-3-yl) amino) nicotinamide (compound 66)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromo-4-nitropyridine produced compound 66: LC-MS (ESI) m/z=521.13 [ M+H ]] + 。
EXAMPLE 67 preparation of (R) -5- ((4-acetamidopyridin-3-yl) amino) -N- (4- (chlorodifluoromethoxy) benzene Phenyl) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 67)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with N- (3-bromopyridin-4-yl) acetamide produced compound 67: LC-MS (ESI) m/z=533.16 [ M+H ]] + 。
EXAMPLE 68 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((4-fluoropyridin-3-yl) amino) -6 ] (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 68)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromo-4-fluoropyridine gave compound 68: LC-MS (ESI) m/z=494.15 [ M+H ]] + 。
EXAMPLE 69 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((4-chloropyridin-3-yl) amino) -6 ] (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 69)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromo-4-chloropyridine gave compound 69: LC-MS (ESI) m/z=510.04 [ M+H ] ] + 。
EXAMPLE 70 preparation of (R) -5- ((4-bromopyridin-3-yl) amino) -N- (4- (chlorodifluoromethoxy) phenyl) -6 ] (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 70)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3, 4-dibromopyridine gave compound 70: LC-MS (ESI) m/z=554.04 [ M+H ]] + 。
EXAMPLE 71 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((4-hydroxypyridin-3-yl) amino) -6 ] (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 71)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromopyridin-4-ol gave compound 71: LC-MS (ESI) m/z=492.15 [ M+H ]] + 。
EXAMPLE 72 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((4 ] Methoxypyridin-3-yl) amino) nicotinamide (compound 72)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromo-4-methoxypyridine gave compound 72: LC-MS (ESI) m/z=506.11 [ M+H ]] + 。
EXAMPLE 73 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((4 ] Methylpyridin-3-yl) amino) nicotinamide (compound 73)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromo-4-methylpyridine gave compound 73: LC-MS (ESI) m/z=490.11 [ M+H ] ] + 。
EXAMPLE 74 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((4 ] (trifluoromethyl) pyridin-3-yl) amino) nicotinamide (Compound 74)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromo-4- (trifluoromethyl) pyridine gave compound 74: LC-MS (ESI) m/z=544.12 [ M+H ]] + 。
EXAMPLE 75 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((4 ] (trifluoromethoxy) pyridin-3-yl) amino) nicotinamide (Compound 75)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromo-4- (trifluoromethoxy) pyridine gave compound 75: LC-MS (ESI) m/z=560.13 [ M+H ]] + 。
EXAMPLE 76 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((4 ] (trifluoromethoxy) -5- (trifluoromethyl) pyridin-3-yl) amino) nicotinamide (Compound 76)
Referring to the procedure of example 49, 2-bromonicotinonitrile was replaced with 3-bromo-4- (tris)Fluoromethoxy) -5- (trifluoromethyl) pyridine to afford compound 76: LC-MS (ESI) m/z=628.13 [ M+H ]] + 。
EXAMPLE 77 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- ((5-fluoro-4- (trifluoromethoxy) pyridine) 3-yl) amino) -6- (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 77)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromo-5-fluoro-4- (trifluoromethoxy) pyridine gave compound 77: LC-MS (ESI) m/z=578.16 [ M+H ]] + 。
Example 78 preparation of (R) -3- ((5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrazole) Pyrrolidin-1-yl) pyridin-3-yl) amino) -5-fluoroisonicotinic acid (compound 78)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromo-5-fluoroisonicotinic acid produced compound 78: LC-MS (ESI) m/z=538.16 [ M+H ]] + 。
Example 79 preparation of (R) -3-chloro-5- ((5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxy) Pyrrolidin-1-yl) pyridin-3-yl) amino isonicotinic acid (Compound 79)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3-bromo-5-chloroisonicotinic acid produced compound 79: LC-MS (ESI) m/z=554.02 [ M+H ]] + 。
Example 80 preparation of (R) -3-bromo-5- ((5- ((4- (chlorodifluoromethoxy) phenyl) aminomethyl)Acyl) -2- (3-hydroxy Pyrrolidin-1-yl) pyridin-3-yl) amino isonicotinic acid (Compound 80)
Referring to the procedure of example 49, substituting 2-bromonicotinonitrile with 3, 5-dibromoisonicotinic acid produced compound 80: LC-MS (ESI) m/z=598.02 [ M+H ]] + 。
EXAMPLE 81 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (cyclopropylamino) -6- (3-hydroxypyrrole Alkan-1-yl) nicotinamide (compound 81)
Into a reaction flask, 49d (200.0 mg,0.5 mmol) and cycloacetone (56.0 mg,1 mmol) were added, and the mixture was dissolved in 3mL of anhydrous methanol, and reacted at 40℃for 2 hours with stirring, followed by adding sodium cyanoborohydride (NaBH) 3 CN,126.0mg,2 mmol), stirring at room temperature for 1 hour, diluting with excessive water, extracting with ethyl acetate for 3-4 times, mixing organic phases, washing with saturated saline, concentrating, purifying by column chromatography, and vacuum drying to obtain compound 81: LC-MS (ESI) m/z=439.17 [ M+H ]] + 。
EXAMPLE 82 preparation of N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-cyanocyclopropyl) amino) -6- ((R) -3 ] Hydroxypyrrolidin-1-yl) nicotinamide (compound 82)
Referring to the procedure of example 81, substituting cyclic acetone for 2-cyanocyclic acetone produced compound 82: LC-MS (ESI) m/z=464.12 [ M+H ]] + 。
EXAMPLE 83 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (cyclobutylamino) propanoic acid6- (3-hydroxypyrroles) Alkan-1-yl) nicotinamide (compound 83)
Referring to the procedure of example 81, substituting cyclobutanone for cyclobutanone produced compound 83: LC-MS (ESI) m/z=453.14 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.18(d,J＝1.9Hz,1H),7.93-7.81(m,2H),7.40-7.27(m,2H),7.08(d,J＝2.0Hz,1H),4.90(dd,J＝13.5,5.6Hz,2H),4.33(q,J＝3.9Hz,1H),3.88(m,1H),3.73(m,2H),3.51-3.43(m,1H),3.33-3.22(m,1H),2.35(m,2H),2.05-1.66(m,6H)。
Example 84 preparation of N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-cyanocyclobutyl) amino) -6- ((R) -3 ] Hydroxypyrrolidin-1-yl) nicotinamide (compound 84)
Referring to the procedure of example 81, substituting cyclopropanone for 2-cyanocyclobutanone produced compound 84: LC-MS (ESI) m/z=478.15 [ M+H ]] + 。
Example 85 preparation of N- (4- (chlorodifluoromethoxy) phenyl) -6- ((R) -3-hydroxypyrrolidin-1-yl) -5- ((2 ] Nitrocyclobutyl) amino nicotinamide (Compound 85)
Referring to the procedure of example 81, substituting cyclopropanone with 2-nitrocyclobutanone produced compound 85: LC-MS (ESI) m/z=498.17 [ M+H ]] + 。
Example 86 preparation of N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-fluorocyclobutyl) amino) -6- ((R) -3-ol Pyrrolidin-1-yl) nicotinamide (compound86)
Referring to the procedure of example 81, substituting cyclopropanone for 2-fluorocyclobutanone produced compound 86: LC-MS (ESI) m/z=471.19 [ M+H ]] + 。
EXAMPLE 87 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (cyclopentylamino) -6- (3-hydroxypyrrole Alkan-1-yl) nicotinamide (compound 87)
Referring to the procedure of example 81, substituting cyclopentanone for cyclic acetone produced compound 87: LC-MS (ESI) m/z=467.11 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.17(d,J＝1.9Hz,1H),7.92-7.84(m,2H),7.34(d,J＝8.7Hz,2H),7.20(d,J＝1.9Hz,1H),4.88(d,J＝3.8Hz,1H),4.50(d,J＝5.6Hz,1H),4.33(q,J＝3.9Hz,1H),3.83-3.60(m,3H),3.47-3.39(m,1H),3.27(dd,J＝11.0,2.5Hz,1H),1.95(m,3H),1.81(m,1H),1.70(m,2H),1.56(m,4H)。
EXAMPLE 88 preparation of N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-cyanocyclopentyl) amino) -6- ((R) -3 ] Hydroxypyrrolidin-1-yl) nicotinamide (compound 88)
Referring to the procedure of example 81, substituting cyclic acetone with 2-cyanocyclopentanone produced compound 88: LC-MS (ESI) m/z=492.11 [ M+H ] ] + 。
Example 89 preparation of 5- ((2-chlorocyclopentyl) amino) -N- (4- (chlorodifluoromethoxy) phenyl) -6- ((R) -3-hydroxy Pyrrolidin-1-yl) nicotinamide (compound 89)
Referring to the procedure of example 81, substituting cyclic acetone with 2-chlorocyclopentanone produced compound 89: LC-MS (ESI) m/z=501.12 [ M+H ]] + 。
Example 90 preparation of N- (4- (chlorodifluoromethoxy) phenyl) -6- ((R) -3-hydroxypyrrolidin-1-yl) -5- (pioglyc Pyrrolidin-3-ylamino) nicotinamide (compound 90)
Referring to the procedure of example 81, substituting cyclic acetone for 3-pyrrolidone produced compound 90: LC-MS (ESI) m/z=468.11 [ M+H ]] + 。
EXAMPLE 91 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (cyclohexylamino) -6- (3-hydroxypyrrole Alkan-1-yl) nicotinamide (compound 91)
Referring to the procedure of example 81, substituting cyclohexanone for cyclohexanone produced compound 91: LC-MS (ESI) m/z=481.17 [ M+H ]] + 。
Example 92 preparation of N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-cyanocyclohexyl) amino) -6- ((R) -3 ] Hydroxypyrrolidin-1-yl) nicotinamide (compound 92)
Referring to the procedure of example 81, substituting cyclohexanone for 2-cyanocyclohexanone produced compound 92: LC-MS (ESI) m/z=506.13 [ M+H ]] + 。
EXAMPLE 93 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (methylphenidate Pyridin-4-ylamino) nicotinamide (compound 93)
Step 1: synthesis of tert-butyl (R) -4- ((5- ((4- (chlorodifluoromethoxy) phenyl) carbamoyl) -2- (3-hydroxypyrrolidin-1-yl) pyridin-3-yl) amino) piperidine-1-carboxylate (Compound 93 a).
Referring to the procedure of example 81, substituting cyclic acetone with tert-butyl 4-oxopiperidine-1-carboxylate produced compound 93a.
Step 2: synthesis of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- (piperidin-4-ylamino) nicotinamide (compound 93).
To the reaction flask was added compound 93a (1.1 g,1.9 mmol) and trifluoroacetic acid (TFA, 2 mL), 20mL of anhydrous DCM was added for dissolution, the reaction was stirred at room temperature for 1 hour, diluted with excess water, extracted 3-4 times with ethyl acetate, the organic phases were combined, washed with saturated brine, concentrated, purified by column chromatography, dried in vacuo to give 637mg of product, yield: 69.7%. LC-MS (ESI) m/z=482.11 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.20(s,1H),8.21(d,J＝2.0Hz,1H),7.91-7.83(m,2H),7.34(d,J＝8.7Hz,2H),7.29(d,J＝2.1Hz,1H),4.93(s,1H),4.72(d,J＝6.6Hz,1H),4.34(tt,J＝5.0,2.9Hz,1H),3.78-3.67(m,2H),3.57(m,1H),3.50-3.42(m,2H),3.33-3.21(m,3H),3.06(m,2H),2.00(m,3H),1.83(m,1H),1.76-1.62(m,2H)。
EXAMPLE 94 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((1 ] Isopropyl piperidin-4-yl) amino) nicotinamide (compound 94)
Referring to the procedure of example 81, substituting cyclic acetone for 1-isopropyl-4-piperidone produced compound 94: LC-MS (ESI) m/z=524.27 [ M+H ] ] + ； 1 H NMR(300MHz,DMSO-d6)δ10.15(s,1H),8.15(d,J＝1.9Hz,1H),7.92-7.80(m,2H),7.41-7.30(m,2H),7.21(d,J＝2.0Hz,1H),4.89(d,J＝4.0Hz,1H),4.39(d,J＝7.3Hz,1H),4.33(d,J＝4.5Hz,1H),3.75-3.61(m,2H),3.47-3.39(m,1H),3.30-3.17(m,2H),2.82-2.56(m,3H),2.37-2.15(m,2H),2.04-1.70(m,4H),1.60-1.35(m,2H),0.97(d,J＝6.5Hz,6H)。
EXAMPLE 95 preparation of (R) -5- ((1-acetylpiperidin-4-yl) amino) -N- (4- (chlorodifluoromethoxy) phenyl) -6 ] (3-hydroxypyrrolidin-1-yl) nicotinamide (compound 95)
Into a reaction flask were charged compound 93 (240.0 mg,0.5 mmol), TEA (101.0 mg,1.0 mmol) and acetic anhydride (Ac) 2 O,51.0mg,0.5 mmol), 2mL of anhydrous DCM is added for dissolution, the reaction is stirred at room temperature for 2 hours, excessive water is added for dilution, ethyl acetate is used for extraction for 3-4 times, the organic phases are combined, saturated saline is used for washing, concentration and column chromatography purification, and the product 130mg is obtained after vacuum drying, the yield is: 49.7%. LC-MS (ESI) m/z=524.16 [ M+H ]] + ； 1 H NMR(400MHz,DMSO-d6)δ10.17(s,1H),8.18(d,J＝1.9Hz,1H),7.94-7.82(m,2H),7.34(d,J＝8.7Hz,2H),7.27(d,J＝2.0Hz,1H),4.89(d,J＝3.7Hz,1H),4.52(d,J＝7.1Hz,1H),4.33(q,J＝4.0Hz,1H),4.14(dt,J＝13.5,4.4Hz,1H),3.73(m,3H),3.54(m,1H),3.46-3.39(m,1H),3.33-3.17(m,2H),2.93(tt,J＝13.8,3.5Hz,1H),2.01(s,3H),1.99-1.76(m,4H),1.58-1.29(m,2H)。
Example 96 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((tetrakis) Hydrogen-2H-pyran-4-yl) amino) nicotinamide (Compound 96)
Referring to the procedure of example 81, substituting cyclic acetone for tetrahydropyranone produced compound 96: LC-MS (ESI) m/z=483.18 [ M+H ]] + 。
Example 97 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -6- (3-hydroxypyrrolidin-1-yl) -5- ((tetray-l) Hydrogen-2H-thiopyran-4-yl) amino) nicotinamide (Compound 97)
Referring to the procedure of example 81, substituting cyclic acetone for tetrahydrothiopyran-4-one produced compound 97: LC-MS (ESI) m/z=499.14 [ M+H ]] + 。
EXAMPLE 98 preparation of (R) -N- (4- (chlorodifluoromethoxy) phenyl) -5- (cycloheptylamino) -6- (3-hydroxypyrrole Alkan-1-yl) nicotinamide (compound 98)
Referring to the procedure of example 81, the substitution of cycloheptanone for cycloheptanone produced compound 98: LC-MS (ESI) m/z=495.23 [ M+H ]] + 。
EXAMPLE 99 preparation of N- (4- (chlorodifluoromethoxy) phenyl) -5- ((2-cyanocycloheptyl) amino) -6- ((R) -3 ] Hydroxypyrrolidin-1-yl) nicotinamide (compound 99)
Referring to the procedure of example 81, substituting cyclic acetone with 2-cyanocycloheptanone produced compound 99:LC-MS(ESI):m/z＝520.15[M+H] + 。
biological Activity test
Protein kinase activity inhibition assay (a):
ABL1 (T315I) Kinase Enzyme System kinase assay kit was used for the test.
The following is a general experimental procedure:
1. 4 Xkinase buffer and 1 Xkinase buffer were prepared.
2. Preparing a compound concentration gradient: compound powders were dissolved in 100% dmso to prepare stock solutions at 300 μm concentration, diluted three-fold to 8 concentration gradients, and the dispenser transferred 1 μl to 384 well plates, two wells per compound concentration.
3. A kinase solution was prepared at a final concentration of 2.5 times using a 4 Xkinase buffer.
4. mu.L of a 2.5-fold final concentration of kinase solution was added to the compound and positive control wells, and 3. Mu.L of 1 Xkinase buffer was added to the negative control wells.
5. The reaction plate was mixed with shaking and incubated at room temperature for 10 minutes.
6. A mixed solution of ATP and Kinase substrate was prepared at a final concentration of 2.5 times using a 4 Xkinase buffer.
7. mu.L of a mixed solution of ATP and Kinase substrate was added to initiate the reaction.
8. Incubation is carried out for 60 minutes at room temperature after shaking and mixing.
9. mu.L of ADP-Glo reagent was added, mixed well with shaking, the reaction stopped, and incubated at room temperature for 60min to consume residual ATP.
10. 10 mu Lkinase detection reagent is added, mixed with shaking and incubated for 40min at room temperature.
11. And (5) reading data by using an enzyme-labeled instrument, and calculating the inhibition rate and the IC50 value.
The primary screening results for inhibition of kinase activity in the examples are summarized in Table 2 below.
TABLE 2 inhibition of kinase Activity by Primary screening of Compounds of examples
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IC for inhibition of kinase Activity in examples 50 The results are summarized in Table 3 below.
TABLE 3 IC50 values for inhibition of kinase Activity of the compounds of the examples
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(II) in vitro tumor cell proliferation (K562, KBM 5) inhibition Activity assay
1: experiments were performed on a KBM5 human chronic myelogenous leukemia cell line in 1640+10% FBS (Gibco) complete medium at 37℃in 5% CO 2 Suspension culture in 95% humidity.
2: the following is a general experimental procedure:
taking logarithmic growth K562 and KBM5 cells, centrifuging to obtain cell sediment, adding fresh culture medium to resuspend, performing dyeing counting on the cell by using a table blue, diluting the cell to a proper concentration, respectively planting 50uL of the cell into 96-well plates, 3000 cells/well, and placing the cell plates into a carbon dioxide incubator for overnight culture.
Preparing mother liquor of the compound to be tested, wherein the DMSO mother liquor of all the compounds is 10mM, storing at-80 ℃, and sub-packaging for use. According to the required working concentration, the compound mother solution is diluted to a proper concentration by a culture medium, 50uL of the compound solution to be tested is taken and added into the cell holes, and each compound to be tested is provided with three compound holes.
The cell plates were placed in a carbon dioxide incubator for 3 days.
3: terminal reading board
The reagents were incubated at room temperature for 2-4 hours at 10-uL Cell Counting Kit-8 per well, absorbance was read at 450nm by an enzyme-labeled instrument, and cell growth inhibition efficiency was calculated.
4: data processing
The data were analyzed using GraphPad Prism 9.0 software, and non-linear S-curve regression was used to fit the data to yield the dose-response curve, and IC50 values were calculated therefrom.
Cell viability (%) = (OD test drug-OD broth control)/(OD cell control-OD broth control) ×100%.
The primary screening results of the inhibition of proliferation of cells in vitro in the examples are summarized in Table 4 below.
TABLE 4 cytotoxicity of example Compound Primary screening
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IC for inhibition of proliferation of cells in vitro in examples 50 The results are summarized in Table 5 below.
TABLE 5 IC50 values for the compounds of the examples
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The experimental results (Table 2) show that the compounds of the invention have significant K562/KBM5 inhibitory activity. Of these, compounds 15, 55 and 57 significantly inhibited the activity of K562 and KBM5, indicating that the compounds of the present invention are well-defined K562/KBM5 inhibitors.
It is apparent that the above examples are merely illustrative of the technical solution and are not limiting of the embodiments of the present invention. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. Any modification, equivalent replacement, improvement, etc. which come within the spirit and principles of the invention are desired to be protected by the following claims.

Claims (10)

1. A compound of formula (I)
Or a pharmaceutically acceptable salt, stereoisomer thereof, wherein:
y is selected from CH or N;
R 1 independently selected from hydrogen, halogen, nitrile, hydroxy, which may be mono-, di-or polysubstituted;
R 2 selected from-CF 2 -Y 1 ；
Y 1 Selected from hydrogen, chlorine, fluorine, methyl, difluoromethyl or trifluoromethyl;
z is selected from the group consisting of a bond, O or S (O) 0-2 ；
or-Z-R 2 Together represent-SF 5 ；
Het is pyrrolidinyl, wherein the pyrrolidinyl is substituted with 1 or more R a Group substitution;
R a independently selected from hydrogen, hydroxy, methyl, halogen, methoxy, hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl, cyano, or amino-carbonyl;
l is O, S or NR b ；
R 3 Selected from the following groups optionally substituted with one, two or three R:
R b Independently selected from hydrogen, acetyl or C 1-3 An alkyl group;
r is independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, aldehyde, carboxyl, acetamido, ethoxycarbonyl, aminoacyl, -NH 2 、-NHC 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 、C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy groups;
the halogen is F, cl or Br.
2. The compound of claim 1, having formula (II):
or a pharmaceutically acceptable salt, stereoisomer thereof, wherein:
R 1 independently selected from hydrogen or halogen;
R a independently selected from hydrogen or hydroxy;
l is O, S or NR b ；
The halogen is F, cl or Br;
R 3 the method of claim 1.
3. The compound of claim 2, having formula (III):
or a pharmaceutically acceptable salt, stereoisomer thereof, wherein:
R 1 r as claimed in claim 1, wherein 3 R as claimed in claim 1, wherein a The method of claim 1.
4. A compound according to claim 3, or a pharmaceutically acceptable salt, stereoisomer thereof, selected from the group consisting of:
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or a pharmaceutically acceptable salt, stereoisomer thereof.
5. A pharmaceutical composition comprising a compound of any one of claims 1-4, or a pharmaceutically acceptable salt, stereoisomer, and pharmaceutically acceptable excipient thereof.
6. A process for the preparation of a compound of formula (III), comprising the steps of:
(1) Preparation of intermediate (V)
Dissolving 5-bromo-6-chloronicotinic acid (IV) in anhydrous DMF, adding 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethyl urea hexafluorophosphate and N, N-diisopropylethylamine, stirring at room temperature for reacting for 1 hr, and adding benzene ring to obtain a mixture of R and N, N ' -tetramethyl urea hexafluorophosphate 1 Substituted 4- (chlorodifluoromethoxy) aniline, stirring at room temperature to obtain intermediate (V), wherein R 1 Independently selected from hydrogen or halogen;
(2) Preparation of intermediate (VI)
Intermediate (V) was dissolved in anhydrous DMSO, DIPEA was added and R was 1 a Group-substituted pyrrolidine, heating and reacting to obtain intermediate (VI), R a Independently selected from hydrogen or hydroxy;
(3) Preparation of the target product (III)
Buchwald coupling reaction, comprising the steps of dissolving intermediate (VI) in anhydrous toluene, adding t-BuXPhos and t-Buona and palladium catalyst or adding XantPhos, cs 2 CO 3 And palladium catalyst, and R is added 3 -NH 2 Heating under inert gas to obtain target product (III), wherein R 3 Selected from the following groups optionally substituted with one, two or three R:
wherein R is b Independently selected from hydrogen, acetyl or C 1-3 An alkyl group;
r is independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, aldehyde, carboxyl, acetamido, ethoxycarbonyl, aminoacyl, -NH 2 、-NHC 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 、C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy groups.
7. A process for the preparation of a compound of formula (III), comprising the steps of:
(1) Preparation of intermediate (VIII)
Dissolving 6-chloro-5-nitronicotinic acid (VII) in anhydrous DCM, adding thionyl chloride, heating and stirring for reaction for 4 hours, vacuum drying, adding anhydrous DCM for dissolving, and adding benzene ring for R 1 Substituted 4- (chlorodifluoromethoxy) aniline, stirring at room temperature to obtain intermediate (VIII), wherein R 1 Independently selected from hydrogen or halogen;
(2) Preparation of Intermediate (IX)
Intermediate (VIII) was dissolved in anhydrous DMSO, DIPEA was added and R was 1 a Group-substituted pyrrolidines, heating to obtain Intermediates (IX), R a Independently selected from hydrogen or hydroxy.
(3) Preparation of intermediate (X)
Intermediate (IX) was dissolved in anhydrous MeOH, palladium on carbon was added to the mixture at H 2 Heating and reacting under the condition to obtain an intermediate (X);
(4) Preparation of the target product (III)
Dissolving an intermediate (X) in absolute methanol, adding corresponding R-substituted cycloalkyl ketone, heating and stirring for reaction for 2 hours, adding sodium cyanoborohydride, and heating for reaction to obtain a target product (III);
wherein R is 3 Selected from the following groups optionally substituted with one, two or three R:
Wherein R is b Independently selected from hydrogen, acetyl or C 1-3 An alkyl group;
r is independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, aldehyde, carboxyl, acetamido, ethoxycarbonyl, aminoacyl, -NH 2 、-NHC 1-3 Alkyl, -N (C) 1-3 Alkyl group 2 、C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy groups.
8. Use of a compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, stereoisomer, or pharmaceutical composition according to claim 5, for the manufacture of a medicament for the treatment and/or prevention of a Bcr-Abl-induced disease in a subject.
9. The use of claim 8, wherein the Bcr-Abl-caused disease is a proliferative disease selected from the group consisting of: solid tumors, sarcomas, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, gastrointestinal stromal tumors, thyroid cancer, gastric cancer, rectal cancer, multiple myeloma, neoplasia, and other proliferative or proliferative diseases.
10. The use of claim 8, wherein the Bcr-Abl-caused disease is metastatic invasive cancer, a viral infection, or a CNS disorder.
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